Kappa Opioid Receptor: Ho tloha ho Lemalla ho Tepella Maikutlo, le ka morao (2014)

. 2014; 5: 170.

E hatisitsoe Inthaneteng 2014 Dec 8. doi:  10.3389 / fpsyt.2014.00170

PMCID: PMC4258993

inahaneloang

Comorbidity ke bothata bo boholo ho mafu a kelello a amanang haholo le matšoao a matla haholoanyane, nako e telele ea ho kula, le ts'ebeliso e phahameng ea litšebeletso. Ka hona, ho khetholla lihlopha tsa mantlha tsa comorbidity le ho hlahloba lits'ebetso tsa motheo tsa pathophysiological li emela mehato ea bohlokoa ho ntlafatseng tlhokomelo ea bophelo bo botle ba kelello. Thutong ea hona joale, re tsepamisa likamano khafetsa lipakeng tsa ho lemalla le ho tepella maikutlo. Ka ho khetheha, re akaretsa kakaretso e kholo ea bopaki bo tsoang mehlaleng ea preclinical e bonts'ang hore kappa opioid receptor (KOR), setho sa tsamaiso ea methapo ea methapo ea opioid, e emela sebapali sa mantlha taolong ea meputso ea bobeli le moputso. Lintlha tsa hajoale li fana ka maikutlo a hore li-modor tsa KOR li fetela marang-rang a li-neuronal tse hokahanyang li-brainstem monoaminergic nuclei le likarolo tsa methapo ea maoto. Thepa e moputso ea lithethefatsi ka bobeli tsa tlhekefetso le tlhaho ea tlhaho, hammoho le litlamorao tsa methapo ea liphihlelo tse sithabetsang, li sebelisana ka matla ho boemo ba KOR signaling. Mefuteng ea bokhoba ba ho lemalla, ts'ebetso ea KOR e ka hlahisoa ke khatello ea maikutlo mme ka mokhoa o hlakileng o laola ho batla lithethefatsi le ho khutlela morao. Literekeng tsa khatello ea maikutlo, KOR ho supa e arabela maemong a fapaneng a khatello, 'me e arabela likarabo tse kang ho nyahama. Ka kakaretso KOR e emela karolo e kaholimo ea protorbidity, eo ka eona liphihlelo tsa bophelo li fetohelang mehlaleng e tloaelehileng ea ts'ebetso ho baka taetsano ea boits'oaro le kotsi e eketsehang bakeng sa li-psychopathologies tse ikhethileng.

Keywords: kappa opioid receptor, boemo ba sebaka, moputso, bokhoba, anhedonia, khatello ea maikutlo, comorbidity, mefuta ea liphoofolo

Selelekela

Bokhoba ba khatello ea maikutlo le khatello ea maikutlo ke mathata a ho boela a sa feleng a nang le litlamorao tse bohloko ho batho ka bomong le tikoloho ea bona ea bophelo (). Ho pepesehela lithethefatsi tsa tlhekefetso, hammoho le ho ila lithethefatsi tsena nako e telele, ho hokahana le ho theoha ha moea le boemo bo bobe. Ka lehlakoreng le leng, ho batho ba bang, ho teneha ho hoholo ho qabola tšebeliso ea lintho tse matlafatsang tsa kelello, e leng ntho eo ho thoeng ke mokhoa oa ho iphekola. Ka hona, lithuto tsa lefu la seoa li bontšitse ka ho hlaka pherekano e pakeng tsa bokhoba le khatello ea maikutlo (, ). Comorbidity ena e tsamaea le bokooa bo boholo ba ts'ebetso, ho kula nako e telele, bokhoni bo fokolang sechabeng, le ts'ebeliso e phahameng ea litšebeletso. Ka hona, ho utloisisa mekhoa ea ts'ebetso ea ts'ebetso ea pathophysiological e nang le bohlokoa ba kalafo.

Tlhahlobo ea hona joale e tla tšohla lintlha tse ngata tsa bopaki bo bokelletsoeng ho hatisa kappa opioid receptor (KOR) e le karoloana ea bohlokoa ho comorbidity lipakeng tsa khatello le khatello ea maikutlo. KOR ke ea tsamaiso ea opioid, e leng neuromodulatory system e hlahisoang haholo lits'ebetsong tsa methapo ea methapo e bohareng le e poteletseng. Sistimi ea opioid e entsoe ka li-receptor tse tharo tsa G protein-coupled opioid: mu (MOR), delta (DOR), le kappa (KOR), eo tlasa maemo a mmele e hlahisoang ke lelapa la li-peptides tsa endo native ho thibela ts'ebetso ea neuronal. Har'a li-peptide tsa opioid, dynorphin (e kentsoeng ke Pdyn gene) haholo-holo kenya ts'ebetsong KOR 'me e na le tumellano e tlase haholo bakeng sa MOR kapa DOR. Ka lehlakoreng le leng, li-peptide tse ling tsa opioid (endorphin le enkephalin) ha li sebelisane hantle le KOR. Ka hona, tsela ea dynorphin / KOR e bonts'a mokhoa o ikhethileng tsamaisong ea opioid (, ).

Li-receptors tsa Opioid li laola ka tieo lits'ebetso tse susumetsang, 'me li khetholloa e le libapali tsa bohlokoa mathateng a kelello a tšoauoang ke ho se sebetse ka moputso, joalo ka tlhekefetso le khatello ea maikutlo (, ). Litlhahlobo tse 'maloa tse matlafatsang li sa tsoa akaretsa lintlha mabapi le karolo ea MOR le DOR mathateng ana,' me ho tla buuoa ka bokhutšoanyane ha ho loketse (, -). Morero oa rona ke ho fa 'mali sebali le nalane-anatomical ea hore na, neng, le hore na li-KOR li qaptjoa joang mefuteng ea tšusumetso ea temallo le psychopathology e amanang le khatello ea maikutlo (-). Taba ea mantlha, re tla akaretsa hore na KOR e tsoetse pele joang e le mokhoa o khahlanong le moputso o kenyang dysphoria le meeli ea litheko tsa lithethefatsi tsa tlhekefetso. Taba ea bobeli, re tla bonts'a KOR e ngolisoa le ho kenngoa ts'ebetsong nakong ea liphihlelo tse sithabetsang, ka ho etsa joalo e kenya letsoho ho hlaha ha maemo a sithabetsang (, , ). Kamora nako, re tla tšohla likarolo tse peli tsa bohlokoa tsa hore likarolo tsena tsa KOR ho bokhoba, boits'oaro bo amanang le khatello ea maikutlo le khatello ea maikutlo li na le bohlokoa ba ho utloisisa moferefere. Ka lehlakoreng le leng, re tla bonts'a hore ho bokella khatello ea maikutlo ka lebaka la khatello ea maikutlo ke tšusumetso e matla ea ho batla lithethefatsi le boits'oaro bo bocha. Ka lehlakoreng le leng, re tla akaretsa lintlha ka ts'ebetso ea KOR maemong a itseng a boitšoaro bo sithabetsang bo hlahang nakong ea ho pepesehela lithethefatsi tsa tlhekefetso, hammoho le nakong ea ts'ebeliso ea lithethefatsi (-).

E le karoloana ea pathophysiological ea comorbidity, KOR e supa sepheo se tšepisang sa pharmacological (, ). Liteko tsa tleliniking ha joale li ntse li il'o hlahloba bahanyetsi ba KOR e le kalafo ea khatello ea maikutlo (), haholoholo maemong a bakuli ba lemaletseng ho tsoa maemong a sithabetsang (, ). Ha re theha boithuto ba bohloeki, re tla bua ka menyetla ea mekhoa ea ho phekola e shebileng KOR.

Kappa Opioid Receptor: Anti-Moputso, Sisteme ea Dysphoric

Thahasello ho litlhare tsa KOR ka nalane e tsoa holima ts'epo ea ho nts'etsapele litlatsetso tse senang tlhekefetso ea mantlha e ka ba teng ea li-agonists tsa MOR, joalo ka morphine. Ka bomalimabe, lithuto tsa batho ba pele ba neng ba hlahloba likarolo tsa agorists tsa KOR li tlalehile litla-morao tsa dysphoric le psychomimetic (, ). Le ha liphetho tsena li fokolitse bokhoni ba kalafo ba KOR kalafong ea bohloko, ba khothalelitse bafuputsi ba sa tsebeng letho ho hlahloba litlamorao tse khahlisang tsa dysphoric.

Ts'ebetso ea MOR e tsejoa ho kenya ts'usumetso ho motho, le ho hlahisa matlafatso mefuteng ea liphoofolo. Ka hona, bafuputsi ba ile ba nahana hore MOR le KOR li ka ba le litlamorao tse fapaneng taolong ea litsamaiso tse susumetsang, ka mokhoa oa ho feto-fetoha ha mekhoa e tloaelehileng ea neuronal. Seketsoana sena se ile sa qala ho hlahlojoa ho sebelisoa boikhethelo ba sebaka (CPP) kapa thibelo ea sebaka se sireletsehileng (CPA). Kopanong ena ea boemo ba Pavlovian, setlhare se kopantsoe khafetsa ka maikutlo a susumetsang a tikoloho a ntseng a tsoela pele ho fumana thepa e khothatsang (CPP) kapa e mpe (CPA). Kamora linako tsa ho pheta-pheta, phoofolo kamora moo e bontša ho rata kapa ho qoba ho pepesoa hape molemong oa tikoloho (moo ho se nang setlhare), boitsoaro bo its'etleha ho ithuteng, ho susumetseng le mekhoeng ea hedonic. Boithuto ba seminal ea Shippenberg le Hertz () e tlaleha hore, joalo ka ha hypothesised, tsamaiso ea methapo ea agonist ea KOR U69593 kapa morphine e hlahisitse litlamorao tse fapaneng, e hlahisang CPA le CPP. Le ha CPP e hlohlellelitsoeng ke morphine e bonts'a thepa ea eona e matlafatsang, KPA e khothalelitsoeng ke CPA e khothalelitse hore mohopolo ona e ka ba mokhoa o khahlanong le moputso o kenyang taolo ea sepheo le litheko tsa hedonic.

Mohato o latelang e ne e le ho etsa lipatlisiso tsa methapo ea methapo ea methapo, ka lipatlisiso tsa pele ho lekola hore na KOR e ka laola tsela ea mesolimbic joang (Setšoantšo. (Figure1) .1). Tsela ena e entsoe ka li-neuron tsa dopaminergic (DA) tse sebakeng sa midbrain ventral tegmental sebakeng (VTA) le morero oa ho bonts'a meetso ea litho tsa maoto, ho kenyelletsa le ventral striatum [kapa nucleus accumbens (NAc)] le preortal cortex (PFC). Lintlha tsa liphoofolo le tsa batho li bontšitse ka ho hlaka hore ts'ebeliso ea lithethefatsi (le mathata a maikutlo, bona Karolo ea 2) e amana le ho sitisoa ho hoholo ha mokokotlo oa moputso oa meputso ea DA (), eo hangata e nkang bohato ba ho bolela esale pele le ho kenyeletsa boiketsetso ba tlhohlelletso ea tikoloho le meputso ea tlhaho. Khopolo ea "bonngoe" ea khale ea bokhoba ba lithethefatsi e hlahisa hore ha e le hantle lithethefatsi tsohle tsa tlhekefetso li ntlafatsa phetisetso ea DA ho NAc, e leng sephetho sa thepa ea bona e ruisang molemo (). Ka har'a moeli ona, liphuputso tse ngata li bontšitse kamehla hore litlamorao tse matla tsa morphine li itšetleha ka disinhibition, ke hore, ts'ebetso ea li-neurons tsa DA. Disinhibition ena e etsahala ka ts'ebetso ea MOR e hlahisoang ke li-interneurons tsa GABAergic tse fumanehang mohatleng oa VTA [tVTA, kapa RMTg e ngata ho Ref. (, )], empa hape le ho VTA le NAc (). Ha ho bapisoa, ho saena ho fokotsehileng ha lets'oao la DA ho ile ha etsoa hore a ikarabelle bakeng sa ho kenya ts'ebetso ea khang ea KOR-Mediated. U sebelisa Microdialysis, Spanagel le basebetsi mmoho () e bonts'itse hore ho lokolloa ha DA ho NAc ho fokotsehile ka ho kenella ha agorist ea KOR ho NAc, empa eseng ho VTA (li-pharmacological agents tse sebelisitsoeng boithuto bo bong le bo bong bo tšohliloeng tlhahlobisong ea hona joale e akaretsoa ho Litafole Lithane11-3). Ntle le moo, ho kenella ha mohanyetsi oa KOR (kapa-BNI) ho NAc ho atolositse ho tsoa ha DA, ho fana ka maikutlo a hore li-dynorphin ka tsela e fokotsang li-neurotransmission tsa DA sebakeng sena. Bopaki bo matlahali bo amang li-neurons tsa DA ho hlohlellelitsoeng ke KOR bo bile haufinyane tjena () ho tsoa ts'ebelisong ea litoeba tse fetotsoeng liphatsa tsa lefutso ho sebelisa sistimi ea ho kopanya ea Cre-lox (). Bals-Kubik et al. o sebelisitse monyetla oa "mouse" ea "knockin" e hlalosang Cre-recombinase tlasa taolo ea "transporter" ea "transcriptal" ea "transporter" ea DA, "letšoao le ikhethang la li-neurons tsa DA ()]. Litoeba tsena li ile tsa pepesoa ke "mouse" e 'ngoe e nang le "knocker" e nang le maemo a itseng "ka hona e ile ea hlakola KOR ho li-neurons tsa DA (DAT KOR-cKO). Boemong ba boits'oaro, CPA e hlahisang COR e ile ea felisoa ka litoeba tsa DAT KOR-cKO, 'me ea khutlisetsoa ho boits'oaro bo akaretsang ba KOR ho VTA ().

Setšoantšo sa 1 

Morero o nolofalitsoeng oa li-circonal tsa neuronal o kenelletseng taolong ea moputso (botala) le khatello ea maikutlo (lamunu), tseo ka bobeli li fetotsoeng ke li-dynorphin le kappa opioid receptor (KOR). KOR-Mediated inhibition ea ventral tegmental area (VTA) dopaminergic ...
Lethathamo 1 

Kappa opioid receptor sebetsa maemong a meputso.
Lethathamo 3 

Ts'ebetso ea Kappa opioid receptor e sebopeho sa moputso le molawana oa tsamaiso.
Lethathamo 2 

Kappa opioid receptor sebetsa maemong a molumo.

Ka mokhoa o tšoanang, bafuputsi ba fumane tlhahlobo-leseling e pharalletseng ea libaka tseo ho hira KOR ho ka bang teng. Kameho ea ts'ebetso ea KOR ea lehae e ile ea hlahlojoa libakeng tse 'maloa e sebelisa paramente ea CPA (). Ts'oaetso ea KOR agonist U50,488H ho NAc e ne e lekane ho kenya CPA e matla, e lumellanang le maikutlo a hore ts'ebetso ea KOR sebakeng sena e fokotsa ho lokolloa ha DA. Ho makatsang ke hore infusions ho PFC, lateral hypothalamus, le VTA (empa eseng ho "anti "nigra le dorsal striatum) li bile le litlamorao tse tšoanang, li fana ka maikutlo a hore matamo a mangata a KOR a ka laola taolo ea tšusumetso le molumo oa hedonic. Liphetho tsena li boetse li bonts'a hore ts'ebetso ea VTA KOR e etsa hore CPA e se ke ea eba le phetoho efe kapa efe ea ho lokolloa ha NAc DA [bona lintlha tse boletsoeng ka holimo tsa neurochemical ()], ho fana ka maikutlo a ho nka karolo ha karolo e 'ngoe ea boko e fumanang bolulo ba DA (ke hore, PFC, bona ka tlase). Ntle le taolo ea phetisetso ea DA, polelo ea KOR le ts'ebetso e se e ntse e etsoa lipatlisiso libakeng tse ling tsa boko tse sebelisang methapo e amanang le moputso le moea [mohlala, bethe ea "stria terminalis", BNST, amygdala, locus coeruleus (LC), sheba ka tlase].

Morero o latelang oa bohlokoa e ne e le ho khetholla mefuta ea lisele tsa neuronal e laoloang ke KOR. Litsela tsa Electron microscopy (, ) e fumane hore ho NAc, halofo ea li-axon tse neng li le KOR-immunoreactive le eona e hlahisitse DAT. Ka ho khahlisang, phuputso ena e fumane hore hoo e ka bang karolo ea boraro (29%) ea li-axon tsena tsa KOR-immunoreactive e ne e se na li-DAT empa e ile ea ikopanya le li-terminals tsa pre-synaptic tsa li-neurons tse ntle tsa DAT, e fana ka maikutlo a hore tsela ea mesolimbic e laoloa boemong ba NAc ka li-neurons tse amanang li hlahisa KOR. Ho ipapisitse le bopaki ba morao-rao (), ho ka etsahala hore li-neuron tse seng tsa DAergic KOR tse ntle, bonyane karolo ea tsona, e be serotonergic (5-HT). Mohlomong, li-KORs tse hlahisitsoeng ke li-neuron tsa 5-HT li ka kena lipakeng tsa DA / 5-HT crosstalk ho NAc, mme li emetse mochine o kenyang tšebelisano lipakeng tsa maikutlo le moputso, hape le lipakeng tsa bokhoba le khatello ea maikutlo (bona ka tlase). Boemong ba NAc (), hape ho na le bopaki ba modumo oa ts'ebetso o itšetlehileng ka KOR oa ho lokolloa ha glutamate, a fana ka maikutlo a hore sebui se ka hlahisoa esale pele ke li-neuron tsa glutamatergic tsa cortical tse sa hlakang kahare ho NAc. Ho tsebo ea rona, bohlokoa ba boitšoaro ba letamo la ho qetela la KOR ha bo rarolloe. Kamora nako, ho PFC (), KOR e ne e fumaneha haholo litulong tsa pre-synaptic, mohlomong li tsamaellana le lipallo tsa DAergic, leha ho sa hlahlojoe hore na methapo ea kutlo ea methapo ena ke efe.

