I-Psychiatry yangaphambili. 2014; 5: 170.
Ishicilelwe kwi-intanethi 2014 Dec 8. ikhonkco: I-10.3389 / fpsyt.2014.00170
PMCID: PMC4258993
Laurence Lalanne,1,2,† Gulebru Ayranci,1,3,† UBrigitte L. Kieffer,3 kwaye Pierre-Eric Lutz3,*
Abstract
I-Comorbidity ngowona mbandela uphambili kwingqondo yengqondo ehambelana ngakumbi neempawu ezinzima, ixesha elide lokugula, kunye nokusetyenziswa kwenkonzo ephezulu. Ke ngoko, ukuchonga amaqela aphambili e-comorbidity kunye nokuhlola iindlela ezisisiseko ze-pathophysiological zimela amanyathelo abalulekileyo ekuphuculeni ukhathalelo lwempilo yengqondo. Kuphononongo lwangoku, sigxile kunxibelelwano oluqhelekileyo phakathi kokulutha kunye nokudakumba. Ngokukodwa, sishwankathela umzimba omkhulu wobungqina obuvela kwiimodeli zangaphambili ezibonisa ukuba i-kappa opioid receptor (KOR), ilungu le-opioid neuromodulatory system, imele umdlali ophakathi kulawulo lweenkqubo zomvuzo kunye neemvakalelo. Idatha yangoku iphakamisa ukuba i-KOR imodareyitha inethiwekhi ye-neuronal edibeneyo edibanisa i-brainstem monoaminergic nuclei kunye ne-forebrain limbic structures. Iipropati ezivuzayo zombini iziyobisi zokusetyenziswa kakubi kunye ne-stimuli yendalo, kunye nemiphumo ye-neurobiological yamava oxinzelelo, isebenzisana kakhulu kwinqanaba le-KOR yokubonisa. Kwiimodeli zokulutha, umsebenzi we-KOR unokwenziwa ngabacinezeli kwaye ulawula ngokungqongqo ukufuna iziyobisi kunye nokubuyela umva. Kwii-paradigms zokudakumba, ukubonakaliswa kwe-KOR kusabela kwiintlobo ezahlukeneyo zoxinzelelo, kwaye idibanisa iimpendulo ezinjengokuphelelwa lithemba. Lilonke, i-KOR imele iprototypical substrate ye-comorbidity, apho amava obomi adibana kwiindlela eziqhelekileyo zobuchopho ukubangela ukungasebenzi kakuhle kokuziphatha kunye nomngcipheko owongeziweyo we-psychopathologies eyahlukileyo kodwa esebenzisanayo.
intshayelelo
Umlutha kunye nokudakumba ziziphazamiso ezingapheliyo eziphinda zibe neziphumo ezibi ebantwini nakwindawo abahlala kuyo (1). Ukuchaneka okungapheliyo kwiziyobisi zokusetyenziswa kakubi, kunye nokuziyeka ixesha elide kula machiza, kunxulunyaniswa ngamandla nemo ephantsi kunye nesimo esibi esichaphazelayo. Ngokuchaseneyo, kwabanye abantu, imo yokudakumba iqhuba ngamandla ukusetyenziswa kwe-euphoric psychoactive substances, inkqubo ebizwa ngokuba kukuzinyanga. Ngokufanelekileyo, izifundo ze-epidemiological zibonise ngokucacileyo ukuhambelana okubonakalayo phakathi kokulutha kunye nokudakumba (2, 3). Esi sifo sihamba kunye nokukhubazeka okukhulu ekusebenzeni, ixesha elide lokugula, ukungabi namandla kwentlalo, kunye nokusetyenziswa okuphezulu kwenkonzo. Ke ngoko, ukuqonda iindlela ze-pathophysiological eziphantsi kwe-comorbidity kuneziphumo ezibalulekileyo zonyango.