Bafuputsi ba bang ba sebelisitse electrophysiology le immunohistochemistry ho tseba li-neurons tse hlahisang KOR. Ts'ebeliso ea agorist e ikhethileng ea KOR ho VTA e fokotsehile nako ea ho thunya ea nakoana ea sehlopha se seholo sa li-neurons (). Thibelo ena ea KOR-mediated e etsahetse feela ka har'a lisele tsa DA, joalo ka ha ho bonts'itsoe ke immunoreactivity bakeng sa tyrosine hydroxylase (tekanyetso e lekantsoeng ea tlhahiso ea DA, le letšoao le leng la li-neurons tsa DA). Electrophysiology, trackback ea morao-rao le microdialysis li ile tsa kopanngoa ho hlahloba hore na li-neurons tsa DA tse kenang ho NAc kapa ho PFC li laoloa ka tsela e fapaneng ke KOR (). Liteko tsena tse khahlisang li senotse hore ts'ebetso ea KOR ea lehae ho VC hyperpolarised PFC-e lebisang li-neurons tsa DA, empa ha e na phello ho li-neurons tsa DA tsa NAc. Ka hona, tokollo ea DA e fokotsehile ho PFC, empa eseng ho NAc, hodima ts'ebetso ea VTA KOR.

Ka kakaretso liphetho tsena li lumellana le lithuto tsa CPA tsa morao-rao le tlhahlobo ea Microdialysis, 'me li fana ka tlhahiso ea hore na VTA KOR ha e laole molumo oa NAc DA empa ho e-na le hoo e ka etsolla tokollo ea DA ho PFC ho hlahisa CPA. Litoeba tse hlalositsoeng pele tsa DAT KOR-cKO li sa tsoa fana ka bopaki bo matla bakeng sa hypothesis ea morao-rao. Tejeda et al. o fumane hore infusions ea agorist ea KOR ho PFC e fokotse ho ata ha DA ka litoeba tse hlaha (WT) empa eseng ho litoeba tsa DAT KOR-cKO (), ho netefatsa taolo ea KOR-Mediated ea phetiso ea DA ho PFC. Habohlokoa, bangoli ba ile ba leka ka kotlolloho boits'oaro ba li-PFC KOR tsa dysphoria ka likhoto. Ts'oaetso ea mohanyetsi oa KOR ho PFC e ne e lekane ho thibela COR-antonist-CPA, e bonts'a ka mokhoa o hlakileng "legic" cortex e le karoloana e hlokahalang bakeng sa ts'ebetso ena ea boits'oaro.

Ka kopanelo, liphetho tse tsoang mekhoeng ena e fapaneng ea mekhoa le tsona li fana ka maikutlo a hore li-neuron tse sebelisang tšebetso ea DA li hlahisa KOR maemong a pre-synaptic, empa eseng ka soma le dendrites (), ha li-neuron tsa projeke tsa ProC li hlahisa KOR maemong ka bobeli (, , ) (Setšoantšo (Figure1) .1). Boemong ba limolek'hule, hajoale ha ho tsejoe hore na li-neurons tsa DA li ka laola ho ts'oaroa ha KOR ho etsa thepa e fapaneng ea karolo joang e le mosebetsi oa sepheo sa bona. Re hakanya hore mofuta oa karabo ea motlakase (e hlasimollang ho tsoa cortex, inhibitory from striatal medium spiny neurons) e fanoeng ho VTA ke sebaka ka seng e ka ba le tshusumetso. Ntle le moo, ts'ebetso ea lisele tse ikemetseng e ka ameha, e na le li-profiles tse ikhethileng ho NAc- le projeke ea projeke ea DAC e lebisang phetolo le phapanyetsano ea KOR ea boits'oaro bo morao. Ho leka ho sebetsana le tšusumetso ea morao-rao, tsoelo-pele ea theknoloji joale e lumella bafuputsi ho khetholla li-transcriptomes ho tsoa ho li-neuronal tse arolelanang sebaka se tloaelehileng sa 'mele empa ba na le lipehelo tse hlakileng (). Ntle le moo, litla-morao tse khutlisetsang morao li ka tsamaisoa le litoeba tsa knockin tse hlahisang li-receptor tsa opioid ka ho ikopanya le protheine ea fluorescent [litoeba tse joalo li fumaneha bakeng sa mu le delta, empa eseng kappa, li-opioid receptors (, )].

Ketsahalo ea dynorphin / KOR tseleng ea methapo ea DA le CPA e na le litlamorao tse hlakileng tsa boits'oaro bo amanang le bokhoba ba tahi, joalo ka ha ho shebelletsoe lithethefatsi tse fapaneng tsa tlhekefetso ho paradigms ea boits'oaro [bona ho Ref. () bakeng sa tlhahlobo e nyarosang]. KOR agonists lethal dose-ka tsela e itšetlehileng fokotsa morphine ho itaola ho litoeba le litoeba (, ). Litlamorao tse tšoanang tsa ts'ebetso ea KOR li fumanoe ethanol (-), cocaine (, -), nicotine (), le cannabis (), mme tsena li ne li amana le tokollo ea DA e theotsoeng lithethefatsing (mohlala, koae, bona ho Ref. (); ethanol, sheba ho Ref. ()). Lefats'e ka bophara, liphetho tsena li fana ka bopaki bo matla ba phello e thibelitsoeng ea KOR litlamorao tse thabisang tsa lithethefatsi tsa tlhekefetso, mme liphuputso tsa morao-rao li fana ka maikutlo a hore meputso ea tlhaho, joalo ka litšebelisano tsa sechaba, le eona e ka ameha. Li-voes tsa prairie, mofuta o mong oa lithunya tse ngata, ho boloka litlamo li tla itšetleha ka polelo ea boitšoaro bo mabifi mabapi le tumellano ea lipale. Ho khahlisang, mofuta ona oa "boiphephetso ba sechaba" o bontšitsoe hore o kopantsoe le KOR ho supa ka har'a NAc (). Litšoantšong, litšoantšiso tsa kahisano li emela boitšoaro bo ithutoang haholo, bo hlahang ka tlhaho bo amohelang li-neuron tsa DA le ho tsosa matla a ho matlafatsa. Ts'ebetso ea ts'ebetso ea KOR e fokotse papali ea sechaba ka likhoto ka bobeli (, ) le litoeba (). Liphumano tsena li bohlokoa kutloisisong ea rona ea khatello ea maikutlo bathong joalo ka anhedonia, kapa pono e fetotsoeng ea thepa e putsa ea bophelo ba letsatsi le letsatsi (ho kenyeletsoa le litšebelisano tsa sechaba), ke letšoao la boemo bona. Ka hona, ha modumo o itšetlehileng ka KOR oa DA le moputso o ne o hlalosoa le ho hlahlojoa liphatlalatsong tsa ho lemalla, hona joale ho hlakile hore o boetse o na le litlamorao tse matla bakeng sa mathata a maikutlo (, ). CPA e bonts'a tšebelisano ea methapo e mengata ea methapo ea kutlo, e tsamaellanang le likarolo tse tharo tsa kelello: ho ithuta, ho susumetsa le hedonia. Intra-cranial self-stimulation (ICSS) ke papali e 'ngoe e hlahlobang lintlha tsena tse tharo: maemong ana a sebetsang, liphoofolo li ithuta ho itaola ka motlakase o khutšoane libakeng tse itseng tsa boko (hangata e le methapo ea methapo ea methapo ()). Ts'ebetso ea ts'ebetso ea KOR e fumanoe e etsa hore ho be le maemo a kang a anthonic ho ICSS, joalo ka ha ho bonts'itsoe ke ho eketseha ha ts'usumetso ea (). Mosebetsing oa morao-rao, li-electrode tsa ts'usumetso li behiloe ho hypothalamus ea morao-rao, e matlafatsa bopaki ba pejana bakeng sa taolo ea KOR e itšetlehileng ka boemo ba hedonic bo hlahang kantle ho NAc (). Ho ea pele, Potter et al o ile a ithuta kinetics ea KOR agonist-e susumetsang tšusumetso ea ICSS ka mor'a ho entoa ka mokhoa o kotsi le o pheta-phetoang (). The agorist ea KOR Salvinorin-A e ile ea eketsa tsitsipano, 'me phello ena e mpe ea phehella ka liente tsa letsatsi le letsatsi ka nako ea matsatsi a 8. Ho khahlisang, liente tse pheta-phetoang li boetse li bakile ho lieha le litlamorao tse fapaneng, joalo ka ha ho bonahala ka ho fokotseha ha sekhahla sa ts'ebetso sa ICSS 24 h, ho fana ka maikutlo a hore mekhoa ea mohanyetsi (, ) e ne e se e ntlafalitsoe.

Tsela ea neuronal e ka kopanyang ts'ebetso ea hypothalamic KOR le phetisetso ea DA le moputso ha li ithutoe hantle. Lintlha tsa morao-rao tse phahameng tse sebelisang microscopy, electrophysiology, ICSS, le tsamaiso ea koae (, ), fana ka maikutlo a pherekano pakeng tsa orexin le dynorphin peptidergic system. Ts'ebetso ea hypocretin / orexin e entsoe ka li-neurons tse tsoang ho hypothalamus ea morao le ho hlahisa likarolo tse 'maloa tsa mesolimbic (). Habohlokoa, ho ile ha fumanoa hore orexin le dynorphin li sebetsa e le li-transmitter tsa li-neurons tsa hypothalamus (): Li-peptide tse peli li sebetsa hammoho ho li-synicic vesicles, 'me li tsamaisoa ka kopanelo ho ts'usumetso ea motlakase oa hypothalamic. Bangoli ba boetse ba bonts'a hore orexin le dynorphin li sebetsa kahare ho VTA ho susumetsa le ho thibela, ka ho latellana, nyakallo ea li-neurons tsa DA, ka tsela eo moputso oa ho feto-fetoha ka litekanyetso (litekong tsa ICSS), le ho itlhompha ka koae (le lithethefatsi tse ling tse ka sebelisang tlhekefetso) ). Ka VTA, lisele tse ngata (65%) li fumanoe e le liphofu tse tloaelehileng ho orexin le dynorphin. Ho ipapisitsoe le bopaki bo fetileng, liteko tsa nako e tlang li ka leka ho nahana ka hore na li-neurons tsa VTA DA tse hlalosang ka bobeli projeke ea KOR le orexin li khetha ho PFC ho fapana le NAc.

Ka kakaretso, datha ea ts'ebetso ea KOR ts'ebetsong ea moputso e totobatsa bohlokoa ba ho hlahloba mahlaseli a mangata a li-peptide le li-neurotransmitters tse hlahisitsoeng tseleng ea mesolimbic le li-circonal tse amanang le tsona. Ho tseba hore na marang-rang ana a fetoha joang maemong a sa feleng e tla ba mosebetsi o monate.

Kappa Opioid Receptor: Sisteme ea Khatello ea Kelello E Ruruhile ho Tepelletseng Maikutlo a Kelello

Ha e bapisoa le lithuto tsena tse mabapi le moputso, data ea morao-rao e bontšitse hore KOR e boetse e laola likarabo tsa maikutlo, haholoholo nakong ea liphihlelo tse sithabetsang. Boithuto ba meriana mabapi le litoeba bo supa hore sisteme ea dynorphin / KOR e laola boits'oaro bo amanang le maikutlo. Litekong, tsamaiso ea methapo ea li-agonist tsa KOR le bahanyetsi li bonts'itse litlamorao tse tšoanang le tsa kalafo, ka ho ts'oana, ho sesa e qobelloang (FS) le liteko tsa ho hloka thuso (LH) [bona ho Ref. (, -) bakeng sa tlhahlobo]. E tsamaellanang le lithuto tsa CPA, ts'ebetso ea KOR ea tšebetso e fokotse ho lokolloa ha DA ka hare (, ), dorsal (, ), le libaka tsa striatal, ha ente ea lehae ea NAc ea setsebi sa kelello sa KOR e etsisa ts'usumetso e kang ea pheko ea manonyeletso (kalafo).). Lintlha tsena li tiisa le ho feta hore modumo e itšetlehileng ka KOR ea DA e na le tšusumetso lithutong tse amanang le maikutlo le bokhoba (). Ho khahlisang, litlamorao tse kang tsa KOR tse amanang le "protepressant" li ka fetoloa ke bong (), ntlha ea bohlokoa ho nahaneloa hore keketseho ea khatello ea maikutlo e phahame ho basali. Ka ho sebelisa ICSS, bangoli ba fumane hore keketseho e susumetsang ea KOR ea ts'usumetso ea maikutlo ho ICSS e ne e phahame ho banna ho feta likhoto tsa basali. Tšusumetso ena e ne e ikemetse ho tsoa maemong a potolohang a li-hormone tsa gonadal, 'me e ne e sa fuoe karohano ea phapang ea thobalano ho pharmacokinetics ea agonist. Ho fapana le moo, phapang pakeng tsa thobalano ho ts'ebetso ea methapo ea kutlo ea KOR agonist-induction, joalo ka ha e senotsoe ke li-c-fos, e fumanoe BNST le PVN, empa eseng ho NAc kapa amygdala. Ka hona, ho kenyelletsa tsela ea mesolimbic, molumo o tobileng oa KOR o lebisang ho hedonic o ka boela oa hlaha maemong a BNST le PVN, likarolo tse peli tse laolang karabelo-maikutlo le maikutlo.

Ho kenyelletsa lithutong tsa pharmacological tse lebileng KOR, ho boetse ho na le bopaki ba hore li-dynorphin li fana ka taolo ea tekanyetso ea tonic ea mekhoa e amanang le maikutlo (, ). Ho NAc, li-neurons tse mahareng tse hlahisang DA D1-receptor li tsejoa ho kopanya le ho lokolla li-dynorphin tlasa taolo ea protheine ea karabo ea cAMP e tlamang protheine (CREB). Ka hona, litheko tsa prodynorphin li ne li fokotsehile ho NAc ea litoeba tsa transgenic ovexpressing mofuta o atileng oa CREB. Phello ena e ne e amahanngoa le ho fokotseha hoa boits'oaro ho paradigm ea LH. Nako le nako, phuputso ea morao tjena e tlalehile hore Pdyn ho kokota (ka polelo ea bongata ho NAc ea anti-Pdyn RNA hairpin RNA e fokotsehileng joaloka boitšoaro bo nyahamisang tekong ea FS ().

Ntle le likarabo tsa maikutlo tsa motheo, data e bonts'a hore ts'ebetso ea dynorphin / KOR system e hlahisoa ke khatello ea maikutlo. Ho imeloa kelellong ho matla, empa eseng ho sa foleng, ho bonts'itse khatello ea maikutlo e mabapi le KOR e ts'ehetso ea KOR (). Hape, ho pepeseha khafetsa khatellong ea FS ho hlahisitse phello e kang pulepressant-e neng e thibetsoe ke mohanyetsi oa KOR kapa-BNI, mme a le sieo ho Pdyn Lintle tsa KO (). Dynorphins e ile ea bontšoa hape ho feto-fetoha le maemo ka mokhoa o iketlileng o etsang hore motho a be le khatello ea maikutlo (). Litsebi tse koetliselitsoeng ho hokahanya monko o fanoeng le khatello ea maikutlo ea FS li ile tsa qoba monko oo. Boitšoaro bona ba ho qoba bo ne bo sa bonoe ho Pdyn Litoeba tsa KO, 'me li ne li koetsoe litoeba tsa WT ka kalafo ea pele le mohanyetsi oa KOR. Ka mokhoa o ts'oanang, moelelo oa taba o neng o kopantsoe khafetsa le footshocks o ne o le phetoho ho litoeba tsa WT; empa hape, phello ena e ne e le sieo ho Pdyn Litoeba tsa KO, hape li thibetsoe ke kalafo ea kalafo ea pele ea KOR. Habohlokoa, bangoli ba bonts'itse hore ho lokolloa ha corticotropin releasing factor (CRF) tsamaisong ea methapo e bohareng ke ketsahalo ea mantlha e ikarabellang bakeng sa ho bokelloa ha khatello ea maikutlo tsamaisong ea dynorphin / KOR. Liphetho li bonts'itse hore ente ea CRF e bakile phosphorylation ea CRF, joalo ka ha e senotsoe sebelisa anti-phospho-KOR antibody. Ho ekelletsa moo, CPA e bakoang ke khatello ea maikutlo (e etsisoa ke ente ea kemiso kapa ea intracerebroventricular ea CRF kapa CRF2-receptor agonist Urocortin III) o ne a le sieo kahare Pdyn Litoeba tsa KO, 'me li thibetsoe ke kalafo ea pele ho BNI. Kamora ho pepesetsoa ha khatello ea maikutlo, ts'ebetso ea KOR, le phosphorylation li ile tsa bonoa mehahong e 'maloa ea boko, ho kenyelletsa basolateral amygdala, hippocampus, dorsal raphe, VTA, le NAc. Ka kakaretso, datha tsena li bonts'a likarolo tsa dysphoric tsa khatello ea maikutlo li hlahella ha CRF e susumetsa tokollo ea dynorphin, e fana ka ts'ebetso ea KOR ().

Khatello ea kelello ke mokhoa o rarahaneng oa ho iphekola ha mmele o nang le boleng bo feto-fetohang, empa bo ka tsosang liketsahalo tsa pathological nakong ea liphihlelo tsa nako e telele le tse tepelletsang maikutlo. Haufinyane, likamano lipakeng tsa khatello ea maikutlo le KOR li 'nile tsa hlahlojoa ho sebelisoa mehlala e atileng haholo ea boitšoaro le khatello ea maikutlo. Ka tlholeho, qhoebeshano pakeng tsa liphoofolo tse ikhethang e ka hlahisa litlamorao ho latela taolo ea lisebelisoa, phihlello ho balekane, le maemo sechabeng. Mohlala, moahi-intruder ea sechaba se hlotseng paradigm () ke mohlala oa tlhaho o khetholloang ka litšebelisanong tse matla tse sa reroang ebile li sa qojoe, ka hona, ho etsa hore ho be le matšoao a kang ahedonia a kang ho fokotseha ha takatso ea thobalano le ho fokotsa ho rata ha (). McLaughlin le basebetsi mmoho le bona e bile ba pele ba ho senola karolo ea dynorphin le KOR ho fetoleng litlamorao tsa khatello ea maikutlo sechabeng (). Litsuonyana tse senotsoeng khahlano ea khafetsa ea sechaba ka matsatsi a 3 li bonts'itse karabelo e hlotsoeng ea postural, hammoho le keketseho e nyarosang ea kelello, kapa analgesia e hatelletsang khatello ea maikutlo (SIA, e bonoang thupelong ea mohala ea ho tlosoa mohatla). Likarolo tsena ka bobeli li ile tsa thibeloa ho litoeba pele ho kalafo ka antagonist ea KOR, kapa ea haelloa ke Pdyn mofuta. Karolo e 'ngoe ea bohlokoa ea mokhoa oa ho hloloa sechabeng ke hore litlamorao li bontša ho fapana ho fapaneng pakeng tsa litoeba le har'a litoeba tse inbred, hore liphoofolo ka tloaelo li ka aroloa ka lihlopha tse hlaselehang le tse ikemiselitseng (). Haufi le mola ona, ho latela Bérubé et al. (), boemo ba polelo ea li-dynorphin ho NAc li fapana lipakeng tsa likhoto tsa Sprague-Dawley tse sa tsubeng. Manane a ntseng a eketseha a dynorphin mRNA (a lekantsoeng ke qPCR) a fumanoe ka har'a likhoto tsa litoeba tse senyehang (khetla ea NAc, e kopaneng le data ea litoeba tse fetileng), ka mokhoa o makatsang o ile oa bonoa ka har'a dorsal striatum ea batho ba tiileng. maikutlo ka dynorphin le KOR e kanna ea rarahana ho feta kamoo ho neng ho lebelletsoe. Lithupelo tse ling li tla hlokahala ho ntšetsa pele khopolo ena e matla. Ho fapana le hoo, phuputso e 'ngoe e tlalehiloe hore ha ho phetoho maemong a dynorphin ho VTA kapa NAc ea litoeba tse hapiloeng sechabeng sa Long-Evans (). Phapano lipakeng tsa lithuto tsena tse peli li ka hlalosoa ke mefuta e fapaneng e sebelisitsoeng, kapa ho se khetholloe lipakeng tsa litheko tse ts'oanang le tse ts'oaroang tsa Long-Evans thutong ea morao-rao. Ea 'nete, Nocjar et al. () fumanoe fokotsehileng dynorphin-A, hammoho le li-orexin tse fokotsehileng le A, B ho hypothalamus ea likhoto tse hlotsoeng. Ka hona, taolo e kopanetsoeng ea tšebetso ea methapo ea VTA DA ka li-peptides tsena tse peli tsa mohanyetsi e ka ba mokhelo o hlotseng boikemelo ba sechaba o itšetlehileng ka KOR, mme ea holofala kamora ho hloloa hoa sechaba.

Re kile ra buisana ka (Karolo ea 1) hore na KOR e ka bonts'a phapang ea selefouno kahare ho lipalo tse peli tsa VTA DA neurons tse kenang ho NAc kapa ho PFC. Tlaleho ea morao-rao e bonts'a hore mokhoa ona oa ho ikarola o ka ba le bohlokoa ba kutloisiso ea litlamorao tsa ho hloleha ho sa feleng sechabeng. Chaudhury le basebetsi mmoho () e bonts'itse hore thibelo e khethiloeng ea li-neurons tsa VTA tse etselitsoeng ho tsoa ho NAc kapa ho PFC, ka ho latellana, li khothalelitse boikemisetso kapa bofokoli ba ho hloloa khafetsa sechabeng. Ka lebaka la khethollo ea sele ea lehae e khethiloeng, e hohela ho nahana hore KOR e kanna ea kopanya matšoao a kang "eprase "a susumetsoang ke thibelo ea tseleng ea VTA-PFC DA.

Ntle le ho tšoaetsoa ke DAergic, liphumano tse ncha li fana ka maikutlo a hore phetisetso ea 5-HT e kanna ea fetoloa ke KOR maemong a khatello ea maikutlo le a khethollo ea sechaba. Liteko tsa Electrophysiology (, ) qalong e bonts'itse hore KOR e laola li-neuron tsa 5-HT boemong ba "dorsal raphe nucleus" (DRN), e leng sehlooho sa "5-HT" nucleus e ka sehloohong. Habohlokoa, liteko tsa pholoso li bonts'itse hore mokhoa o ikhethileng oa KOR ho DRN ea litoeba tsa KOR KO o lekane ho khutlisa CPA e hlahisitsoeng ke ho ts'oaroa ha agorist ea KOR ho NAc (). Hammoho le liphumano tse fetileng, liphetho tsena li bonts'a hore KOR ho PFC, le KOR tse hlahisitsoeng ke li-neurons tse teng DRN, tse lebileng NAc (eo ho ka etsahalang hore ke li-neurons tsa 5-HT), li hlokahala ebile li lekane, ka ho latellana, bakeng sa polelo ea KOR agonist e hlohlellelitsoeng. Boemong ba limolek'hule, ho hloloa ho matla sechabeng ho ile ha bontšoa ho baka phosphorylation ea KOR le p38cy kinase ho DRN (). Ho koetlisoa ha li-neuron tsa XXUMUMX ho li-neuron tsa 38-HT ho bohlokoa, hobane tšibollo ea boiketlo ba sechaba e felisitsoe ho litoeba tsa cKO moo p5cy e hlakotsoeng ka ho khetheha ho serotonin transporter (SERT) -expressing neurons (p38α-cKOSERT). Phosphorylated p38cy le eona e phahamisa phetisetso ea SERT ho ea kahara membrane ea plasma, ka hona e eketsa 5-HT ho khutlisetsa hape ho ka 'nang ha e-ba molemong oa ho qoba botsoalle. Lirekoto tsa electrophysiological likhechong tsa boko () e boetse e bonts'a hore ts'ebetso ea KOR e hlokisa thabo ea li-neurons tsa DRN 5-HT ka mekhoa e 'meli: tšusumetso ea pele ea synaptic ea ho kenella ha glutamatergic, le tšusumetso ea post-synaptic ea G-protein-gated ka hare e hlophisang litsela tsa potasiamo (GIRKs). Ho pepesetsoa khafetsa ho khatello ea maikutlo ea FS ho senya boemo ba post-synaptic, empa eseng preaptaptic, litlamorao tsa ts'ebetso ea KOR. Habohlokoa, ts'ebetso e bakiloeng ke khatello ea methapo ea methapo ea KOR e ile ea felisoa ka p38cy-cKOSERT litoeba. Qetellong, bopaki ba morao-rao bo bonts'a hore taolo ea KOR ea li-neurons tsa DA le 5-HT e kanna ea fetoha maemong a NAc ho hlahisa dysphoric le khatello ea maikutlo joalo ka eona. Khatello ea maikutlo ea FS e phetoang ka mokhoa o ikhethileng oa SERT maemong a potral striatum, empa eseng libakeng tse ling tse hlahlojoang (dorsal striatum, hippocampus, PFC, amygdala, kapa DRN). Phello ena ea khatello ea maikutlo ho SERT e thibetsoe ke pharmacological blockade ea KOR signaling ho NAc, empa eseng ho DRN (). Ka kakaretso, liphihlelo tse sithabetsang li bonahala li hapile CRF-dynorhin-KOR-p38cy-GIRK e bonts'ang bohlasoa kahare ho li-neuron tsa DRN 5-HT, hammoho le ts'ebetso ea KOR ho NAc. Liphetoho tsena tsa limolek'hule li lebisa ho ntlafatsong ea taolo ea tšebetso ea SERT ho NAc, 'me qetellong e ama ts'ebetso ea DA ho hlahisa matšoao a boitšoaro. Hore na ho tšoaea DRN ho ts'oanang ho kenyelletsa le khaello ea nako e telele e amanang le ho feto-fetoha ha maikutlo, haholo maemong a ho pepesehela lithethefatsi tsa tlhekefetso (Karolo ea 3), ha e sa tlameha ho tsejoa.

Ntle le lipotoloho tsa 5-HT le DA, libaka tse ling tsa tsamaiso ea maikutlo a itšetlehileng ka KOR ha li kenyeletse hippocampal neurogeneis le noradrenergic (NA). Tlaleho e 'ngoe e fumane hore ho litoeba, phello ea antidepressant-like ea KOR antagonist nor-BNI () e amanang le hippocampus, hammoho le mehahong e meng (mohlala, frontal cortex, amygdala, hippocampus, le endopiriform cortex), e nang le litekanyetso tsa mRNA tsa BDNF, neurotrophic factor e laolang synaptic plasticity le neurogeneis. Ho hlokahala lithuto tse ling hape ho utloisisa bohlokoa ba tšebelisano ena ea KOR / BDNF.

Kappa Opioid Receptor ho Kopano ea Ho Tepella Maikutlo le Bokhoba ba Bokhoba

Re fupere karolo ea KOR taolo ea mekhoa ea meputso (Karolo ea 1), le phetolong ea likarabo tsa khatello ea maikutlo le linaha tse amehang (Karolo ea 2). Ho ipapisitsoe le lintlha tsena, lihlopha tse 'maloa li sa tsoa lekola hore na KOR e ka kopanya puisano pakeng tsa bokhoba le khatello ea maikutlo. Kamano lipakeng tsa mathata ana a mabeli e ka ba likeletso tse peli: litla-morao li bonts'a kotsi e kholo ea bophelo bo botle bakeng sa matšoenyeho kapa khatello ea maikutlo, ha, bakuli ba tepelletseng maikutlo khafetsa ba sebelisa lithethefatsi ho itlhahisa ka matšoao a bona a sithabetsang. Lintlha tsena ka bobeli li ntse li sebetsoa ka mehlala ea liphoofolo.

Boikutlo ba khatello ea maikutlo, ho khutlela bocha le ho hlaha ha matšoao a sithabetsang ho batho ba lemaletseng

Ho sithabela maikutlo ho bakileng khatello ea maikutlo nakong ea bokhoba ba tahi

Mefuta ea Rodent ea CPP le tsamaiso ea lithethefatsi e sebelisitsoe haholo ho fuputsa lisosa tse fapaneng tsa ho khutla hape, kapa ho qalella hoa boits'oaro bo batlang lithethefatsi. Kamora nako ea maemo a pheta-phetoang, kapa boits'oaro bo tsitsitseng ba lithethefatsi, liphoofolo li buloa hangata ho CPP kapa likamore tse sebetsang moo ho se nang lithethefatsi, e le hore ts'ebeliso ea lithethefatsi le karabelo e sa sebeliseng matla ha e sa matlafatsoa ebile e tsoela pele butle-butle, ke ts'ebetso e boletsoeng ho fela. Taba ea bohlokoa ke hore, kamora hore ts'enyeho e fumanoe, ho khutlisetsoa morao ho ka ts'oaroa ka ho pepesetsoa hape (ke ho re, "priming") ho lithethefatsi tsa tlhekefetso (puseletso e khothalletsoang ke lithethefatsi), kapa ka ho pepesetsoa khatello ea maikutlo (khatello e tlisoang ke khatello ea maikutlo). Haholo-holo liphihlelo tse sithabetsang li supa mabaka a mantlha a bophelo bakeng sa ho hlaha ha khatello ea maikutlo () hape ke lekhoba la tahi () mathata. Ntle le moo, lithethefatsi tsa tlhekefetso li ka baka litlamorao tsa khatello ea maikutlo le boits'oaro ba khatello e fapaneng, eo ka nako e 'ngoe e ka bakang litlamorao tsa lithethefatsi tsa tlhekefetso sethaleng se khopo (bona ka tlase ho khutlisetsoa khatello ea kelello ke CPP) (). Ka hona, bokhoba ba khatello ea maikutlo le khatello ea kelello li sebelisana haholo, 'me lisosa tsa methapo ea kutlo li hlahisa lintho tse tlatsetsang ho phelisang pakeng tsa bokhoba ba taolo le psychopathology e amanang le khatello ea maikutlo.

Ho ipapisitse le bopaki bo teng bo kenyang KOR litlamorao tsa khatello ea maikutlo (Karolo ea 2), bafuputsi ba ile ba tsoela pele ho fumana karolo ea sebui se ho khutlisetsa khatello kelellong. Ka kakaretso, liphetho li bonts'a hore KOR ho supa ka mokhoa o hlakileng ho buella ho khutlisetsoa hoa khatello ea maikutlo bakeng sa lithethefatsi tse fapaneng tsa tlhekefetso. Litšebelisong, kalafo ea pele ho motsoako oa KOR antagonist (ebang ke JDTic kapa nor-BNI) e fokotse haholo khatello ea maikutlo (footshock), empa eseng ka lebaka la cocaine, ho khutlisetsoa hoa ts'ebetso ea koae). Ho litoeba, ho fumanoe liphuputso tse tšoanang bakeng sa ho khutlisetsa khatello ea maikutlo le lithethefatsi ka lebaka la ts'ebetso ea koae ka ts'ebeliso ea CPP [o sebelisa mohanyetsi e mocha ea sebetsang oa KOR peptidergic ea nako e khuts'oane ea ts'ebetso ()]. Ho feta moo, ho pepesetsoa khatello ea maikutlo e mpe haholo kapa e phetoang hangata e khutliselitseng cocaine CPP ho WT, empa eseng ho KOR kapa Pdyn Koe litoeba, kapa ho latela litlolo tsa limela KOR blockade (). Khatello ea kelello le KOR li boetse li sebetsa maemong a amanang le koae: khatello ea kelello e tsebahala ka ho sebelisa k'hok'heine ea koae, 'me sena se etsoa ke ts'ebetso ea ts'ebetso ea KOR.). Ka hona, KOR e hokahanya ts'ebelisano ea khatello ea kelello / k'hok'heine nakong ea ho pepeseha lithethefatsi, hammoho le ho timela.

E lumellana le datha ea cocaine, mekhoa ea liphatsa tsa lefutso le ea meriana e bonts'itseng hore khatello e matlafatseng ts'ebeliso ea ts'ebeliso ea ethanol ka mokhoa o ts'oanang e itšetleha ka dynorphin le KOR ka bobeli ba CPP le li-paradigms tsa tsamaiso.). Liphetho tsena li ts'ehetsa maikutlo a hore KOR ke moemeli ea lemallang nakong ea khatello ea maikutlo, ho fapana le ts'ebetso ea eona ea thibelo ho thepa ea lithethefatsi tsa tlhekefetso (bona Karolo ea 1). Joalokaha ho tla tšohloa ka tlase, ho hlakisa pherekano ena e hlakileng ho tla hloka hore ho be le tatellano ea hore na ke lipalo life tsa KOR tse nkuoang bokong bohle bo latelang liketsahalo tsa khatello ea maikutlo (le tokollo e latelang ea CRH ea mantlha le li-corticosteroids tse amanang le khatello ea maikutlo le hore na ts'oaetso ena e bakiloeng ke khatello e fapana joang le ts'ebetso ea KOR ( ka li-dynorphin tsa endo native kapa li-systemic pharmacological agents) ka na inve, liphoofolo tse sa hatelloang.

Boemong ba neuro-anatomical, liphumano ho pholletsa le lithethefatsi tse 'maloa tsa tlhekefetso le mekhoa e hatellang e fana ka maikutlo a hore ho khutlisetsoa ha khatello ea khatello ea lithethefatsi ho itšetleha ka litšebelisano tse ngata lipakeng tsa lits'ebetso tsa KOR le monoaminergic, le likarolo tse' maloa tsa forebrain limbic. Ho DRN, liphetho li tsamaisana le datha tse boletsoeng pele mabapi le CPA e itšetlehileng ka KOR. Khatello ea maikutlo e bakiloeng ke khatello ea sechaba ea cocaine CPP e felisitsoe kamora ho tlosoa hoa maemo ha p38cy ho li-neuron tsa 5-HT, joalo ka ha ho bonts'itsoe ho sebelisa p38cy-cKOSERT litoeba (). Boemong ba ho lemalla ha nicotine, ts'ebetso ea khatello ea maikutlo ea FS e bakang khatello ea maikutlo ea dynorphin / KOR e bonts'itsoe ho hlahisa nicotine CPP (), phello e ka thibeloang ke infusion ea kapa-BNI ho amygdala. Ka sebopeho sa boko ba morao-rao, lipatlisiso tsa morao-rao li se li qalile ho senola, tseo li-neuron li hlalosang KOR (bona ka tlase). Ho tla hlokahala lithuto tse eketsehileng ho hlahloba hore na li-neuron tsa KOR-positive amygdala li romela lipehelo tsa mofuta ofe, le hore na ho se sebetse hantle ha li-receptor tsa nicotinic, sepheo se tobileng sa nicotine, se etsahala sebakeng sena kapa se seng sa boko kamora ho pepesetsoa khatello ea maikutlo.