Uphononongo lwangoku luya kuxoxa ngemigca yobungqina obuninzi obuqokelelweyo ukuze kubhalwe i-kappa opioid receptor (KOR) njengenxalenye ebalulekileyo ye-comorbidity phakathi komlutha kunye noxinzelelo. I-KOR yeyenkqubo ye-opioid, inkqubo ye-neuromodulatory ebonakaliswa ngokubanzi kwiinkqubo ze-nervous central kunye ne-peripheral. Inkqubo ye-opioid iqulethwe ngama-receptors e-opioid amathathu e-protein edibeneyo ye-G: mu (MOR), i-delta (DOR), kunye ne-kappa (KOR), phantsi kweemeko ze-physiological zisebenze yintsapho ye-peptides engapheliyo ukuze inqanda umsebenzi we-neuronal. Phakathi kweepeptides ze-opioid, iidynorphins (ezifakwe kwi- Pdyn gene) ikakhulu yenza i-KOR kwaye ibenobudlelwane obuphantsi kakhulu be-MOR okanye i-DOR. Ngokwahlukileyo, enye i-opioid peptides (endorphin kunye ne-enkephalins) isebenzisana kakubi ne-KOR. Ngoko ke, indlela yokubonisa i-dynorphin / KOR yenza inkqubo eyahlukileyo ngaphakathi kwenkqubo ye-opioid (4, 5).
I-opioid receptors zilawula ngokuqinileyo iinkqubo ezikhuthazayo, kwaye zichongwa njengabadlali ababalulekileyo kwiziphazamiso zengqondo eziphawulwa kukungasebenzi kakuhle komvuzo, njengokulutha kunye nokudakumba (6, 7). Uphononongo oluninzi olugqibeleleyo lusanda kushwankathela idatha malunga nendima ye-MOR kunye ne-DOR kwezi ngxaki, kwaye iya kukhankanywa ngokufutshane xa kufanelekile (6, 8-11). Injongo yethu kukubonelela umfundi ngembono yembali kunye ne-neuro-anatomical apho, nini, kwaye njani ii-KORs zigaywa njani kwiimodeli ze-rodent zokulutha kunye ne-psychopathology enxulumene noxinzelelo (12-16). Okokuqala, siya kushwankathela indlela i-KOR eyavela ngayo ngokuqhubekayo njengenkqubo echasene nomvuzo efaka i-dysphoria kunye nokunciphisa iimpawu ezikhuthazayo zeziyobisi zokuxhatshazwa. Okwesibini, siya kubonisa ukuba i-KOR iqeshwe kwaye isebenze ngexesha lamava oxinzelelo, ngaloo ndlela igalelo ekuveleni kweemeko ezixinzelelekileyo (10, 17, 18). Okokugqibela, siza kuxoxa ngemiba emibini ephambili yendlela ezi ndima ze-KOR ekuzikhohliseni, izimilo ezinxulumene noxinzelelo kunye noxinzelelo zineziphumo ezibalulekileyo ekuqondeni i-comorbidity. Kwelinye icala, siya kubonisa ukuba ukufunwa koxinzelelo-olunyanzeliswa kukusayinwa kwe-KOR sisisiqalo esinamandla sokufuna iziyobisi kunye nokuziphatha okubuyela umva. Ngakolunye uhlangothi, siya kushwankathela idatha malunga nomsebenzi we-KOR kumxholo othile wokuziphatha okudakumba okuvela ngexesha lokuvezwa okungapheliyo kwiziyobisi zokusetyenziswa kakubi, kunye nangexesha lokuyeka iziyobisi (19-21).
Njengenxalenye ye-pathophysiological ye-comorbidity, i-KOR imele i-pharmacological target ethembisayo (10, 18). Ulingo lwezonyango okwangoku luyaqhubeka nokuvavanya abachasi be-KOR njengonyango loxinzelelo (22), ngokukodwa kumxholo wezigulane ezixhomekeke kwiimeko ezixinzelelekileyo ze-comorbid (23, 24). Ukwakha kwizifundo zeempuku, siya kuxoxa ngamaqhinga anokubakho onyango olujolise kwi-KOR.
I-Kappa Opioid Receptor: I-Anti-Reward, i-Dysphoric System
Umdla kwi-KOR pharmacology ngokwembali usuka kwithemba lokuphuhlisa iikhompawundi ze-analgesic ezingenamandla okuxhatshazwa kwe-MOR agonists, njenge-morphine. Ngelishwa, izifundo zabantu zakuqala eziphonononga iipropathi ze-KOR agonists zixele iziphumo ezinamandla zedysphoric kunye ne-psychomimetic.25, 26). Ngelixa ezi ziphumo zanciphisa ngokucacileyo amandla onyango e-KOR kunyango lweentlungu, baphinde babongoza abaphandi bezonyango ukuba baphonononge ezi ziphumo zedysphoric.