Tšebelisano e sebetsang pakeng tsa phetisetso ea NA le tsamaiso ea dynorphin / KOR e boetse e kenya letsoho ho khutlisetsong khatello ea maikutlo bakeng sa ho batla lithethefatsi. Boithuto ba Anatomical qalong bo bonts'itse hore KOR e hlahisoa ka har'a li-cellular tse ngata kahare ho LC, karolo ea mantlha ea boko ea NA. Microscopy e bobebe le ea elektrone e bontšitse hore KOR e sebelisana hantle le "transporter" ea vesicular glutamate le CRF (), hammoho le preprodynorphin (), liteisheneng tsa axon tsa LC. KOR e boetse e bontšoa ke LC NA neurons, ha KOR immunoreactivity e fumanoe lits'ebetsong tsa TH-positive somatodendritic (). Lirekoto tsa electrophysiological li bonts'itse hore ts'ebetso ea KOR ho LC e bonts'a ts'ebetso ea methapo e fumanoang ka ho kenya litlatsetso tse khothatsang kapa tse ntle tsa CRF. Ka lehlakoreng le leng, ts'ebetso ea KOR e ne e se na phello mesebetsing ea li-neuron tsa LC), e fana ka tlhahiso ea hore li-agorist tsa KOR li qete ho kopitsa li-KOR tsa pre-synaptic tlasa maemo a basal. Boemong ba boitšoaro, litšebelisano tsa KOR / NA li sa tsoa hlahlojoa maemong a taolo ea heroin (). Systemic Yohimbine ente e sebelisitsoe ho etsa phepelo ea ho oela hape, ho ipapisitse le thepa ea mochini ona ho kenya letsoho axis ea HPA le NA neurons (e sebetsang joalo ka mohanyetsi ho α2 NA inhibitory autoreceptors). Liphetho li bonts'itse hore Yohimbine e hlahisitse puseletso ea bohlokoa litoyeng tsa taolo, empa eseng ho litoeba pele ho kalafo le antoronist oa KOR kapa BNI. Hobane thuto ena e sebelisitse tsamaiso ea methapo ea Yohimbine le nor-BNI, ho thata ho etsa qeto ea hore na litlamorao li hlahisitsoe ke KOR blockade ho LC, kapa sebakeng se seng sa kelello, kamora ts'ebetso ea ts'ebetso ea khatello ea kelello (e ka bakang ts'oaetso). Khoele ea CRF le dynorphin). Tlaleho e 'ngoe ea morao-rao e khetholotse mekhoa ena ka qeto e ntlafalitsoeng ea tlhaho, e nka monyetla ka mokhoa o bobebe oa boits'oaro ba KOR agonist-e susumetsang ho khutlisetsoa ha koae ea cocaine (). Thibelo ea KOR ka mokhoa o ikhethileng oa LC e ne e thibetse ho khutlisetsoa hoa KOR. Kamehla, ho lopolla KOR ho LC ea KOR KO litoeba tse khutliselitsoeng ka mokhoa o fokolang tsa KP tse itšetlehileng ka KOR. Joalo ka lipotoloho tse ling tsa monoaminergic (, ), ts'ebetso ea 'mele ea "neurons" e itšetleha ka li-subtypes tse ngata tse fapaneng, ho kenyelletsa le inhibitory α2-autoreceptors le post-synaptic β1- le β2-Bahlahisi. Li-pharmacological tse khethiloeng li ile tsa sebelisoa ho bontša hore thibelo ea NA neurons (α2-receptor agonist), kapa blockade ea ketso ea NA ho post-synaptic β1-Barekisi (β1-antagonist), ka bobeli bo ka kenyang matlafatso ea KOR-e khothalelitse. Liphetho tsena li bontša mohlala oo khatello ea maikutlo le KOR-Mediated inhibition ea li-neuron li thusang ho khutla hape, mme li tsamaellana le data e fetileng e bonts'ang hore ts'ebetso ea LC KOR ea lehae e fokotsa ts'ebetso ea methapo. Ho khahlisang ke hore, bobeli ba ts'ebetso ea koae e khutliselitsoeng cocaine CPP, hammoho le CPA e kentsoeng ke KPA, ha ba anngoe ke mananeo a NA ho supa, ba fana ka maikutlo a hore KOR / NA interplay ka boomo e sebetsana le likarolo tse amanang le khatello ea lithethefatsi. Phuputsong e boletsoeng pejana, Yohimbine o ile a khutla hape ha a ntse a nkoa e le mohatelli oa li-axis tsa HPA ka bobeli le li-neurons tsa NA. Ha ho bapisoa lithuto tse peli, motho a ka nahana hore litlamorao tsena tsa ho hlasimolla tsa Yohimbine li kanna tsa lateloa mme qetellong tsa hanyetsoa ke CRF- le KOR-induction inhibition ea LC NA neurons, ea lebisang ho oeleng hape. Qetellong, lintlha tsena li hlahisa lipotso tse 'maloa bakeng sa lithuto tsa nako e tlang: CRF-receptors le KOR li sebelisana joang LC? Ke mekhoa efe e bonts'ang limolek'hule e hokelitsoeng ho li-neuron tsa LC tse latelang ts'ebetso ea KOR, mme li tšoana le tse hlalositsoeng ho DRN? Ke meaho efe ea sebopeho e anngoeng ts'ebetsong ea LC KOR?

Haufinyane tjena, polasetiki ea synaptic e hlahile e le boemo bo bong ba tlhahlobo ho utloisisa hofetisisa botjha ba KOR-tumellano ea ho batla lithethefatsi. Ho ipapisitse le bopaki bo fetileng ba hore: (i) khatello ea maikutlo e senya bokhoni ba nako e telele (LTP, mofuta oa ntlafatso ea nako e telele ho phetiso ea synaptic pakeng tsa li-neurons tse peli) ho VTA, le hore (ii) KOR e laola tsela ea mesolimbic (Karolo ea 2) , Tlaleho ea morao-rao e fuputsitse modumo oa KOR oa PDP ho VTA e le ts'ebetso ea khatello ea maikutlo (). Liphetho li bonts'itse hore systemic pharmacological blockade ea KOR e thibetse khatello ea kelello e bakiloeng ke ts'ebetso ea PDP ho GABAergic synapses (LTPGABA), empa eseng khatello ea maikutlo e susumetsang ea li-synapses tsa thabo, ka har'a VTA. Ts'ebetso ea KOR ho VTA e ne e lekane ho etsisa phello ea khatello ea maikutlo, le ho thibela LTPGABA ho li-neuron tsa DA. Habohlokoa, ts'ebetso ea intra-VTA kapa-BNI, pele ho khatello ea maikutlo ea FS, e bonts'itsoe ho thibela ho khutlisetsoa ha khatello ea maikutlo le boits'oaro ba koae. Sehlopha sona seo sa bafuputsi se bontšitse tšobotsi ea kinetics ea khatello ea maikutlo / KOR playplay () ka ho sheba KOR le glucocorticoid receptor (GR), e hlahisoang nakong ea liphihlelo tse sithabetsang le tokollo ea kemiso ea corticosteroids. Kamora khatello ea FS, GR e ile ea hiroa nakoana (nakong ea 1), athe bonyane matsatsi a 4 a ts'ebetso ea tonic ea KOR e ne e hlokahala ho kopanya litlamorao tsa khatello ea maikutlo nako e telele ho LTPGABA ho li-neuron tsa DA. Kamehla, e thibela KOR ho supa ka mor'a Matšoenyeho a FS a thibela ho khutlisetsoa ha k'hok'heine ea koae. Lefats'e ka bophara liphuputso tsena tse peli li khothaletsa ka matla hore GR- le KOR-blockade ea mofuta oa PDPGABA ho li-neurons tsa DA, ka boomo li loantšana le khatello ea maikutlo e hlohlellelitsoeng ea ho batla lithethefatsi. Ho latela lintlha tsena, ho ka etsahala hore ka mefuta ea karabelo ea khatello ea maikutlo le bokhoba, lits'ebetso tse ikhethang tsa polasetiki li ka boela tsa hlaha libakeng tse ngata tsa boko ka mor'a ts'ebetso ea KOR.

Ka kakaretso, sistimi ea dynorphin / KOR e na le tšusumetso e kholo ea ho khutlisetsa liphapang tsa liphoofolo le lithethefatsi tsa tlhekefetso ka ho sebelisana ka thata le 5-HT, DA, le NA ho supa. Tlas'a maemo a motheo, ts'ebetso e matla ea KOR e thibela thepa e matlafatsang ea lithethefatsi tsa tlhekefetso (Karolo ea 1). Ho fapana le moo, tlhaiso-leseling e fana ka maikutlo a hore bathong, ho bokelloa ha KOR nakong ea liphihlelo tse sithabetsang tsa bophelo ho ka kopanya ho khutlisetsoa ha batho ba batlang lithethefatsi ho batho ba lemaletseng ho leka ho tlohela ts'ebetso ea lithethefatsi, ka hona ba ka kenya letsoho ho bolokeng temallo.

Ho hlaha ha matšoao a sithabetsang ho batho ba lemaletseng

Ho ntlafatsa khatello ea kelello nakong ea ho pepesetsoa nako e telele, le ho ila, lithethefatsi tsa tlhekefetso li thusa ho hlaha matšoao a sithabetsang, a ka fetohelang maemong a sa foleng a ikemetse ho tloha tlatsong e lemalloang.

Ho pepeseha khafetsa lithethefatsi tsa tlhekefetso ho bonts'itsoe ho hlahisa matšoao a emelang tlhaho ho tsoa ho KOR. Ho pepesetsoa khafetsa khafetsa ho eketsang likhathatso tsa dynorphin ka har'a striatum le substantia nigra ho likhoto (). Ka mokhoa o ts'oanang, taolo ea nako e telele ea heroin e ile ea lebisa ho eketseha Pdyn expression in the khetla ea NAc le khubu ea bohareng ba amygdala, ha e na phello Penk, mofuta o kenyetsang lipeptelete tsa pepephalin opioid li sebetsa ka ho khetheha ho MOR le DOR (). Tahi e sa foleng e boetse e amahanngoa le polelo e eketsehileng ea dynorphin le tokollo ho NAc (, ) le Amygdala (). Joalokaha ho se ho boletsoe, ho eketsoa ha dynorphin ho NAc ho ka etsahala ka tsela ea cAMP-CREB e tšoaeang tsela (). Ka hona, lithethefatsi tsa tlhekefetso li eketsa tokollo ea DA ho NAc, e lebisang ts'ebetsong e ntlafalitsoeng le ea nako e telele ea DA D1-receptor, e amohelang malapa hore e susumetse G.s-protheine. Sena le sona se eketsa sebopeho sa cAMP sa selefounu, 'me se eketsa CREB e tlamang likarolo tsa eona tsa karabelo, e lebisang polelo e eketsehang ea polelo Pdyn mofuta. Liphumano tsena li kentsoe bathong libakeng tse ka pele tsa cortical tseo, tse tšoanang le NAc, li fumanang bolulo bo boholo ba DA. Phuputsong e hlahlobang lisele tsa post-mortem tse tsoang ho lino tse tahang tsa 14 le li-taolo tse phetseng hantle tsa 14, li ile tsa eketseha Pdyn mRNA le dynorphin peptides A le B li ile tsa bonoa ka har'a dorsolateral PFC, hammoho le KOR mRNA e ntseng e eketseha ka cortex ea orbito, athe ha ho phetoho e fumanoeng bakeng sa li-peptide tse ling tsa opioid le li-receptor () libakeng tsena.

Ka lebaka la ts'ebetso e tšoanang le ea hae ea karolo e matla (Karolo ea 2), polelo e eketsehang ea sisteme ea dynorphin / KOR kamora ho pepesetsoa hoa lithethefatsi tsa tlhekefetso e bile le ts'oaetso matšoao a khahlapetsang a ho tlohela haholo, le ho hlaha ha matšoao a sithabetsang nakong e telele. mekhahlelo ea ho tlohela kapa ho tlohela. Litla-morao li ama tšebeliso e mpe ea lithethefatsi ("hypo" ea ho iphekola), ka ho etsa joalo ho matlafatsa ho batlana le lithethefatsi le ho tlatsetsa ho lemeng ho hobe. Ntle le moo, ho haelloa ke maikutlo ke lithethefatsi ka lebaka la lithethefatsi ho ka boela ha lebisa ho, bathong ba tlokotsing, mafu a sithabetsang a itlhahisang ntle le ts'ebeliso e mpe ea lithethefatsi. Mefuteng ea litoeba, ho ikhula ho matla ho pepeseng hoa ethanol ho sa ts'oaneng ho amana le maemo a mabe a maikutlo [sheba mehlala ho Ref. (-), ho kenyelletsa mekhoa ea boits'oaro hangata e hlalosoang e le matšoenyeho- () kapa amanang le khatello ea maikutlo ()]. Ho ka etsahala hore likarolo tsena ka bobeli tsa karabelo ea maikutlo li sebelisane (-), le hore boits'oaro bo khahlisang bo kang ho ikarola bo ka bakang matšoao a nyahamisang. Ho litoeba, ho itšetleha ka ethanol ho ka theoa ka ho pepesehela nako e telele ea lijo tsa ethanol () kapa ho mouoane oa ethanol (). Litsing tsa Wistar (), ho ts'epahalla ho bontšitsoe ho bonts'a mokhoa o ntlafalitsoeng oa ho tšoenyeha (joalo ka tlhahlobo ea liteko tse phahameng tsa maze) nakong ea ho khaotsa ho matla, 'me phello ena e ne e thibetsoe ke kalafo ea systemic le KOR antagonist nor-BNI. Kissler et al. () hape e hlokometse hore ho khaola ho matla ho tsoang ho boits'ebetso ba ho itšetleha ka ethanol le ho itaola ho eketsehileng, le keketseho ea 22-kHz melalizations ea maqhubu, e emelang "boitšoaro bo nang le boitshwaro bo sebetsang bo khethollang habonolo maemo a mabe"(). Liphetoho tsena tsa boits'oaro tse amanang le ho eketseha hoa thibelo ea Dynorphin-A tikolohong ea capy ea amygdala (CeA) le keketseho e matla ea "protheine ea G-protein" ea KOR [joalo ka ha e lekantsoe ho sebelisoa classical [35S] -GTPγS mokhoa ()]. Blockade ea KOR ho CeA e ile ea bontšoa ho thibela boitšoaro bo phahameng ba ethanol literekeng tse itšetlehileng. Kameho ea thetso ena ea lehae ho melumo ea ultrasonic ha ea ka ea hlahlojoa; leha ho le joalo, ho na le monyetla oa hore ho supa ha CeA KOR ho ka kenya letsoho kameho e mpe kamora ho pepesetsoa ha ethanol e sa foleng. Boemong ba potoloho, ho tsebisoa ha tikoloho ea KOR ho amygdala le bohlokoa ba eona ba 'mele ho se ho qalile ho ananeloa,' me liphetho tsa morao-rao li bonts'a hore receptor e fumaneha haholo lits'oants'o tsa pre-synaptic tsa li-neurons tsa GABAergic (). Kamehla, taolo ea agorist ea KOR le mohanyetsi litokisetsong tsa lithaelese tsa amygdala, ka ho theoha li ile tsa fokotseha le ho eketsa phetiso ea GABAergic [li-IPSC tse nyane,)]. Ho makatsang ke hore li-complex tsena tse peli li fumanoe li na le litlamorao tse mpe kamora linako tsa ho ikoetlisa tsa koae, 'me ka lebaka leo li ile tsa eketsa le ho fokotsa ts'ebetso ea GABAergic. Litlamorao tsena li ile tsa bonoa feela ho likhoto tse ileng tsa mpefatsa tšebeliso ea koae ka nako e telele (6 h) ea ho itaola, empa eseng litekong tse bonts'ang ts'ebeliso e tsitsitseng ea koae ka linako tsa nakoana (1 h). Ka hona, ha re ntse re pepesehetse lithethefatsi tsa tlhekefetso potentiate dynorphin / KOR ho supa, ho ka etsahala hore tahlehelo ea taolo ea ts'ebeliso ea lithethefatsi e ka fetola ka kotloloho phello ea ts'ebetso ea KOR lits'ebetsong tse khethehileng tsa li-neuronal (joalo ka mohlala oa CeA) , mohlomong ka lebaka la liphetoho mefuteng ea lisele tse hlalosang KOR, kapa ho tumellano ea selefouno ea KOR. Boemong ba boits'oaro, CeA micro-infusion ea kapa-BNI e bonts'itse ts'ebetso e ts'oanang le ho tšoenyeha joalo ka "paradigm" ea ts'ireletso e ileng ea bonoa nakong ea ho tlohela ente ea cocaine e sa foleng, e neng e etsoa ka teko. Le ha tšusumetso ena ea KOR blockade le eona e lokela ho lekoa kamora ts'ebeliso ea boikoetliso ba koae, litlamorao tsena li fana ka maikutlo a hore li-amygdala KOR li laola likarabo tsa maikutlo nakong ea ho khaotsa koae.

Nakong ea khafetsa ea ho tahoa le ho khaotsa ho tsuba, boits'oaro bo itseng ba tikoloho bo ikamahanya le maemo a fosahetseng, mme bo ka hlahisa litlamorao ntle le tšenyo ea lithethefatsi leha e le life [esita le ho kenyelletsa matšoao a kang a ho tlosoa))]. Haufi le mola ona, Berger et al. () e bonts'itse hore air-puff e susumetsang 22-kHz molumo oa maqhubu a phallo e ka sebelisoa nakong ea ho tlosoa ts'episong ea ethanol (e hlahisitsoeng ke 2-beke le beke e qobelloang ho pepesehela li-ethanol vapor), 'me phello ena e ne e koetsoe ka mokhoa o itšetlehileng ka ho qhekelloa ke systemic KOR antagonism. Boemong bo bong ba liteko, lingoli li amahanya monko o sa jeleng paate (monko oa almond), hammoho le likarolo tse nyarosang tsa ts'ebetso ea systemic KOR. Ho khahlisang, ho pepesetsoa hape monko o nang le boemo bona ho ile ha bontšoa ho iketsetsa tsamaiso ea litekanyetso tsa ethanol maemong a sa tšepahale, mme phello ena e ne e thibetsoe ke KOR systemic blockade. Ka mokhoa o ts'oanang, ho batho, ho pepesetsoa bocha litekanyetsong tse khaotsoeng khafetsa tse nang le tšusumetso e mpe ho ka hlahisa boemo ba dysphoric bo itšetlehileng ka KOR, ka ho etsa joalo ho kenya letsoho ts'ebetsong ea ts'ebetso ea ho lemalla le ho hlaha ha matšoao a sithabetsang.

Litlamorao tsa maikutlo tsa lithethefatsi tsa tlhekefetso li ata ho feta karolo e mpe ea ho ikhula, e hlalosoang e le nako eo ka eona moriana o hlakoloang 'meleng. Phuputso ea morao-rao e hlokometse liphetoho tse telele tse itšetlehileng ka KOR tse amanang le ho tlosoa hoa tlhaho ho ethanol (). Likhoto li ile tsa feptjoa lino tse tahang tsa joala bakeng sa matsatsi a 25-30, li sebelisa boits'oaro ba molomo ka paradigm ea likhetho tse peli. Libeke tse tšeletseng tse latelang ho tlosoa hoa ethanol, boits'oaro bo ts'oanang le boits'oaro (bo lekantsoeng hang kamora khatello ea phepelo ea 20-min, ka har'a maze e phahameng) bo ne bo le teng litlamong tsa ethanol tse emisang. Phello ena e ne e koetsoe ke mofuta oa kalafo oa pele ho kalafo oa 24 h kapa BNI pele ho tlhahlobo, ho fana ka maikutlo a hore khatello ea khatello ea ts'ebetso ea dynorphin / KOR e ka tsoela pele nako e telele haholo kamora ho pepesetsoa ha ethanol ea pele. Sehlopha sa rona sa morao-rao se atolositse 'mele ona o ntseng o eketseha oa bopaki ho opaate tlhekefetso, le ho kenya KOR bofokoli ba maikutlo nakong ea ho tlohela lithethefatsi ka nako e telele ho litoeba. Pele re bonts'a hore ho ila thipa morphine butle-butle ho lebisa ho hlaheng ha boitšepo bo feteletseng ba boits'oaro (litekong tsa ho emisoa ka mohatla) le ho tlosoa sechabeng (, ). Liphoso tsena ka bobeli li fumanoe libeke tsa 4, empa eseng bekeng ea 1, kamora ho leka ho tlisoa tekanyetso e phahameng ea morphine. E sa foleng ka os kalafo ka antidepressant Fluoxetine (serotonin reuptake inhibitor) ka nako ea beke ea 4-beke ea ho ila e khutlisitse bofokoli ba morphine bo susumetsang. Ho feta moo, metabolism ea 5-HT () le 5-HT1A-receptor function () li ne li entsoe nakong ea ho itšoaetsa morphine, haholo-holo DRN, ho fana ka maikutlo a tlatsetso ea bohlokoa ea mekhoa ea 5-HT. Ho matlafatsa mohlala ona, re ile ra supa sebopeho se fapaneng sa kinetic re sebelisa heroin (): libekeng tsa 4 tsa ho ila, ke ho tlosoa feela sechabeng ho fumanoeng litoeba tsa heroin pele ho kalafo; ka libeke tsa 7 tsa ho ila, lets'oao lena la pele le ne le tsamaisana le ho eketseha ha boits'oaro bo botle (litekong tsa FS). Habohlokoa, re bonts'itse hore phokotseho e matla ea ts'ebetso ea sechaba (e bonoang ho lahloa ka bobeli morphine le heroin) e itšetleha ka ts'ebetso ea bobeli ba MOR le KOR (): phenotype ena e ne e le sieo: (i) ka litoeba tsa cKO, moo MOR e ileng ea hlakoloa ka ho khetheha ho DRN pele ho kalafo ea heroin; le (ii) ka litoeba tse kholo tsa KOR KO. Ha ho nahanoa data ea pejana ho khokahano ea 5-HT le DA maemong a NAc ka mehlala ea CPA e itšetlehileng ka CPA le k'hok'heine ea Cocaine, monyetla o khahlisang ke hore litšebelisano tse tšoanang tsa monoamine li ka baka pherekano ea maikutlo nakong ea ts'ebeliso ea opiate, mohlomong ka li-cascade tse tšoanang tsa limolek'hule. .

Mosebetsi oa bohlokoa bakeng sa ho etsa lipatlisiso tsa nako e tlang e tla ba ho fumana likarabo tse kang maikutlo maikutlong le mefuta e makatsang ea boits'oaro bo joalo. Ka tekanyo ea phylogenic le phetolelo, le ho sebelisa mekhoa ea boits'oaro, lihlopha tse 'maloa li atlehile ho fetisa litekanyetso tsa ts'ebetso ea ts'ebetso ea DSM ho ba le ts'ebetso e mpe ea ts'ebetso ea ts'ebeliso ea lithethefatsi, ho kenyelletsa le ho hlaha ha ts'ebetso e qobelloang ea ho batla lithethefatsi le ho ts'oara lithethefatsi leha e le litlamorao tse mpe. (, ). Re hakanya hore mekhoa e joalo e fetelletsang ea ho sebelisa lithethefatsi e ka boela ea lebisa khaellong e matla ea maikutlo le ea nako e telele ho litoeba, mme e ka emela mehlala e metle ea ho hlasimoloha maikutlong ho amanang le ho lemalla. Mekhoa e joalo e boetse e na le monyetla oa ho senola, ka mokhoa o fapaneng, mekhoa ea boits'oaro e sa boletseng feela phetoho ho ts'ebeliso e qobelloang ea lithethefatsi (joalo ka ho qhekelloa ho phahameng), empa hape le kotsi ea ho hlasimoloha ha maikutlo.

Ka kopanelo, lingoliloeng tse ntseng li eketseha ka potlako tsa KOR li hlahisitse thahasello e kholo ho nts'etsopele ea maikutlo a KOR e le litlhare tsa meriana ea khatello ea maikutlo le khatello ea maikutlo, hammoho le ho ntlafatsa taolo ea khatello ea maikutlo le ho fokotsa dysphoria maemong a tlhekefetso. Le ha li-ligor tse ling tsa KOR li sa bonts'a litheko tse nepahetseng tsa meriana, tse ling li bontšitsoe hore ke bakuli ba sebetsang ba lithethefatsi (). Ka kakaretso, bahanyetsi ba KOR ba ka (i) thibela tšusumetso e bakoang ke tšebeliso ea lithethefatsi, (ii) ho thibela ho fokotseha ho bakoang ke khatello ea maikutlo nakong ea ho khaotsa ho tsuba, le (iii) ho fokotsa maemo a mabe a maikutlo nakong ea ho khaotsa ho matla le linako tse telele tsa ho ila. Leha lits'ebetso tsa nako e telele le lithuto tse laoloang hantle li le phephetso ho batho ba lemaletseng lithethefatsi, liphetho tsena li tsamaisana le tlaleho ea tlhekefetso ea bakuli ba nang le khatello ea maikutlo mabapi le litlamorao tsa buprenorphine, mohanyetsi oa MOR agonist / antoronist ea KOR (ha a bapisoa le methadone, agorist a MOR); Phuputso e 'ngoe, leha ho le joalo, e ile ea sitoa ho bona phapang lipakeng tsa metsoako ena e' meli (). Patlisiso e matla ho k'hemisteng ea KOR e se e hlahisitse bongata ba nakoana [Zyklophin (), LY-2456302 (, )] le bahanyetsi ba nako e telele (kapa-BNI, GNTI, JDTic)). Lithuto tsa nako e tlang li tla tlameha ho sekaseka thepa ea bona ea matšoao ho latela sebopeho seo ba se fihletseng le KOR, ke hore, tšimo e tšepisang ea agonism e nang le leeme [bona ka mohlala ho Ref. (-)]. Lintlha tse ling li ka hlaha ha li bapisoa le ho supa ha KOR hohle le mefuta ea batho (), kapa joalo ka ts'ebetso ea polymorphisms ()-). Hape, monyetla oa morao-rao oa ho ithuta KOR ea motho Ka vivo, o sebelisa PET-Scans ka radiotracer 11C-LY2795050 (), ea tšepisa. Kamor'a nako e telele, mekhoa ea meriana ea pharmacogenomic e na le monyetla oa ho bolela mekhoa ea kalafo e lebisitsoeng ho KOR, ka hona e ka ba senotlolo sa ho fumana litlhahiso tsa bongaka tse sebetsang.

Ha khatello ea maikutlo e tla pele ho ts'oaetso

Ho sebetsana le mekhoa ea methapo ea kutloano lipakeng tsa khatello ea maikutlo le bokhoba, mokhoa o mong o tlatselletsang mehlaleng ea liphoofolo ke ho ithuta kamoo maemo a sithabetsang a ka bang le litlamorao tsa boitšoaro le mekhoa ea ts'ebeliso ea lithethefatsi tsa tlhekefetso (, ). Ha ho bapisoa le kamano e bakiloeng ke ho ferekana e kenelletseng ka har'a komello, karolo ea morao-rao ha e ithutoe hantle, 'me ke lithuto tse fokolang tse ileng tsa hlahloba karolo e ka bang teng ea KOR.

Moralong ona, bopaki bo fumanehang bo sa lumellane, 'me mehlala e sa foleng ea khatello ea maikutlo e amahanngoa le litlamorao tsa lithethefatsi tsa tlhekefetso (tlhokomeliso ea litsela tsa moputso tse tla tsamaellana le komorbidity ea motho) kapa litlamorao tse fokotsehileng. Krishnan et al. () e bonts'itse hore litoeba tse anngoeng habonolo ke litlamorao tse sa feleng tsa setjhaba, tse hlahisang maemo a tepelletsang a tepelletsang joaloka maikutlo, ho kenyelletsa le khetho e fokotsoang ea sucrose le phemelo ea sechaba, le tsona li bonts'a CPP ea bohlokoa litekanyetsong tsa koae tse sa ntlafatseng litoeba tse sa fetotsoeng, kapa tse hlotsoeng empa litoeba tse matlafatsang.

Ho sithabela maikutlo ho sa feleng ke mofuta o mong oa khatello ea maikutlo, e thehiloeng ho pepesong e sa lebelloang ea litoeba ho li-stress tse ngata tse bonolo, hangata ho feta libeke tsa 4-8. Moetso ona o sebelisoa haholo ka lebaka la sefahleho sa ona, se a haha, ebile se sebetsa hantle.-). Sesebelisoa se tsebahalang ka ho fetisisa litekong tse sa feleng tsa khatello ea maikutlo (CMS) ke khetho e fokotsehileng (e fetang metsi) bakeng sa tharollo ea sucrose, kapa anhedonia. Mofuta ona oa anhedonic o boetse o bonahala o atoloha ho matlafatsang thepa ea lithethefatsi tsa tlhekefetso, ha CPP e fokotsehile bakeng sa amphetamine () le morphine) ho tlalehiloe ho latela CMS ka likhoto. Ho makatsang ke hore ha ho na thuto e fumanehang, tsebong ea rona, ka litlamorao tsa CMS ho litoeba tsa KOR KO: na polelo ea KOR e amehile ka litoeba tsa WT tse hatelletsoeng? Libakeng life tsa boko? Na litoeba tsa KOR KO li ne li tla sireletsoa khahlanong le litlamorao tsa khatello ea maikutlo e sa foleng? Ha a sebetsana le lekhalo lena ka har'a lingoliloeng, Al-Hasani et al. haufinyane tjena ho fuputse litlamorao tsa ho khutlisetsoa ha CPP mefuta e meraro e sithabetsang: CMS, "ho hlola bophelo bo sa feleng" (mofuta o khuts'oane oa matsatsi a 5 oa tlhaselo ea sechaba), le khatello e matla ea maikutlo ea FS (). Liphetho li bonts'itse hore, joalo ka ha ho hlalositsoe pele, khatello e matla ea maikutlo e bakang KOR-mediated ho khutlisetsoa ha k'hok'heine ea koae. Ho fapana le hoo, ka bobeli CMS le ho hlola bophelo bo sa foleng ba sechaba ho fumanoe hore ba khutlisetsoa ka ts'ebeliso ea kelello ea KOR ea cocaine le nicotine CPP. Joalokaha ho ne ho lebelletsoe, ho khutlisetsoa kahare ho lithethefatsi tsa cocaine kapa nicotine CPP ho ne ho sa angoe ke CMS, ho eketsa bopaki bo fetileng mabapi le moelelo o ikhethang oa KOR ho khutlisetsong khatello ea maikutlo. Liphetho tsena tse hanyetsanang li fana ka maikutlo a hore bonyane mehlaleng ea litoeba, CMS e kanna ea ba le litlamorao kapa tšireletso khahlano le ho khutlisetsoa hoa lithethefatsi, khopolo e sa lumellaneng hantle le liphumano tsa lefutso le tleliniki ho batho.

Ka kakaretso, re nahana hore boits'oaro bo kang ba anhedonia bo latelang CMS kapa ho hlola bophelo ba nako e telele bo ka fokotsa maemo a matlafatsang a lithethefatsi tsa tlhekefetso (joalo ka ha ho hlahlojoa ho sebelisa likarolo tse khethollang maemo a lithethefatsi, ho timela le ho oela hape), mohlomong ho beha ts'ebetso e itšetlehileng ka KOR. . Ka nako e ts'oanang, anhedonia e hatelletsoeng ke khatello ea maikutlo e kanna ea baka tšohanyetso ea tšebeliso e mpe ea lithethefatsi nakong ea ts'ebeliso e mpe ea boithaopo ea lithethefatsi tsa tlhekefetso, ka hona e rata ho kenella ts'ebelisong ea lithethefatsi. Ho hlahloba monyetla ona, lithuto tsa nako e tlang li tla kopanya likarolo tse peli tsa paradigms e tsoetseng pele ea boits'oaro: CMS kapa ho hlola taolo e sa feleng ea sechaba, ho lateloe ke boits'oaro bo eketsehileng ba ts'ebetso ea lithethefatsi. Keketseho ea litoeba tsa cKO tse fumanehang hona joale e lokela ho ba le thuso ho utloisisa karolo ea KOR ka mekhoa ena e kopaneng ea preorinical ea comorbidity.

Litataiso tsa Bokamoso le sephetho

Phephetso e kholo nakong e tlang e tla ba ho utulla mekhoa e metle ea tsoelo-pele ea dynorphin / KOR, 'me ha e sa ba le phumano le meputso. Taba ena ke ea bohlokoa ba bongaka bo amanang le maemo ana a mabeli. Haholo-holo, bopaki bo fumanehang bo bonts'a hore KOR e fana ka li-control tse ngata holim'a monoamine e kholo litonong. Ho khahlisang, lipatlisiso tsa bokhoba ba ho lemalla ho fana ka maikutlo a hore ho pepesehela lithethefatsi tsa tlhekefetso ho senya mekhoa ea maikutlo pakeng tsa monoaminergic nuclei, e ka bakang ho se sebetse hantle ha nako e telele (, ). Hore na mekhoa e joalo e sitisa le taolo ea mehopolo e itšetlehileng ka KOR ke mohopolo o tsotehang maemong a comorbidity.

Bopaki bo ntseng bo eketseha tšimong ea KOR haufinyane bo khothalelitse baoki ho etsa lithuto tsa kelello tsa boko le liteko tsa tleliniki (). Haufinyane tjena, thuto ea pele ea PET-Scan e sebelisang mohanyetsi oa radio radio KOR e khonne ho bonts'a pherekano e kholo le e pharalletseng ea KOR Ka vivo ho fumaneha lithutong tse nang le tšabo le matšoao a ho hlaseloa ke dysphoric kamora ho pepesetsoa ho sithabetsoa ke kotsi e mpe (). Le ha diphetho li lumellana hantle le datha ea liphoofolo ho KOR le tsela ea mesolimbic, li boetse li fana ka maikutlo a hore libaka tse ling tsa boko, tseo hajoale li sibolotsoeng hampe maemong a preclinical, le tsona li ka ba bohlokoa ka tsela e tšoanang (mohlala, thalamus le infort cortex). Lithuto tse ling li tla hlokoa ho lekola ho fumaneha ha KOR ka har'a li-cohorts tse hlahelletseng tsa lithuto tse tepelletseng maikutlo, tse lemalloang, le li-comorbid. Kamora nako, ho latela pono ea bongaka, lefapha le iphetotsang la ts'oaetso ea "bion agonism" (kapa ligand e laetsoeng ke ligand) le hlahisa tšepo e kholo bakeng sa kalafo e lebisang ho KOR (). Morero o ka sehloohong tšimong ea li-receptor tse kopaneng le G-protein ke ho tsebahatsa litsela tse ikhethang tse ka sebelisang ho laola likarabo tse ikhethang tsa boitšoaro. Haufinyane, mekhoa e joalo e kanna ea thusa ho nts'etsopele ea litlhare tse sebetsanang le bahanyetsi ba KOR le ba se nang litlamorao tse ka bang teng (mohlala, hyperalgesia).

Ka ho phethela, re akaretse hakhutšoanyane hona joale sehlopha se seholo sa bopaki se tšehetsang karolo ea KOR ho laola moputso le maikutlo. Re boetse re hlalositse hore na li-receptor tsena li behiloe joang hantle ho hokahanya lipuisano tse matla pakeng tsa khafetsa le likhathatso tse matla tsa kelello, ho lemalla le khatello ea maikutlo. Ka kakaretso, patlisiso e entsoeng pele ho KOR e bontša kamoo lithuto tse fetolelang ho mefuta e mengata ea liphoofolo li nang le monyetla oa ho khetholla mekhoa ea boko e kenyang ts'ebetso ea transdiagnostic pathophysiological, ka hona e emela lipheo tsa mantlha tsa kalafo bakeng sa taolo ea komorbidity, e 'ngoe ea lintlha tse hlahelletseng tsa lefats'e ka kelellong. bophelo bo botle.

Tlhōlisano ea Tlhaloso

Bangoli ba bolela hore lipatlisiso li ne li etsoa ka ho se be le likamano leha e le life tsa khoebo kapa tsa lichelete tse ka nkoang e le khohlano e ka 'nang ea e-ba le thahasello.

lumela hore baa fokola

Bangoli ba leboha Dr. Laura Fiori ka ho bala ka hloko buka e ngotsoeng ka letsoho. Mosebetsi ona o ne o tšehelitsoe ke Agence Nationale de la Recherche (ANR-Abstinence).