Ukusebenza kwe-MOR kwaziwa ngokubangela ukonwaba emntwini, kunye nokuvelisa ukuqinisa kwimodeli yezilwanyana. Ke ngoko, abaphandi bacingela ukuba i-MOR kunye ne-KOR inokuba neziphumo ezichaseneyo kulawulo lweenkqubo ezikhuthazayo, ngokunokwenzeka ngokumodareyitha kweendlela eziqhelekileyo ze-neuronal. Esi sikhokelo saphononongwa kuqala kusetyenziswa indawo ekhethwayo enemeko (CPP) okanye ukuphepha indawo enemeko (CPA). Kule Pavlovian conditioning paradigm, iyeza lidityaniswa ngokuphindaphindiweyo kunye neseti ye-environmental stimuli eqhubekayo ifumana izinto ezintle (CPP) okanye ezimbi (CPA) ezikhuthazayo. Ukulandela iiseshoni zokulungiswa ngokuphindaphindiweyo, isilwanyana emva koko sibonisa ukhetho okanye ukuphepha ekubonakalisweni kwakhona kwi-stimuli yendalo (ngokungabikho kweyeza), ukuziphatha okuxhomekeke ekufundeni, ekukhuthazeni, kunye neendlela ze-hedonic. Uphononongo lwempuku eseminalini nguShipenberg noHertz (27) ingxelo yokuba, njenge-hypothesized, ulawulo lwenkqubo ye-agonist ye-KOR U69593 okanye i-morphine ivelise iziphumo ezichaseneyo, ngokulandelelanayo ivelisa i-CPA kunye ne-CPP. Ngelixa i-CPP eyenziwa yi-morphine ibonisa iimpawu zayo zokuqinisa, i-CPA eyenziwe yi-KOR iphakamise ukuba le receptor ingaba yindlela yokulwa nomvuzo eyenza igalelo kummiselo we-bi-directional of motivation kunye ne-hedonic tone.
Isinyathelo esilandelayo yayikukuphanda i-substrates ye-neurochemical ephantsi, kunye nezifundo zangaphambili ezihlola indlela i-KOR inokulawula ngayo indlela ye-mesolimbic (Figure). (Figure1) .1). Le ndlela yenziwe nge-dopaminergic (DA) neurons ebekwe kwindawo ye-midbrain ventral tegmental (VTA) kunye neprojekthi ye-forebrain limbic structures, kubandakanya i-ventral striatum [okanye i-nucleus accumbens (NAc)] kunye ne-prefrontal cortex (PFC). Idatha yezilwanyana kunye neyabantu ibonise ngokucacileyo ukuba likhoboka leziyobisi (kunye nokuphazamiseka kweemvakalelo, bona iCandelo 2) linxulumana nokuphazamiseka okukhulu kwengqondo ye-DA yomvuzo wesekethe (28), edla ngokusebenza ukuqikelela kunye nokufaka ikhowudi yokubaluleka kokusingqongileyo kunye nemivuzo yendalo. Ithiyori ngoku yakudala "yobunye" yokulutha ichaza ukuba zonke iziyobisi zokuxhatshazwa ziphucula ukuhanjiswa kwe-DA kwi-NAc, isiphumo esingundoqo kwiipropathi zabo ezinomvuzo (29). Ngaphakathi kwalo mgca, uphando oluninzi luye lwabonisa ukuba iziphumo zokuqinisa i-morphine zixhomekeke kwi-disinhibition, okt, ukusebenza kwee-neurons ze-DA. Olu thintelo lwenzeka ngokusebenza kwe-MOR echazwe yi-GABAergic interneurons ebekwe ikakhulu kumsila we-VTA [tVTA, okanye i-RMTg, jonga kwiRef. (30, 31)], kodwa nakwi-VTA kunye ne-NAc (32). Ngokwahlukileyo koko, ukuncipha kokubonakaliswa kwe-DA kwacingelwa ukuba kunoxanduva lokufakwa kwekhowudi ye-KOR-mediated aversion. Ukusebenzisa i-microdialysis, i-Spanagel kunye nabalingane (33) ibonise ukuba ukukhululwa kwe-DA kwi-NAc kwancitshiswa ngokufakwa kwe-agonist ye-KOR kwi-NAc, kodwa kungekhona kwi-VTA (i-pharmacological agents ezisetyenziswe kuzo zonke izifundo ezixutyushwa kuphononongo lwangoku zishwankathelwa kwiiThebhile. Iitheyibhile11-3). Ukongeza, ukunyuswa komchasi we-KOR (okanye-BNI) kwi-NAc kwandisa ukukhutshwa kwe-DA, ecebisa ukuba i-dynorphins inciphisa ukuhanjiswa kwe-neurotransmission ye-DA kulo mmandla. Obona bungqina bunyanzelisayo bubandakanya i-DA neurons kwi-KOR-induced aversion beza mva nje (12) ukusuka ekusetyenzisweni kweempuku eziguqulwe ngokwemfuza kusetyenziswa inkqubo ye-Cre-lox yokubuyisela kwakhona (34). Bals-Kubik et al. ithathe ithuba lemouse enkqonkqozayo ebonisa i-Cre-recombinase phantsi kolawulo olubhaliweyo lomgqugquzeli ongapheliyo womthuthi weDA [DAT, umakishi othile we-DA neurons.35)]. Ezi mpuku zaye zakhuliswa kunye nenye i-knockin mouse ene-conditional "floxed" ye-KOR allele, ngaloo ndlela ifezekisa ukucinywa okuthe ngqo kwe-KOR kwii-neuron ze-DA (DAT KOR-cKO). Kwinqanaba lokuziphatha, i-KOR-induced CPA yapheliswa kwiimpuku ze-DAT KOR-cKO, kwaye yabuyiselwa kwi-virally mediated KOR-expression kwi-VTA (12).
Ngokunxuseneyo, abaphandi benze uhlalutyo lwengqondo ngokubanzi lwemimandla apho ukuqeshwa kwe-KOR kunokubanakho ukufaka inzondo. Isiphumo sokusebenza kwe-KOR yendawo yavavanywa kwiindawo ezininzi kusetyenziswa i-paradigm ye-CPA (49). Ukunyuswa kwe-agonist ye-KOR i-U50,488H kwi-NAc yayanele ukukhuthaza i-CPA eyomeleleyo, ehambelana nombono wokuba ukusebenza kwe-KOR kulo mmandla kunciphisa ukukhululwa kwe-DA. Okumangalisayo kukuba, i-infusions kwi-PFC, i-lateral hypothalamus, kunye ne-VTA (kodwa kungekhona kwi-substantia nigra kunye ne-dorsal striatum) ibe nemiphumo efanayo, ebonisa ukuba amachibi amaninzi e-KOR anokulawula ukukhuthaza kunye nethoni ye-hedonic. Ezi ziphumo zikwabonisa ukuba ukusebenza kwe-VTA KOR kubangela i-CPA ngokungabikho naluphi na utshintsho ekukhutshweni kwe-NAc DA [jonga idatha ye-neurochemical ekhankanywe ngasentla.33)], okuthetha ukubandakanyeka komnye ummandla wobuchopho ofumana i-DA innervation (oko kukuthi, i-PFC, jonga ngezantsi). Ukongeza kulawulo losasazo lwe-DA, ukubonakaliswa kwe-KOR kunye nomsebenzi ngoku kuphantsi kophando kwezinye iindawo zobuchopho kusetyenziswa iimvavanyo zeempuku ezifanelekileyo kumvuzo kunye nomoya [umzekelo, i-nucleus yebhedi ye-stria terminalis, i-BNST, i-amygdala, i-locus coeruleus (LC), bona ngezantsi].
Injongo elandelayo ebalulekileyo yayikukubona ukuba zeziphi iintlobo zeeseli ze-neuronal ezilawulwa yi-KOR. Iindlela ze-electronic microscopy (50, 51) yafumanisa ukuba kwi-NAc, isiqingatha se-axons esasiyi-KOR-immunoreactive siphinde sibonise i-DAT. Okubangela umdla kukuba, olu phononongo lufumanise ukuba phantse isinye kwisithathu (29%) sezi KOR-immunoreactive axons zaziyi-DAT-negative kodwa zaqhagamshelana ne-pre-synaptic terminals ye-DAT-positive neurons, ecebisa ukuba indlela ye-mesolimbic ilawulwa kwinqanaba le-NAc ngo. i-neurons edibeneyo ebonisa i-KOR. Ngokusekelwe kubungqina bamva nje (16), kunokwenzeka ukuba i-non-DAergic KOR-positive neurons, ubuncinane inxalenye, i-serotonergic (5-HT). Ngokunokwenzeka, ii-KORs ezichazwe yi-5-HT neurons zinokulamla i-DA/5-HT crosstalk kwi-NAc, kwaye imele indlela enegalelo kunxibelelwano phakathi kweemvakalelo kunye nomvuzo, kunye naphakathi kokulutha kunye nokudakumba (jonga ngezantsi). Kwinqanaba le-NAc (52), kukho ubungqina bokuguqulwa kokuxhomekeka kwe-KOR yokukhululwa kwe-glutamate, ebonisa ukuba le receptor inokubonakaliswa kwangaphambili nge-synaptically yi-glutamatergic cortical neurons egxininisekileyo i-NAc. Kulwazi lwethu, ukufaneleka kokuziphatha kwephuli yamva ye-KOR ayikaqwalaselwa. Ekugqibeleni, kwiPFC (53), i-KOR yayibekwe ikakhulu kwi-pre-synaptic terminals, mhlawumbi ihambelana negalelo le-DAergic, nangona i-neurochemical identity yale neurons ayizange ihlolwe.
Abanye abaphandi basebenzisa i-electrophysiology kunye ne-immunohistochemistry ukuchonga i-KOR-expressing neurons. Ukusetyenziswa kwe-agonist ekhethiweyo ye-KOR kwi-VTA yehla umsebenzi ozenzekelayo wokudubula weqela elincinci le-neurons (54). Le inhibition ye-KOR-mediated yenzeke kuphela kwiiseli ze-DA, njengoko kuboniswa yi-immunoreactivity ye-tyrosine hydroxylase (izinga lokunciphisa i-enzyme ye-DA synthesis, kunye nenye i-marker ye-DA neurons). I-Electrophysiology, i-retrograde tracing kunye ne-microdialysis ziye zadityaniswa ukuze kuhlolwe ukuba ngaba i-DA neurons eprojekthi i-NAc okanye kwi-PFC ilawulwa ngokwahlukileyo yi-KOR (55). Olu vavanyo luhle lubonakalise ukuba ukusebenza kwe-KOR yendawo kwi-VTA i-hyperpolarized PFC-ejolise kwi-DA neurons, kodwa ayizange ibe nefuthe kwi-NAc-thageting DA neurons. Ngokufanelekileyo, ukukhutshwa kwe-DA kwancitshiswa kwi-PFC, kodwa hayi kwi-NAc, ekusebenzeni kweVTA KOR.
Ngokubanzi ezi ziphumo ziyahambelana ne-CPA yangaphambili kunye nezifundo ze-microdialysis, kwaye zicebisa imodeli apho ii-VTA KORs zingalawuli ithoni ye-DA ye-NAc kodwa endaweni yoko zimodareyitha ukukhutshwa kwe-DA kwi-PFC ukuvelisa i-CPA. Iimpuku ezichazwe ngaphambili ze-DAT KOR-cKO kutshanje zinike ubungqina obuqinileyo be-hypothesis yokugqibela. Tejeda et al. ufumanise ukuba ukufakwa kwe-agonist ye-KOR kwi-PFC yehlise ukuphuphuma kwe-DA kwi-wildtype (WT) kodwa hayi kwi-DAT KOR-cKO iimpuku (13), eqinisekisa ulawulo olulawulwa yi-KOR losasazo lwe-DA kwi-PFC. Okubalulekileyo, ababhali ke bavavanya ngokuthe ngqo ukufaneleka kokuziphatha kwePFC KORs kwi-dysphoria kwiimpuku. Ukufakwa komchasi we-KOR kwi-PFC kwakwanele ukukhusela i-KOR ye-agonist-induced CPA, ukuchonga ngokucacileyo i-limbic cortex njenge-substrate efunekayo kule mpembelelo yokuziphatha.