References

1. Volkow ND, Baler RD, Goldstein RZ. Tlatsetso: ho hohela ka methapo ea boitšoaro bo botle ba sechaba. Neuron (2011) 69 (4): 599-602.10.1016 / j.neuron.2011.01.027 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
2. Bakken K, Landheim AS, mafu a Vaglum P. Axis I le II e le baetapele ba nako e telele ba khatello ea kelello: tlhahlobo e tlang ea lilemo tse ts'eletseng ea bakuli ba ts'ehetsang lithethefatsi. BMC Psychiatry (2007) 7: 29.10.1186 / 1471-244X-7-29 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
3. de Graaf R, Bijl RV, Ten Be M, Beekman AT, Vollebergh WA. Litsela tsa ho fihlela comorbidity: phetoho ea mohatsela o hloekileng, ho tšoenyeha le ts'ebeliso ea lithethefatsi maemong a comorbid thutong e thehiloeng ho baahi e telele. J Afimate Disord (2004) 82 (3): 461-7.10.1016 / j.jad.2004.03.001 [E fetotsoe] [Ref Ref Cross]
4. Goldstein A, Tachibana S, Lowney LI, Hunkapiller M, Hood L. Dynorphin- (1-13), peptide e fetang e tloaelehileng ea opioid peptide. Proc Natl Acad Sci USA (1979) 76 (12): 6666-70.10.1073 / pnas.76.12.6666 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
5. Chavkin C, James IF, Goldstein A. Dynorphin ke lesapo le khethehileng la semmuso sa kappa opioid receptor. Mahlale (1982) 215 (4531): 413-5.10.1126 / science.6120570 [E fetotsoe] [Ref Ref Cross]
6. Le Merrer J, Becker JA, Befort K, Kieffer BL. Ts'ebetso ea moputso ke sistimi ea opioid bokong. Physiol Rev (2009) 89 (4): 1379-412.10.1152 / physrev.00005.2009 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
7. Nestler EJ. Na ho na le tsela e tloaelehileng ea limolek'hule ea ho lemalla? Nat Neurosci (2005) 8 (11): 1445-9.10.1038 / nn1578 [E fetotsoe] [Ref Ref Cross]
8. Pradhan AA, Befort K, Nozaki C, Gaveriaux-Ruff C, Kieffer BL. Delta opioid receptor: sepheo sa ho fetolela pheko bakeng sa kalafo ea mathata a bokong. Trends Pharmacol Sci (2011) 32 (10): 581-90.10.1016 / j.tips.2011.06.008 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
9. Lutz PE, Kieffer BL. Likarolo tse ngata tsa ts'ebetso ea li-opioid receptor: litlamorao tsa ho lemalla. Curr Opin Neurobiol (2013) 23 (4): 473-9.10.1016 / j.conb.2013.02.005 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
10. Lutz PE, Kieffer BL. Li-receptor tsa Opioid: likarolo tse ikhethileng tsa mathata a ho feto-fetoha ha maikutlo. Trends Neurosci (2013) 36 (3): 195-206.10.1016 / j.tins.2012.11.002 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
11. Charbogne P, Kieffer BL, Befort K. 15 lilemo tsa mekhoa ea liphatsa tsa lefutso ho vivo bakeng sa lipatlisiso tsa ho lemalla: ho amohela li-opioid receptor le peptide gene ka mefuta ea panya ea lithethefatsi. Neuropharmacology (2014) 76: 204-17.10.1016 / j.neuropharm.2013.08.028 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
12. Chefer VI, Backman CM, Gigante ED, Shippenberg TS. Li-receptor tsa Kappa opioid tse fumanehang ho dopaminergic neurons lia hlokahala bakeng sa ho hanyetsa sebaka sa kappa-Mediated. Neuropsychopharmacology (2013) 38 (13): 2623-31.10.1038 / npp.2013.171 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
13. Tejeda HA, Counotte DS, Oh E, Ramamoorthy S, Schultz-Kuszak KN, Backman CM, et al. Pele ho cortical korta-opioid receptor module ea methapo ea kutlo ea sebakeng seo le boemo ba leholimo bo hanyetsang. Neuropsychopharmacology (2013) 38 (9): 1770-9.10.1038 / npp.2013.76 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
14. Bruchas MR, Schindler AG, Shankar H, Messinger DI, Miyatake M, Land BB, et al. Ho tlosoa ha p38alpha MAPK ho serotonergic neurons ho hlahisa khatello ea maikutlo mefuteng ea khatello ea maikutlo le bokhoba. Neuron (2011) 71 (3): 498-511.10.1016 / j.neuron.2011.06.011 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
15. Ahmad T, Lauzon NM, de Jaeger X, Laviolette SR. Phetisetso ea canannabinoid ho prelimbic cortex e laole ka mokhoa o hlakileng moputso le ho tlohela ho saena ka mokhoa o fapaneng oa kappa o bapisoang le li-process tsa li-receptor tsa mo-opiate. J Neurosci (2013) 33 (39): 15642-5110.1523 / JNEUROSCI.1686-13.2013 [E fetotsoe] [Ref Ref Cross]
16. Schindler AG, Messinger DI, Smith JS, Shankar H, Gustin RM, Schattauer SS, et al. Khatello ea maikutlo e hlahisa moputso oa ho khopamisa le o ka behang moputso oa koae ka ho lokolla li-dynorphin tsa mehleng ea phepelo ea moea hore e hlohlelle ho busetsoa hoa serotonin. J Neurosci (2012) 32 (49): 17582-96.10.1523 / JNEUROSCI.3220-12.2012 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
17. Bruchas MR, Land BB, Chavkin C. Sisteme ea dynorphin / kappa opioid e le modulara ea boits'oaro bo hatelletsang maikutlo le bo lematsang. Brain Res (2010) 1314: 44-55.10.1016 / j.brainres.2009.08.062 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
18. Knoll AT, Carlezon WA., Jr Dynorphin, khatello ea maikutlo le khatello ea maikutlo. Brain Res (2010) 1314: 56-7310.1016 / j.brainres.2009.09.074 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
19. Berger AL, Williams AM, McGinnis MM, Walker BM. Ho eketseha hoa tlhoko-hloko ea tlhaselo e amanang le tahi le ho phahamisa mantsoe a 22-kHz nakong ea ho itlopa joala: karolo ea li-receptor tsa kappa-opioid. Neuropsychopharmacology (2013) 38 (4): 647-54.10.1038 / npp.2012.229 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
20. Smith JS, Schindler AG, Martinelli E, Gustin RM, Bruchas MR, Chavkin C. Khatello e matla ea khatello ea maikutlo ea dynorphin / kappa-opioid receptor tsamaisong ea amygdala potentiates nicotine e maemong a ikhethileng. J Neurosci (2012) 32 (4): 1488-9510.1523 / JNEUROSCI.2980-11.2012 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
21. Kallupi M, Wee S, Edward S, Whitfield TW, Jr, Oleata CS, Luu G, et al. Kappa opioid receptor-mediated dysregulation ea gamma-aminobutyric acidergic transmission ho amygdala e bohareng ka ho lemalla koae. Biol Psychiatry (2013) 74 (7): 520-8.10.1016 / j.biopsych.2013.04.028 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
22. Oache ea liteko ea Harrison C.: opioid receptor blocker e bonts'a tšepiso ea karolo ea II ea khatello ea maikutlo. Nat Rev Drug Discov (2013) 12 (6): 415.10.1038 / nrd4028 [E fetotsoe] [Ref Ref Cross]
23. Gerra G, Borella F, Zaimovic A, Moi G, Bussandri M, Bubici C, et al. Buprenorphine kgahlano le methadone ya ho itshetleha ha opioid: dintho tse boletsoeng esale pele bakeng sa sephetho sa kalafo. Phokotso ea Lithethefatsi tsa Lithethefatsi (2004) 75 (1): 37-45.10.1016 / j.drugalcdep.2003.11.017 [E fetotsoe] [Ref Ref Cross]
24. Gerra G, Fantoma A, Zaimovic A. Naltrexone le koprenorphine motsoako kalafong ea ts'oaetso ea opioid. J Psychopharmacol (2006) 20 (6): 806-14.10.1177 / 0269881106060835 [E fetotsoe] [Ref Ref Cross]
25. Pfeiffer A, Brantl V, Herz A, Emrich HM. Psychotomimesis mediated ke kappa opiate receptors. Mahlale (1986) 233 (4765): 774-610.1126 / science.3016896 [E fetotsoe] [Ref Ref Cross]
26. Roth BL, Baner K, Westkaemper R, Siebert D, Rice KC, Steinberg S, et al. Salvinorin A: agonist e ikhethileng ea tlhaho eo e seng ea tlhaho. Proc Natl Acad Sci USA (2002) 99 (18): 11934-9.10.1073 / pnas.182234399 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
27. Shippenberg TS, Herz A. Liphetoho tse fapaneng tsa li-system tsa mu and kappa opioid lits'ebetsong tse susumetsang. NIDA Res Monogr (1986) 75: 563-6. [E fetotsoe]
28. Nestler EJ, Carlezon WA, Jr. potoloho ea moputso oa mesolimbic dopamine maemong a sithabetsang. Biol Psychiatry (2006) 59 (12): 1151-9.10.1016 / j.biopsych.2005.09.018 [E fetotsoe] [Ref Ref Cross]
29. Di Chiara G, Imperato A. Lithethefatsi tse hlekefetsoang ke batho ka mokhoa o ikhethileng li eketsa ho tsepamisa mohopolo ho dopamine ka har'a sisteme ea mesolimbic ea likhoto tse tsamaeang ka bolokolohi. Proc Natl Acad Sci USA (1988) 85 (14): 5274-8.10.1073 / pnas.85.14.5274 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
30. Johnson SW, North RA. Opioids e khahlisa li-dopamine neurons ka hyperpolarization ea li-interneurons tsa lehae. J Neurosci (1992) 12 (2): 483-8. [E fetotsoe]
31. Jalabert M, Bourdy R, Courtin J, Veinante P, Manzoni OJ, Barrot M, et al. Li-circuits tsa Neuronal tse ka tlas'a ketso e mpe ea morphine ho dopamine neurons. Proc Natl Acad Sci USA (2011) 108 (39): 16446-50.10.1073 / pnas.1105418108 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
32. Matsui A, Jarvie BC, Robinson BG, Hentges ST, Williams JT. Lipapatso tsa GABA tse arohaneng ho dopamine neurons Mediate ketso e matla ea opioids, nts'etsopele ea mamello, le polelo ea ho tlohela. Neuron (2014) 82 (6): 1346-56.10.1016 / j.neuron.2014.04.030 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
33. Spanagel R, Herz A, Shippenberg TS. Ho hanyetsana le li-system tsa endio native opioid tse sebetsang ka tsela e hlophisehileng li fetole tsela ea mesolimbic dopaminergic. Proc Natl Acad Sci USA (1992) 89 (6): 2046-50.10.1073 / pnas.89.6.2046 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
34. Metzger D, Chambon P. Sete- le mofuta o ikhethileng oa gene o tobileng ho panya. Mekhoa (2001) 24 (1): 71-8010.1006 / meth.2001.1159 [E fetotsoe] [Ref Ref Cross]
35. Backman CM, Malik N, Zhang Y, Shan L, Grinberg A, Hoffer BJ, et al. Tšoaetso ea khatello ea panya e bonts'ang Cre recombinase e tsoang tikolohong ea 3 'e sa fetoloang ea sebaka sa dopamine transporter. Genese (2006) 44 (8): 383-90.10.1002 / dvg.20228 [E fetotsoe] [Ref Ref Cross]
36. Paterson NE, Markou A. Mefuta ea liphoofolo le kalafo bakeng sa ho lemalla koae le khatello ea maikutlo. Neurotox Res (2007) 11 (1): 1-32.10.1007 / BF03033479 [E fetotsoe] [Ref Ref Cross]
37. Land BB, Bruchas MR, Lemos JC, Xu M, Melief EJ, Chavkin C. Karolo ea khatello ea methapo e kopantsoe ke ts'ebetso ea sistimi ea dynorphin kappa-opioid. J Neurosci (2008) 28 (2): 407-14.10.1523 / JNEUROSCI.4458-07.2008 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
38. Land BB, Bruchas MR, Schattauer S, Giardino WJ, Aita M, Messinger D, et al. Ho kenngwa tshebetsong ha kappa opioid receptor ka hara dorsal raphe nucleus ho buella litlamorao tse sithabetsang tsa khatello ea maikutlo le ho khutlisa ho batla lithethefatsi. Proc Natl Acad Sci USA (2009) 106 (45): 19168-73.10.1073 / pnas.0910705106 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
39. Al-Hasani R, McCall JG, Foshage AM, Bruchas MR. Locus coeruleus kappa-opioid receptors e hlophisa ho khutlisoa ha thato ea sebaka sa koae ka mochine oa noradrenergic. Neuropsychopharmacology (2013) 38 (12): 2484-97.10.1038 / npp.2013.151 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
40. Lemos JC, Roth CA, Messinger DI, Gill HK, Phillips PE, Chavkin C. Ho pheta-pheta khatello ea maikutlo dysregulates kappa-opioid receptor e sa bonts'ang phetoho ea dorsal ka mochine o itšetlehileng ka P38alpha MAPK. J Neurosci (2012) 32 (36): 12325-36.10.1523 / JNEUROSCI.2053-12.2012 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
41. Beardsley PM, Howard JL, Shelton KL, Carroll FI. Litlamorao tse fapaneng tsa mohanyetsi oa kappa opioid receptor antagonist, JDTic, mabapi le ho khutlisetsoa ha k'hok'heine ea koae e ts'oaroang ke liphihlelo tsa koae le litlamorao tsa koae le litlamorao tse joalo tsa litla-morao. Psychopharmacology (2005) 183 (1): 118-26.10.1007 / s00213-005-0167-4 [E fetotsoe] [Ref Ref Cross]
42. Mague SD, Pliakas AM, Todtenkopf MS, Tomasiewicz HC, Zhang Y, Stevens WC, Jr., et al. Litlamorao tse kang tsa kappa-opioid receptor antagonists litekong tse qobelloang tsa ho sesa lithupeng. J Pharmacol Exp Ther (2003) 305 (1): 323-30.10.1124 / jpet.102.046433 [E fetotsoe] [Ref Ref Cross]
43. Shirayama Y, Ishida H, Iwata M, Hazama GI, Kawahara R, Duman RS. Khatello ea maikutlo e eketsa ts'ebetso ea dynorphin libakeng tsa bokong ba litho tsa 'mele' me khatello ea kelello ea dynorphin e hlahisa litlamorao tse kang antidepressant. J Neurochem (2004) 90 (5): 1258-68.10.1111 / j.1471-4159.2004.02589.x [E fetotsoe] [Ref Ref Cross]
44. Carlezon WA, Jr, Beguin C, DiNieri JA, Baumann MH, Richards MR, Todtenkopf MS, et al. Litlamorao tse kang khatello ea maikutlo ea "kappa-opioid receptor agonist salvinorin A" mabapi le boitšoaro le methapo ea kutlo ho likhoto. J Pharmacol Exp Ther (2006) 316 (1): 440-7.10.1124 / jpet.105.092304 [E fetotsoe] [Ref Ref Cross]
45. Falcon E, Maier K, Robinson SA, Hill-Smith TE, Lucki I. Liphello tsa luprenorphine litekong tsa boits'oaro bakeng sa lithethefatsi tse loantšang khatello ea maikutlo le lithethefatsi tse amanang le litoeba. Psychopharmacology (2014) .10.1007 / s00213-014-3723-y [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
46. Cohen A, Whitfield TW, Kreifeldt M, Koebel P, Kieffer BL, Contet C, et al. ShRNA e kenyellelitsoeng ka har'a "virus" ea "prodynorphin" ka har'a "nucleus" ea "rat" e bonts'a khatello ea maikutlo joalo ka boits'oaro le maikutlo a cocaine locomotor sensitization. PloS One (2014) 9 (5): e97216.10.1371 / journal.pone.0097216 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
47. Muschamp JW, Hollander JA, Thompson JL, Voren G, Hassinger LC, Onvani S, et al. Hypocretin (orexin) e nolofalletsa moputso ka ho bona litla-morao tsa mokokotlo oa eona oa "cotransmitter dynorphin" sebakeng se khubung ea mokokotlo. Proc Natl Acad Sci USA (2014) 111 (16): E1648-55.10.1073 / pnas.1315542111 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
48. Li X, Hlakubele NJ, Shaham Y. Ho hloa karolo ea ho hanana ha dynorphin le hypocretin ka moputso le tšusumetso. Proc Natl Acad Sci USA (2014) 111 (16): 5765-610.1073 / pnas.1403603111 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
49. Bals-Kubik R, Ableitner A, Herz A, Shippenberg TS. Liwebsaete tsa Neuroanatomical tse sebelisang matla a susumetsang a li-opioid ha li ntse li hlophisitsoe ke maemo a khethollo ea sebaka ho litheko. J Pharmacol Exp Ther (1993) 264 (1): 489-95. [E fetotsoe]
50. Svingos AL, Chavkin C, Colago EE, Pickel VM. Coexpression e kholo ea li-receptor tsa kappa-opioid le transporter ea dopamine ho li-profus tsa nucleus e bokella lintlha tsa axonal. Synapse (2001) 42 (3): 185-92.10.1002 / syn.10005 [E fetotsoe] [Ref Ref Cross]
51. Meshul CK, McGinty JF. Kappa opioid receptor immunoreacuction ho bokong ba nucleus le caudate-putamen e amana haholo le li-synaptic vesicles ka li-axon. Neuroscience (2000) 96 (1): 91-9.10.1016 / S0306-4522 (99) 90481-5 [E fetotsoe] [Ref Ref Cross]
52. Hjelmstad GO, Masimong HL. Kappa opioid receptor activation ka har'a nucleus accumbens inhibits glutamate le tokollo ea GABA ka mekhoa e fapaneng. J Neurophysiol (2003) 89 (5): 2389-95.10.1152 / jn.01115.2002 [E fetotsoe] [Ref Ref Cross]
53. Svingos AL, Colago EE. Li-receptor tsa Kappa-opioid le NMDA glutamate li shebiloe ka mokhoa o fapaneng kahare ho cortex ea rat medial prefrontal. Brain Res (2002) 946 (2): 262-71.10.1016 / S0006-8993 (02) 02894-9 [E fetotsoe] [Ref Ref Cross]
54. Margolis EB, Hjelmstad GO, Bonci A, Fields HL. Kappa-opioid agonists ka kotloloho e thibella methapo ea methapo ea mokokotlo ea "midbrain" dopaminergic neurons. J Neurosci (2003) 23 (31): 9981-6. [E fetotsoe]
55. Margolis EB, Lock H, Chefer VI, Shippenberg TS, Hjelmstad GO, Fields HL. Kappa opioids e khetha ka ho khetheha dopaminergic neurons tse kenang cortex ea pele. Proc Natl Acad Sci USA (2006) 103 (8): 2938-42.10.1073 / pnas.0511159103 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