Ngokudibeneyo, iziphumo ezivela kwezi ndlela zahlukeneyo zeendlela zikwacebisa ukuba i-NAc-projecting DA neurons ichaza i-KOR kwii-terminal pre-synaptic, kodwa hayi kwi-soma kunye ne-dendrites (33), ngelixa i-PFC-iprojekthi ye-DA neurons ibonisa i-KOR kuwo omabini amacandelo (13, 54, 55) (Umzobo (Figure1) .1). Kwinqanaba leemolekyuli, okwangoku ayaziwa ukuba i-DA neurons inokulawula njani ukuthengiswa kwe-KOR ukuya kumacandelo ahlukeneyo eeselula njengomsebenzi wokujolisa ekujoliswe kuko. Siqikelela ukuba uhlobo lwengxelo ye-electrophysiological (uchulumanco olusuka kwi-cortex, inhibitory ukusuka kwi-striatal medium spiny neurons) enikezelwe kwi-VTA ngummandla ngamnye inokuchaphazeleka. Kungenjalo, iinkqubo zokuzimela kweeseli zinokubandakanyeka, kunye neeprofayili ezibhalwe ngokucacileyo kwi-NAc- kunye ne-PFC-iprojekthi ye-DA neurons ekhokelela kuhlengahlengiso olwahlukileyo lwe-KOR emva koguqulo kunye nokurhweba. Ukuzama ukulungisa le ngqikelelo yamva, inkqubela phambili yetekhnoloji ngoku ivumela abaphandi ukuba bahlule iitranscriptomes ezivela kubantu be-neuronal ababelana ngendawo eqhelekileyo yomzimba kodwa ngoqikelelo olwahlukileyo (56). Kungenjalo, ukulandelela ukubuyisela umva kunokudityaniswa neempuku ze-knockin reporter ezibonisa i-opioid receptors ngokudityaniswa neeprotein ze-fluorescent [ezo mpuku zikhoyo ngoku kwi-mu kunye ne-delta, kodwa hayi i-kappa, i-opioid receptors (57, 58)].
Umsebenzi wendlela ye-dynorphin/KOR kwi-DA neurotransmission nakwi-CPA ineempembelelo ezicacileyo zokuziphatha okunxulumene nokukhotyokiswa, njengoko kuqwalaselwe iintlobo ngeentlobo zeziyobisi zokuxhatshazwa kwiiparadigms zokuzilawula [jonga kwiRef. (59) kuphononongo olupheleleyo]. I-KOR i-agonists i-dose ixhomekeke ekunciphiseni ukuzilawula kwe-morphine kwiimpuku kunye neempuku (60, 61). Iziphumo ezifanayo zokuthintela ukusebenza kwe-KOR zifunyenwe kwi-ethanol (62-64), icocaine (61, 65-68, i-nicotine (69) kunye ne-cannabis (70), kwaye ezi zazinxulunyaniswa nokukhutshwa kwe-DA okuncitshisiweyo kweziyobisi (umzekelo, icocaine, jonga kwiRef.71); ethanol, jonga kwiNgxelo. (72)). Ehlabathini jikelele, ezi ziphumo zibonelela ngobungqina obuqinileyo besiphumo sokuthintela i-KOR kwiziphumo ezivuzayo zeziyobisi zokusetyenziswa kakubi, kwaye iziphumo zamva nje zibonisa ukuba imbuyekezo yendalo, efana nokunxibelelana kwezentlalo, inokuchaphazeleka. Kwi-prairie voles, uhlobo lweempuku ezihlala ngumfazi omnye, ukugcinwa kwezibini ezikhwelanayo kuxhomekeke ekubonakalisweni kokuziphatha okundlongondlongo ngokubhekiselele kwizinto zenoveli. Okubangel 'umdla kukuba, olu hlobo "lokuchaswa koluntu" lubonakaliswe ukuba lulamlwa ngumqondiso we-KOR ngaphakathi kwe-NAc (73). Kwiimpuku, umdlalo wentlalo umele indlela yokuziphatha efundwe kakhulu, eyenzeke ngokwendalo ethi ifune ii-neurons ze-DA kwaye ibangele ukomelezwa okunamandla. Ukusebenza okucwangcisiweyo kwe-KOR kwehle umdlalo wentlalo kuzo zombini iimpuku (74, 75) kunye neempuku (76). Ezi ziphumo zibalulekile ekuqondeni kwethu ukudakumba emntwini njenge-anhedonia, okanye imbono etshintshileyo yeempawu ezinomvuzo wobomi bemihla ngemihla (kubandakanywa nokusebenzisana kwezentlalo), luphawu lwale meko. Ke ngoko, ngelixa ukumodareyitha okuxhomekeke kwi-KOR kwe-DA kunye nomvuzo kwaqalwa kwacingwa kwaye kuphononongwa kwiiparadigms zokulutha, ngoku kuyacaca ukuba kukwaneziphumo ezinamandla zokuphazamiseka kweemvakalelo.17, 18). I-CPA ibonisa intsebenziswano yeendlela ezininzi ze-neurobiological, ezihambelana nolwakhiwo lwezengqondo ezintathu: ukufunda, ukukhuthaza, kunye ne-hedonia. I-Intra-cranial self-stimulation (ICSS) yenye iparadigm evavanya le miba mithathu: kule meko isebenzayo, izilwanyana zifunda ukuzilawula ngokwazo ii-pulses zombane ezimfutshane kwimimandla ethile yobuchopho (ngokuqhelekileyo i-medial forebrain bundle)77)). Ukusebenza okucwangcisiweyo kwe-KOR kwafunyaniswa ukuba kuphembelele imeko efana ne-anhedonic kwi-ICSS, njengoko kubonisiwe kukunyuka komda wokuvuselela (78). Kulo msebenzi wokugqibela, i-electrode yokuvuselela ifakwe kwi-hypothalamus esecaleni, ukomeleza ubungqina obudlulileyo bokulawulwa kwe-KOR exhomekeke kwi-hedonic eyenzeka ngaphandle kwe-NAc (49). Ngapha koko, uPotter et al wafunda i-kinetics ye-KOR agonist-induced ICSS modulation kulandela iinaliti ezibukhali neziphindaphindiweyo (79). I-agonist ye-KOR i-Salvinorin-A yandisa umda wokuvuselela, kwaye le mpembelelo enzima iqhubekile kunye ne-injection yemihla ngemihla kwixesha le-8. Okubangela umdla kukuba, iinaliti eziphindaphindiweyo zibangele ukulibaziseka kunye neziphumo ezichaseneyo, njengoko kungqinwa kukuncipha komda wokuvuselela we-ICSS we-24 h emva kokutofa, ebonisa ukuba iinkqubo zeqela elichasayo.80, 81) yaphuhliswa.
Indlela ye-neuronal enokuthi idibanise umsebenzi we-hypothalamic KOR kunye nokudluliselwa kwe-DA kunye nomvuzo awufundwanga kakuhle. Idatha entle yamva nje isebenzisa i-electron microscopy, i-electrophysiology, i-ICSS, kunye nolawulo lwe-cocaine (47, 48), cebisa ukudibana okuchasayo phakathi kwe-orexin kunye ne-dynorphin peptidergic systems. Inkqubo ye-hypocretin/orexin yenziwe ngemithambo-luvo evela kwi-hypothalamus esecaleni kwaye ijonge kwizakhiwo ezininzi ze-mesolimbic.82). Okubalulekileyo, i-orexin kunye ne-dynorphin zifunyenwe zisebenza njenge-co-transmitters kwi-neurons ye-hypothalamus.47): ezi peptides zimbini zidibana kwindawo ethile kwi-synaptic vesicles, kwaye zikhutshiwe kuvuselelo lombane lwe-hypothalamic. Ababhali baphinda babonisa ukuba i-orexin kunye ne-dynorphin zisebenza ngaphakathi kwe-VTA ukuvuselela kunye nokuthintela, ngokulandelelana, ukomelela kwe-neuron ze-DA, ngaloo ndlela kuhlengahlengiswa umvuzo (kwimifuniselo ye-ICSS), kunye nokuzilawula kwe-cocaine (kunye nezinye iziyobisi ezinokubakho zokuxhatshazwa. ). Kwi-VTA, iiseli ezininzi (i-65%) zifunyenwe njengeethagethi eziqhelekileyo zombini i-orexin kunye ne-dynorphin. Ngokusekwe kubungqina bangaphambili, iimvavanyo zexesha elizayo zinokuvavanya i-hypothesis yokuba i-VTA DA neurons echaza zombini iprojekthi ye-KOR kunye ne-orexin receptors ngokukhethayo kwi-PFC kune-NAc.