56. Ekstrand MI, Nectow AR, Knight ZA, Latcha KN, Pomeranz LE, Friedman JM. Boitsebiso ba limolek'hule tsa li-neurons bo thehiloe ho khokahano. Sele (2014) 157 (5): 1230-42.10.1016 / j.cell.2014.03.059 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
57. Erbs E, Faget L, Scherrer G, Matifas A, Filliol D, Vonesch JL, et al. Mofuta oa boko oa mu-delta opioid receptor o senola ho hlaha ha neuronal marang-rang a subcortical. Brick Struct Funct (2014) .10.1007 / s00429-014-0717-9 [E fetotsoe] [Ref Ref Cross]
58. Scherrer G, Tryoen-Toth P, Filliol D, Matifas A, Laustriat D, Cao YQ, et al. Knicein litoeba tse hlahisang li-fluorescent delta-opioid receptors li senola G protein-coupled receptor dynamics in vivo. Proc Natl Acad Sci USA (2006) 103 (25): 9691-6.10.1073 / pnas.0603359103 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
59. Wee S, Koob GF. Karolo ea sistine ea dynorphin-kappa opioid litlamorao tse matlafatsang tsa lithethefatsi tsa tlhekefetso. Psychopharmacology (2010) 210 (2): 121-35.10.1007 / s00213-010-1825-8 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
60. Kuzmin AV, Semenova S, Gerrits MA, Zvartau EE, Van Ree JM. Kappa-opioid receptor agonist U50,488H e hlophisa boikoetliso ba koae le morphine ka har'a litoeba le litoeba tse se nang lithethefatsi. Euro J Pharmacol (1997) 321 (3): 265-71.10.1016 / S0014-2999 (96) 00961-2 [E fetotsoe] [Ref Ref Cross]
61. Glick SD, Maisonneuve IM, Raucci J, Archer S. Kappa opioid inhibition of morphine and cocaine self-management in rats. Brain Res (1995) 681 (1-2): 147-52.10.1016 / 0006-8993 (95) 00306-B [E fetotsoe] [Ref Ref Cross]
62. Nestby P, Schoffelmeer AN, Homberg JR, Wardeh G, De Vries TJ, Mulder AH, et al. Bremazocine e fokotsa boitšoaro bo sa lefelloeng ba ethanol ntle le litekanyetso tsa khetho ea sucrose. Psychopharmacology (1999) 142 (3): 309-17.10.1007 / s002130050894 [E fetotsoe] [Ref Ref Cross]
63. Lindholm S, Werme M, Brene S, Franck J. Mokhethoa oa kappa-opioid receptor agonist U50,488H o bonts'a ho kenella ka boithatelo ho ethanol ho rat. Behav Brain Res (2001) 120 (2): 137-46.10.1016 / S0166-4328 (00) 00368-5 [E fetotsoe] [Ref Ref Cross]
64. Logrip ML, Janak PH, Ron D. Blockade ea moputso oa ethanol ke kappa opioid receptor agonist U50,488H. Alcohol (2009) 43 (5): 359-65.10.1016 / j.alcohol.2009.05.001 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
65. Negus SS, Mello NK, Portoghese PS, Lin CE. Liphello tsa li-opioid tsa kappa mabapi le ho itaola ka koae ka litšoene tsa rhesus. J Pharmacol Exp Ther (1997) 282 (1): 44-55. [E fetotsoe]
66. Mello NK, Negus SS. Litlamorao tsa kappa opioid agonists ho cocaine- le karabelo e bolokiloeng ke lijo ke litšoene tsa rhesus. J Pharmacol Exp Ther (1998) 286 (2): 812-24. [E fetotsoe]
67. Schenk S, Partridge B, Shippenberg TS. Litlamorao tsa kappa-opioid receptor agonist, U69593, holima nts'etsopele ea maikutlo le tlhokomeliso ea taolo ea koae. Neuropsychopharmacology (2001) 24 (4): 441-5010.1016 / S0893-133X (00) 00190-1 [E fetotsoe] [Ref Ref Cross]
68. Schenk S, Partridge B, Shippenberg TS. U69593, agonist ea kappa-opioid, e fokotsa boitšoaro ba k'hok'heine 'me e fokotsa ho batla lithethefatsi tsa koae. Psychopharmacology (1999) 144 (4): 339-46.10.1007 / s002130051016 [E fetotsoe] [Ref Ref Cross]
69. Galeote L, Berrendero F, Bura SA, Zimmer A, Maldonado R. Prodynorphin pherekano ea liphatsa tsa lefutso e eketsa boikemelo ba ho itaola ka nicotine ka litoeba. Int J Neuropsychopharmacol (2009) 12 (5): 615-25.10.1017 / S1461145708009450 [E fetotsoe] [Ref Ref Cross]
70. Mendizabal V, Zimmer A, Maldonado R. Ho kenyelletsa tsamaiso ea kappa / dynorphin ho WIN 55,212-2 ea tsamaiso ea litoeba ho litoeba. Neuropsychopharmacology (2006) 31 (9): 1957-66.10.1038 / sj.npp.1300957 [E fetotsoe] [Ref Ref Cross]
71. Maisonneuve IM, Archer S, Glick SD. U50,488, kappa opioid receptor agonist, e bonts'a keketseho e khothalletsoang ea koae ka dopamine ea extracellular ho li-ruru ea methapo ea methapo. Neurosci Lett (1994) 181 (1-2): 57 – 60.10.1016 / 0304-3940 (94) 90559-2 [E fetotsoe] [Ref Ref Cross]
72. Femenia T, Manzanares J. Ho eketseha ha ethanol ho litoeba tsa prodynorphin knockout ho amana le liphetoho mosebetsing le phetisong ea dopamine. Addict Biol (2011) 17 (2): 322-37.10.1111 / j.1369-1600.2011.00378.x [E fetotsoe] [Ref Ref Cross]
73. Resendez SL, Kuhnmuench M, Krzywosinski T, Aragona BJ. Li-receptor tsa Kappa-opioid tse kahara khubu li bokella polokeho ea maqhama a matla a khoheli. J Neurosci (2012) 32 (20): 6771-84.10.1523 / JNEUROSCI.5779-11.2012 [E fetotsoe] [Ref Ref Cross]
74. Vanderschuren LJ, Niesink RJ, Spruijt BM, Van Ree JM. Liphello tsa opioid tsa Mu- le kappa-opioid receptor-mediated lipapaling tsa boithabiso lipapaling tsa bana. Euro J Pharmacol (1995) 276 (3): 257-66.10.1016 / 0014-2999 (95) 00040-R [E fetotsoe] [Ref Ref Cross]
75. Trezza V, Baarendse PJ, Vanderschuren LJ. Monate oa papali: temohisiso ea pharmacological ka mekhoa ea meputso ea sechaba. Trends Pharmacol Sci (2010) 31 (10): 463-9.10.1016 / j.tips.2010.06.008 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
76. Robles CF, McMackin MZ, Campi KL, Doig IE, Takahashi EY, Pride MC, et al. Litlamorao tsa li-receptor tsa kappa opioid maemong a behiloeng sebakeng sa boikhutso le tšebelisano-mmoho ho banna le basali. Behav Brain Res (2014) 262: 84-93.10.1016 / j.bbr.2014.01.003 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
77. Carlezon WA, Jr, Chartoff EH. Intracranial self-stimulation (ICSS) ka litoeba ho ithuta neurobiology ea sepheo. Nat Protoc (2007) 2 (11): 2987-95.10.1038 / nprot.2007.441 [E fetotsoe] [Ref Ref Cross]
78. Todtenkopf MS, Marcus JF, Portoghese PS, Carlezon WA, Jr. Liphello tsa kappa-opioid receptor ligands ho intracranial ho ikhatholla ho likhoto. Psychopharmacology (2004) 172 (4): 463-70.10.1007 / s00213-003-1680-y [E fetotsoe] [Ref Ref Cross]
79. Potter DN, Damez-Werno D, Carlezon WA, Jr, Cohen BM, Chartoff EH. Ho pepesetsoa khafetsa ho kappa-opioid receptor agonist salvinorin A modulates extracellular sign-regated kinase le teboho ea moputso. Biol Psychiatry (2011) 70 (8): 744-53.10.1016 / j.biopsych.2011.05.021 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
80. Solomon RL, Corbit JD. Mohopolo oa mohanyetsi oa tšusumetso. II Ho lemalla koae. J Abnorm Psychol (1973) 81 (2): 158-7110.1037 / h0034534 [E fetotsoe] [Ref Ref Cross]
81. Tlhahlobo ea Koob GF, Le Moal M. Tlhahlobo. Mehato ea Neurobiological bakeng sa mohanyetsi oa ts'usumetso ea ts'ebetso ea ho lemalla. Philos Trans R Soc Lond B Biol Sci (2008) 363 (1507): 3113-23.10.1098 / rstb.2008.0094 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
82. Thompson AC, Zapata A, Justice JB, Jr, Vaughan RA, Sharpe LG, Shippenberg TS. Kappa-opioid receptor activation e fetola ho nka dopamine ka har'a boksi ba bile e hanyetsa litlamorao tsa koae. J Neurosci (2000) 20 (24): 9333-40. [E fetotsoe]
83. Ebner SR, Roitman MF, Potter DN, Rachlin AB, Chartoff EH. Litlamorao tse kang khatello ea maikutlo ea kappa opioid receptor agonist salvinorin A li amahanngoa le ho theoha ha phasic dopamine e tsoang ka har'a li-nucleus accumbens. Psychopharmacology (2010) 210 (2): 241-52.10.1007 / s00213-010-1836-5 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
84. Gehrke BJ, Chefer VI, Shippenberg TS. Litholoana tsa tsamaiso e matla le e pheta-phetoang ea salvinorin A ts'ebetsong ea dopamine ho rat dorsal striatum. Psychopharmacology (2008) 197 (3): 509-17.10.1007 / s00213-007-1067-6 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
85. Zhang Y, Butelman ER, Schlussman SD, Ho A, Kreek MJ. Litlamorao tsa hallucinogen salvinorin ea semela e fumanehang maemong a basal dopamine ka har'a caudate putamen le sebakeng se phetheselang se ke keng sa hlola se utloa litoeba: liketso tsa agonist ho li-receptor tsa kappa opioid. Psychopharmacology (2005) 179 (3): 551-8.10.1177 / 0269881105056526 [E fetotsoe] [Ref Ref Cross]
86. Muschamp JW, Van't Veer A, Parsegian A, Gallo MS, Chen M, Neve RL, et al. Ho kenya ts'ebetso ea CREB ka khetla ea "nucleus accumbens" ho hlahisa "anhedonia" le ho hanela ho felisoa hoa tšabo ho likhoto. J Neurosci (2011) 31 (8): 3095-103.10.1523 / JNEUROSCI.5973-10.2011 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
87. Russell SE, Rachlin AB, Smith KL, Muschamp J, Berry L, Zhao Z, et al. Phapang pakeng tsa botona le botšehali ho litlamorao tse kang khatello ea maikutlo ea kappa opioid receptor agonist u-50488 ka likhoto. Biol Psychiatry (2014) 76 (3): 213-22.10.1016 / j.biopsych.2013.07.042 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
88. Newton SS, Thome J, Wallace TL, Shirayama Y, Schlesinger L, Sakai N, et al. Ho thibela protheine ea cAMP e kopanyang karolo kapa "dynorphin" e bokellaneng ea nucleus ho hlahisa phello e kang antidepressant-like. J Neurosci (2002) 22 (24): 10883-90. [E fetotsoe]
89. del Rosario Capriles N, Cancela LM. Litlamorao tse susumetsang mu- le kappa-opioid agonists tse latelang khatello ea maikutlo le ka boiketsetso tse sa feleng: ho nka karolo ha dopamine D (1) le D (2) receptors. Behav Brain Res (2002) 132 (2): 159-69.10.1016 / S0166-4328 (01) 00414-4 [E fetotsoe] [Ref Ref Cross]
90. McLaughlin JP, Marton-Popovici M, Chavkin C. Kappa opioid receptor antagonism le prodynorphin gene disrupt blockchain-ikiwalelo tsa karabelo tsa boitšoaro. J Neurosci (2003) 23 (13): 5674-83. [Tlhahiso ea mahala ea PMC] [E fetotsoe]
91. Miczek KA, Yap JJ, Covington HE, III. Matšoenyeho a sechaba, kalafo le tšebeliso e mpe ea lithethefatsi: mehlala ea pele ea boikoetliso bo ntseng bo eketseha le bo sithabetsang. Pharmacol Ther (2008) 120 (2): 102-28.10.1016 / j.pharmthera.2008.07.006 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
92. McLaughlin JP, Li S, Valdez J, Chavkin TA, Chavkin C. Likarabo tsa boitšoaro tse tlisoang ke khatello ea maikutlo tse susumetsoang ke sechaba li kopants'oa ke tsamaiso ea endiozala kappa opioid. Neuropsychopharmacology (2006) 31 (6): 1241-8. [Tlhahiso ea mahala ea PMC] [E fetotsoe]
93. Krishnan V, Han MH, Graham DL, Berton O, Renthal W, Russo SJ, et al. Liphetoho tsa limolek'hule tse tlatsetsang habonolo le ho hanyetsanang le ho hloloa hoa sechaba libakeng tsa moputso oa boko. Sele (2007) 131 (2): 391-404.10.1016 / j.cell.2007.09.018 [E fetotsoe] [Ref Ref Cross]
94. Berube P, Laforest S, Bhatnagar S, Drolet G. Enkephalin le polelo ea dynorphin mRNA li amahanngoa le ho hloka botsitso kapa ho ba kotsing ea khatello ea khatello ea kelello ea khatello ea kelello. Physiol Behav (2013) 122: 237-45.10.1016 / j.physbeh.2013.04.009 [E fetotsoe] [Ref Ref Cross]
95. Nocjar C, Zhang J, Feng P, Panksepp J. Mohlala oa liphoofolo o hlotsoeng oa khatello ea maikutlo o bonts'a maemo a fokotsehileng a orexin libakeng tse mesocortical tsa sisteme ea dopamine, le dynorphin le orexin ho hypothalamus. Neuroscience (2012) 218: 138-5310.1016 / j.neuroscience.2012.05.033 [E fetotsoe] [Ref Ref Cross]
96. Chaudhury D, Walsh JJ, Friedman AK, Juarez B, Ku SM, Koo JW, et al. Melao e potlakileng ea boits'oaro bo amanang le khatello ea maikutlo ka taolo ea methapo ea methapo ea mokokotlo ea midbrain dopamine. Tlhaho (2013) 493 (7433): 532-6.10.1038 / nature11713 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
97. Tao R, Auerbach SB. Li-opioid receptor subtypes ka mokhoa o fapaneng li fetole serotonin efflux tsamaisong ea methapo ea kutlo. J Pharmacol Exp Ther (2002) 303 (2): 549-56.10.1124 / jpet.102.037861 [E fetotsoe] [Ref Ref Cross]
98. Tao R, Auerbach SB. mu-opioids disinhibit le kappa-opioids inhibit serotonin efflux bokong ba dorsal raphe. Brain Res (2005) 1049 (1): 70-9.10.1016 / j.brainres.2005.04.076 [E fetotsoe] [Ref Ref Cross]
99. Zhang H, Shi YG, Woods JH, Watson SJ, Ko MC. Litlamorao tse kang tsa kappa-opioid receptor-mediated antidepressant-like or nor-Binaltorphimine: lithuto tsa boitšoaro le BDNF mRNA. Euro J Pharmacol (2007) 570 (1-3): 89-96.10.1016 / j.ejphar.2007.05.045 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
100. Belmaker RH, Agam G. Mathata a sithabetsang a maholo. N Engl J Med (2008) 358 (1): 55-6810.1056 / NEJMra073096 [E fetotsoe] [Ref Ref Cross]
101. Koob GF, Volkow ND. Neurocircuitry ea ho lemalla. Neuropsychopharmacology (2010) 35 (1): 217-3810.1038 / npp.2009.110 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
102. Sinha R, Garcia M, Paliwal P, Kreek MJ, Rounsaville BJ. Likarabo tse khahlisang khatello ea kelello tsa koae le khatello ea maikutlo tse fanoang ke khatello ea maikutlo. Arch Gen Psychiatry (2006) 63 (3): 324-31.10.1001 / archpsyc.63.3.324 [E fetotsoe] [Ref Ref Cross]
103. Aldrich JV, Patkar KA, McLaughlin JP. Zyklophin, mohanyetsi ea sebetsang oa kappa opioid receptor peptide o sebetsang ka nako e telele ha a nka khato. Proc Natl Acad Sci USA (2009) 106 (43): 18396-401.10.1073 / pnas.0910180106 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
104. Redila VA, Chavkin C. Khatello e matla ea khatello ea kelello e bakiloeng ke khatello ea koae e kopantsoe ke tsamaiso ea kappa opioid. Psychopharmacology (2008) 200 (1): 59-70.10.1007 / s00213-008-1122-y [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
105. McLaughlin JP, Land BB, Li S, Pintar JE, Chavkin C. Pele ho ts'ebetso ea li-receptor tsa kappa opioid ke li-mimics tsa U50,488 tse pheta-phetoang li hatelletse khatello ea ho sesa bakeng sa ho rata maemo a cocaine. Neuropsychopharmacology (2006) 31 (4): 787-94.10.1038 / sj.npp.1300860 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
106. Sperling RE, Gomes SM, Sypek EI, Carey AN, McLaughlin JP. Endo native kappa-opioid mediation ea khatello e nang le khatello ea maikutlo ea boikhethelo ba sebaka sa ethanol le boikhethelo. Psychopharmacology (2010) 210 (2): 199-209.10.1007 / s00213-010-1844-5 [E fetotsoe] [Ref Ref Cross]
107. Kreibich A, Reyes BA, Curtis AL, Ecke L, Chavkin C, Van Bockstaele EJ, et al. Presynaptic inhibition ea mefuta e fapaneng ea litumellano ho locus ceruleus ke li-receptors tsa kappa-opiate: mokhoa o mocha oa ho laola sisteme e bohareng ea norepinephrine. J Neurosci (2008) 28 (25): 6516-25.10.1523 / JNEUROSCI.0390-08.2008 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
108. Reyes BA, Chavkin C, van Bockstaele EJ. Ho tsetsisoa ha subcellular ea li-receptor tsa kappa-opioid ho "rat nucleus locus coeruleus". J Comp Neurol (2009) 512 (3): 419-31.10.1002 / cne.21880 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
109. Zhou Y, Leri F, Grella SL, Aldrich JV, Kreek MJ. Kenyelletso ea dynorphin le kappa opioid receptor ho yohimbine e kentsoeng phetisong ea heroin e batlang likotong. Synapse (2013) 67 (6): 358-6110.1002 / syn.21638 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
110. Lutz PE. Mekhoa e mengata ea serotonergic e lebisang ho katleho ea katleho linthong tse hlokang tlhokomelo. J Neurophysiol (2013) 109 (9): 2245-9.10.1152 / jn.01093.2012 [E fetotsoe] [Ref Ref Cross]
111. McDevitt RA, Neumaier JF. Taolo ea tšebetso ea li-dorsal raphe nucleus ke serotonin autoreceptors: pono ea boitšoaro. J Chem Neuroanat (2011) 41 (4): 234-46.10.1016 / j.jchemneu.2011.05.001 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
112. Graziane NM, Polter AM, Briand LA, Pierce RC, Kauer JA. Li-receptor tsa Kappa opioid li laola khatello ea maikutlo ea khatello ea koae le khatello ea kelello ea synaptic. Neuron (2013) 77 (5): 942-54.10.1016 / j.neuron.2012.12.034 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
113. Polter AM, Bishop RA, Briand LA, Graziane NM, Pierce RC, Kauer JA. Posttress block of kappa opioid receptors e boloka bokhoni ba nako e telele ba li-synapses tsa inhibitory le ho thibela ho khutlisoa ha ho ts'oaroa ha koae. Biol Psychiatry (2014) .10.1016 / j.biopsych.2014.04.019 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
114. Sivam SP. Cocaine ka khetho e eketsa litekanyo tsa dynorphin ka mokhoa o ikhethileng ka mochine oa dopaminergic. J Pharmacol Exp Ther (1989) 250 (3): 818-24. [E fetotsoe]
115. Solecki W, Ziolkowska B, Krowka T, Gieryk A, Filip M, Przewlocki R. Liphetoho tsa polelo ea mofuta oa prodynorphin tsamaisong ea rat mesocorticolimbic nakong ea tsamaiso ea heroin. Brain Res (2009) 1255: 113-21.10.1016 / j.brainres.2008.12.002 [E fetotsoe] [Ref Ref Cross]
116. Przewlocka B, Turchan J, Lason W, ho khaotsa ha Przewlocki R. Ethanol ho ntlafatsa ts'ebetso ea sistimi ea prodynorphin ho li-nucleus accumbens tsa rat. Neurosci Lett (1997) 238 (1-2): 13-6.10.1016 / S0304-3940 (97) 00829-X [E fetotsoe] [Ref Ref Cross]
117. Lindholm S, Ploj K, Franck J, Nylander J. Tsamaiso ea ethanol e phetoang e tlisa liphetoho tse khutšoane le tsa nako e telele ho phepelo ea lithane tsa tetephalin le dynorphin bokong ba rat. Alcohol (2000) 22 (3): 165-71.10.1016 / S0741-8329 (00) 00118-X [E fetotsoe] [Ref Ref Cross]
118. D'Addario C, Caputi FF, Rimondini R, Gandolfi O, Del Borrello E, Candeletti S, et al. Litlhaloso tse fapaneng tsa joala li baka liphetoho tse ikhethang ho polelo ea dynorphin le li-nociceptin tse amanang le liphatsa tsa lefutso tsa bokong ba rat. Addict Biol (2013) 18 (3): 425-33.10.1111 / j.1369-1600.2011.00326.x [E fetotsoe] [Ref Ref Cross]
119. Muschamp JW, Carlezon WA, Jr. Karolo ea li-nucleus e bokella CREB le dynorphin maemong a tšusumetso ea takatso. Cold Spring Harb Perspect Med (2013) 3 (2): a012005.10.1101 / cshperspect.a012005 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
120. Bazov I, Kononenko O, Watanabe H, Kuntic V, Sarkisyan D, Taqi MM, et al. Sistimi ea opoidine ea nako e telele ea lino tse tahang: litloaelo tsa limolek'hule libakeng tsa boko tse kenyelletsang taolo ea bokhoba ba tahi. Addict Biol (2013) 18 (1): 161-9.10.1111 / j.1369-1600.2011.00366.x [E fetotsoe] [Ref Ref Cross]
121. Rassnick S, Heinrichs SC, Britton KT, Koob GF. Microinjection ea corticotropin-releasing factor antagonist ho "nucleus" e bohareng ea amygdala e khutlisa litlamorao tse ts'oanang le ethanol. Brain Res (1993) 605 (1): 25-32.10.1016 / 0006-8993 (93) 91352-S [E fetotsoe] [Ref Ref Cross]
122. Rasmussen DD, Mitton DR, Green J, Puchalski S. E sa feleng ethanol le ho tlosa: 2. Liphetoho tsa boitaolo nakong ea ha motho a qeta nako e telele a ikoetlisa Alcohol Clin Exp Res (2001) 25 (7): 999-1005.10.1111 / j.1530-0277.2001.tb02308.x [E fetotsoe] [Ref Ref Cross]
123. Valdez GR, Sabino V, Koob GF. Keketseho e ts'oanang ea boits'oaro bo ts'oanang le boits'oaro ba ethanol ho litsi tse itšetlehileng: ho khutlisoa ka ts'ebetso ea corticotropin-releading factor-2 receptor activation. Alcohol Clin Exp Res (2004) 28 (6): 865-72.10.1097 / 01.ALC.0000128222.29875.40 [E fetotsoe] [Ref Ref Cross]
124. Valdez GR, Zorrilla EP, Roberts AJ, Koob GF. Ho ts'oaroa ha corticotropin-releasing factor ho hlahisa karabelo e ntlafalitsoeng ea khatello ea maikutlo e bonoang nakong ea ho itšunya-tšunya ha ethanol. Alcohol (2003) 29 (2): 55-60.10.1016 / S0741-8329 (03) 00020-X [E fetotsoe] [Ref Ref Cross]
125. Valdez GR, Harshberger E. kappa opioid molaoana oa boits'oaro bo ts'oanang le ho tšoenyeha nakong ea ho khaoha hoa ethanol. Pharmacol Biochem Behav (2012) 102 (1): 44-7.10.1016 / j.pbb.2012.03.019 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
126. Williams AM, Reis DJ, Powell AS, Neira LJ, Nealey KA, Ziegler CE, et al. Litlamorao tsa phallo ea joala ba nakoana kapa kapa "pulsatile heroin" ka linako tse ling le tse mpe tse amanang le mathata nakong ea ho ikhula ho litheko tsa Wistar. Psychopharmacology (2012) 223 (1): 75-88.10.1007 / s00213-012-2691-3 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
127. Kessler RC, Avenevoli S, Costello EJ, Georgiades K, Green JG, Gruber MJ, et al. Bokapele, phehella, le litaba tsa sechaba tsa mathata a DSM-IV tlhahlobisong ea lipatlisiso tsa bongoana ea phetoho. Arch Gen Psychiatry (2012) 69 (4): 372-80.10.1001 / archgenpsychiatry.2011.160 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
128. Barnett K, Mercer SW, Norbury M, Watt G, Wyke S, Guthrie B. Epidemiology ea multimorbidity le meelelo ea tlhokomelo ea bophelo bo botle, lipatlisiso, le thuto ea bongaka: thuto ea sefapano. Lancet (2012) 380 (9836): 37-43.10.1016 / S0140-6736 (12) 60240-2 [E fetotsoe] [Ref Ref Cross]
129. Cerda M, Sagdeo A, Galea S. Comorbid mekhoa ea psychopathology: mekhoa ea bohlokoa le lintlha tsa morao-rao tsa lipatlisiso. Epidemiol Rev (2008) 30: 155-77.10.1093 / epirev / mxn003 [E fetotsoe] [Ref Ref Cross]
130. Kissler JL, Sirohi S, Reis DJ, Jansen HT, Quock RM, Smith DG, et al. Khoele e le 'ngoe ea botaoa ba joala: karolo ea li-amygdala dynorphins tse ka hare / kappa-opioid receptors. Biol Psychiatry (2014) 75 (10): 774-82.10.1016 / j.biopsych.2013.03.014 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
131. Wright JS, Panksepp J. Toward ea mofuta o mong le o mong oa likhathatso tse thehiloeng maemong a sithabetsang: ho tsosa moferefere oa PAG ho lebisa tlhokomelong e ntle ea tšusumetso e ntle literekeng. Neurosci Biobehav Rev (2011) 35 (9): 1902-15.10.1016 / j.neubiorev.2011.08.004 [E fetotsoe] [Ref Ref Cross]
132. Melao-motheo ea Milligan G.: ho eketsa ts'ebeliso ea [35S] GTP gamma S bindning assays. Trends Pharmacol Sci (2003) 24 (2): 87-90.10.1016 / S0165-6147 (02) 00027-5 [E fetotsoe] [Ref Ref Cross]
133. Kang-Park M, Kieffer BL, Roberts AJ, Siggins GR, Moore SD. li-receptor tsa kappa-opioid tse bohareng ba amygdala li laola liketso tsa ethanol libakeng tsa presynaptic GABAergic Sites. J Pharmacol Exp Ther (2013) 346 (1): 130-7.10.1124 / jpet.112.202903 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
134. Kenny PJ, Chen SA, Kitamura O, Markou A, Koob GF. Boemo bo tlosoang bo hulang tšebeliso ea li-heroin mme bo fokotsa tebello ea moputso. J Neurosci (2006) 26 (22): 5894-900.10.1523 / JNEUROSCI.0740-06.2006 [E fetotsoe] [Ref Ref Cross]
135. Gillett K, Harshberger E, Valdez GR. Ho tlosa ho thibetsoeng ho tsoa ho ethanol le khatello ea karabelo e ntlafalitsoeng: Taolo ka tsamaiso ea dynorphin / kappa opioid receptor. Alcohol (2013) 47 (5): 359-65.10.1016 / j.alcohol.2013.05.001 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
136. Goeldner C, Lutz PE, Darcq E, Halter T, Clesse D, Ouagazzal AM, et al. Boitšoaro bo bobebe bo kang maikutlo le ts'ebetso ea serotonergic nakong ea nako e telele ea ho itima lijo morphine o sa foleng. Biol Psychiatry (2011) 69 (3): 236-44.10.1016 / j.biopsych.2010.08.021 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
137. Lutz PE, Reiss D, Ouagazzal AM, Kieffer BL. Nalane ea ho pepesetsoa morphine e sa foleng nakong ea bocha e eketsa boits'oaro bo ts'oanang le ho sithabela ka mokhoa o itšetlehileng ka ho khothaletsa botsoalle ho litoeba tsa batho ba baholo tse sa laoleheng. Behav Brain Res (2013) 243: 44-52.10.1016 / j.bbr.2012.12.049 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
138. Lutz PE, Pradhan AA, Goeldner C, Kieffer BL. Liphetoho tse fapaneng le tse hanyetsanang tsa ts'ebetso ea li-receptor tsa 5-HT (1A) nakong ea ho ikhula morphine e sa foleng. Eur Neuropsychopharmacol (2011) 21 (11): 835-40.10.1016 / j.euroneuro.2011.02.002 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
139. Lutz PE, Ayranci G, Chu-Sin-Chung P, Matifas A, Koebel P, Filliol D, et al. Ho khetholla mu, delta le kappa opioid receptor mekhoa e tlase e nang le botsoalle bo tlase le boits'oaro bo joalo bo sithabetsang nakong ea taolo ea heroin. Neuropsychopharmacology (2014) 39 (11): 2694-705.10.1038 / npp.2014.126 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
140. Belin D, Mar AC, Dalley JW, Robbins TW, Everitt BJ. Ho ts'oaroa ho hoholo ho bolela esale pele phetoho ea ho tsuba koae. Mahlale (2008) 320 (5881): 1352-5.10.1126 / science.1158136 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
141. Deroche-Gamonet V, Belin D, Piazza PV. Bopaki ba boits'oaro bo kang bokhoba ba lithethefatsi ho rat. Mahlale (2004) 305 (5686): 1014-710.1126 / science.1099020 [E fetotsoe] [Ref Ref Cross]
142. Spetea M, Asim MF, Noha S, Wolber G, Schmidhammer H. Hona joale kappa opioid receptor ligands le ho sibolloa ha scaffold e ncha ea molek'hule e le mohanyetsi oa kappa opioid receptor o sebelisang tlhahlobo ea litlatsetso tse thehiloeng ho pharmacophore. Curr Pharm Des (2013) 19 (42): 7362-72.10.2174 / 138161281942140105162601 [E fetotsoe] [Ref Ref Cross]
143. Dean AJ, Bell J, Christie MJ, Mattick RP. Matšoao a sithabetsang nakong ea tlhokomelo ea buprenorphine vs methadone: liphumano tse tsoang ho teko e sa sebetseng, e laoloang ho ts'ebelisong ea opioid. Eur Psychiatry (2004) 19 (8): 510-3.10.1016 / j.eurpsy.2004.09.002 [E fetotsoe] [Ref Ref Cross]
144. Rorick-Kehn LM, Witkin JM, Statnick MA, Eberle EL, McKinzie JH, Kahl SD, et al. LY2456302 ke pale e nyane, e nang le tšusumetso e matla, e nang le bioavaase e nyane molek'hule le ts'ebetso mefuteng ea liphoofolo e nahanang hore e tla sebetsa hantle mokhoeng oa ho ferekanya le mathata a ho lematsa. Neuropharmacology (2014) 77: 131-44.10.1016 / j.neuropharm.2013.09.021 [E fetotsoe] [Ref Ref Cross]
145. Urbano M, Guerrero M, Rosen H, Roberts E. Liphephetso tsa kappa opioid receptor. Bioorg Med Chem Lett (2014) 24 (9): 2021-3210.1016 / j.bmcl.2014.03.040 [E fetotsoe] [Ref Ref Cross]
146. Carroll FI, Carlezon WA, Jr. Nts'etsopele ea bahanyetsi ba kappa opioid receptor. J Med Chem (2013) 56 (6): 2178-95.10.1021 / jm301783x [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
147. Melief EJ, Miyatake M, Carroll FI, Beguin C, Carlezon WA, Jr, Cohen BM, et al. Nako ea ts'ebetso ea mefuta e mengata e fapaneng ea boikhethelo ba kappa-opioid receptor antandon e lumellana hantle le ts'ebetso ea c-Jun N-terminal kinase-1. Mol Pharmacol (2011) 80 (5): 920-9.10.1124 / mol.111.074195 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
148. Melief EJ, Miyatake M, Bruchas MR, Chavkin C. Ligand e tsamaisitsoeng c-Jun N-terminal kinase activation sign opioid receptor signation. Proc Natl Acad Sci USA (2010) 107 (25): 11608-13.10.1073 / pnas.1000751107 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
149. Pradhan AA, Smith ML, Kieffer BL, Evans CJ. Ligand o laetsoeng ke Ligand kahare ho lelapa la opioid receptor. Br J Pharmacol (2012) 167 (5): 960-9.10.1111 / j.1476-5381.2012.02075.x [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
150. Al-Hasani R, Bruchas MR. Mechine ea limolek'hule ea ts'oaetso le boits'oaro ba opioid-based. Anesthesiology (2011) 115 (6): 1363-8110.1097 / ALN.0b013e318238bba6 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
151. Schattauer SS, Miyatake M, Shankar H, Zietz C, Levin JR, Liu-Chen LY, et al. Ligand o laetse liphapang tse bonts'ang lipakeng tsa litoeba le batho ba amohelang kappa-opioid. J Biol Chem (2012) 287 (50): 41595-607.10.1074 / jbc.M112.381368 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
152. Wang SC, Tsou HH, Chung RH, Chang YS, Fang CP, Chen CH, et al. Kopano ea li-polymorphisms tsa liphatsa tsa lefutso ho kappa-opioid receptor 1 gene ka boima ba 'mele, tšebeliso ea joala, le matšoao a ho tlohela ho bakuli ba nang le tlhokomelo ea methadone. J Clin Psychopharmacol (2014) 34 (2): 205-11.10.1097 / JCP.0000000000000082 [E fetotsoe] [Ref Ref Cross]
153. Nielsen DA, Hamon SC, Kosten TR. Mofuta oa kappa-opioid receptor gene e le selelekela sa karabelo tekong ea kalafo ea thibelo ea koae. Psychiatr Genet (2013) 23 (6): 225-32.10.1097 / YPG.0000000000000008 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
154. Gerra G, Somaini L, Leonardi C, Cortese E, Maremmani I, Manfredini M, et al. Kopano lipakeng tsa liphatsa tsa lefutso le karabelo kalafong ea tlhokomelo ea buprenorphine. Psychiatry Res (2014) 215 (1): 202-7.10.1016 / j.psychres.2013.11.001 [E fetotsoe] [Ref Ref Cross]
155. Zheng MQ, Nabulsi N, Kim SJ, Tomasi G, Lin SF, Mitch C, et al. Tlhatlhobo le tlhahlobo ea 11C-LY2795050 e le radiopracer ea kappa-opioid receptor antagonist bakeng sa monahano oa PET. J Nucl Med (2013) 54 (3): 455-63.10.2967 / jnumed.112.109512 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
156. Markou A, Kosten TR, Koob GF. Ho ts'oana ha neurobiological ho khatello ea maikutlo le ts'ebeliso ea lithethefatsi: hypothesis ea ho ikatisa. Neuropsychopharmacology (1998) 18 (3): 135-74.10.1016 / S0893-133X (97) 00113-9 [E fetotsoe] [Ref Ref Cross]
157. Hill MN, Hellemans KG, Verma P, Gorzalka BB, Weinberg J. Neurobiology ea khatello e matla ea maikutlo e ts'oanang: ho ts'oana le khatello e kholo ea maikutlo. Neurosci Biobehav Rev (2012) 36 (9): 2085-117.10.1016 / j.neubiorev.2012.07.001 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
158. Mokhathala o mong oa khatello ea maikutlo oa Willner P. (CMS) o ile a boela a pheta: concordance e ts'oanang le ea boits'oaro litlamorao tsa CMS. Neuropsychobiology (2005) 52 (2): 90-110.10.1159 / 000087097 [E fetotsoe] [Ref Ref Cross]
159. Bambico FR, Belzung C. Novel e utloisisa maikutlo a ho tepella maikutlo le li-antidepressants: tumellano pakeng tsa synaptogeneis le neurogeneis? Curr Top Behav Neurosci (2013) 15: 243-91.10.1007 / 7854_2012_234 [E fetotsoe] [Ref Ref Cross]
160. Papp M, Willner P, Muscat R. Mohlala oa phoofolo ea "anhedonia": tšebeliso ea tšebeliso ea sucrose le maemo a ratang ho khetholloa ke khatello ea maikutlo e sa reroang e sa reroang. Psychopharmacology (1991) 104 (2): 255-9.10.1007 / BF02244188 [E fetotsoe] [Ref Ref Cross]
161. Valverde O, Smadja C, Roques BP, Maldonado R. Phallo ea sebaka se ikhethileng se nang le morphine se latelang khatello ea maikutlo e bobebe e khutlisoa ke mohanyetsi oa CCKB receptor. Psychopharmacology (1997) 131 (1): 79-85.10.1007 / s002130050268 [E fetotsoe] [Ref Ref Cross]
162. Al-Hasani R, McCall JG, Bruchas MR. Ho pepesetsoa khatello ea maikutlo e sa foleng ho thibela Kappa opioid-Mediated mediation ea phepelo ea koae le nicotine. Front Pharmacol (2013) 4: 96.10.3389 / fphar.2013.00096 [Tlhahiso ea mahala ea PMC] [E fetotsoe] [Ref Ref Cross]
163. Lanteri C, Doucet EL, Hernandez Vallejo SJ, Godeheu G, Bobadilla AC, Salomon L, et al. Ho pepesetsoa khafetsa ho MDMA ho baka polasetiki ea nako e telele ea li-neurons tsa li-neradrenergic le serotonergic. Mol Psychiatry (2014) 19 (7): 823-33.10.1038 / mp.2013.97 [E fetotsoe] [Ref Ref Cross]
164. Tassin JP. Ho se kopane pakeng tsa Noradrenergic le serotonergic neuron e le motheo oa liphetoho lipakeng tsa boitšoaro bo khothalletsoang ke lithethefatsi tse khafetsa tsa tlhekefetso. Biochem Pharmacol (2008) 75 (1): 85-97.10.1016 / j.bcp.2007.06.038 [E fetotsoe] [Ref Ref Cross]
165. Pietrzak RH, Naganawa M, Huang Y, Corsi-Travali S, Zheng MQ, Stein MB, et al. Mokhatlo oa ho ba teng ka vivo kappa-opioid receptor le tšobotsi ea transdiagnostic expression of trauma-amanang le psychopathology. JAMA Psychiatry (2014) 71 (11): 1262-70.10.1001 / jamapsychiatry.2014.1221 [E fetotsoe] [Ref Ref Cross]