Ngokubanzi, idatha yomsebenzi we-KOR kulawulo lomvuzo iqaqambisa ukubaluleka kokuvavanya i-spectrum epheleleyo yeepeptides kunye nee-neurotransmitters ezichazwe ecaleni kwendlela ye-mesolimbic kunye neesekethe ezinxulumene ne-neuronal. Ukumisela ukuba le nethiwekhi iguquka njani phantsi kweemeko ezingapheliyo ze-pathologic iya kuba ngumzamo onomdla.
I-Kappa Opioid Receptor: Inkqubo yoxinzelelo echaphazelekayo kwiPathophysiology yoxinzelelo
Ngokunxuseneyo nezi zifundo ngomvuzo, idatha yamva nje ibonise ukuba i-KOR ikwalawula iimpendulo zeemvakalelo, ngakumbi ngexesha loxinzelelo. Uphononongo lwe-Pharmacological kwiimpuku lubonisa ukuba inkqubo ye-dynorphin/KOR ilawula ukuziphatha okunxulumene nemo. Kwiigundane, ulawulo lwenkqubo ye-KOR agonists kunye nabachasi babonisa i-pro- kunye ne-antidepressant-like effects, ngokulandelanayo, kwi-swim enyanzeliswayo (FS) kunye neemvavanyo ezingenakunceda (LH) [jonga kwi-Ref. (10, 41-45) kuphononongo]. Ngokuhambelana nezifundo ze-CPA, ukusebenza kwenkqubo ye-KOR kunciphisa ukukhutshwa kwe-DA kwi-ventral (44, 83), umqolo (84, 85), kunye nemimandla ye-striatal, ngelixa inaliti ye-NAc yendawo ye-agonist ye-KOR ilingisa impembelelo efana ne-prodepressant yonyango lwenkqubo (86). Ezi datha ziqinisekisa kwakhona ukuba ukumodareyitha okuxhomekeke kwi-KOR kwe-DA kubandakanyeka kuzo zombini iimo kunye nokuziphatha okunxulumene nokulutha.28). Okubangela umdla kukuba, iziphumo ezixhomekeke kwi-KOR-ezifana ne-prodepressant-zinokuguqulwa ngokwesini (87), inkalo ebalulekileyo eqwalasela ukuba ukuxhaphaka kokudakumba kuphezulu kwabasetyhini. Besebenzisa i-ICSS, ababhali bafumanise ukuba ukonyuka kwe-KOR agonist-induced ku-ICSS stimulation threshold yayiphezulu kwindoda kuneempuku zabasetyhini. Esi siphumo sasizimele kumanqanaba ajikelezayo ehomoni ye-gonadal, kwaye ayizange ibalwe ngokwahlukana ngokwesondo kwi-pharmacokinetics ye-agonist. Kunoko, ukungafani kwezesondo kwi-KOR agonist-induced neuronal activation, njengoko kutyhilwa yi-c-fos staining, yafunyanwa kwi-BNST kunye ne-PVN, kodwa kungekhona kwi-NAc okanye i-amygdala. Ngoko ke, ukongeza kwindlela ye-mesolimbic, ukulawulwa kwe-KOR-exhomekeke kwisini kwi-hedonic tone inokuthi yenzeke kwinqanaba le-BNST kunye ne-PVN, izakhiwo ezimbini ezilawula uxinzelelo-impendulo kunye neemvakalelo.
Ukongeza kwizifundo zamachiza ezijolise kwi-KOR, kukho ubungqina bokuba iidynorphins zibonelela ngolawulo lwetonic engapheliyo yeempawu ezinxulumene neemvakalelo (43, 88). Kwi-NAc, i-spiny neurons ephakathi ebonisa i-DA D1-receptor iyaziwa ngokudibanisa kunye nokukhulula iidynorphins phantsi kolawulo lwe-cAMP impendulo ye-protein ebophezelayo (CREB). Ngokufanelekileyo, amanqanaba eprodynorphin aye ancipha kwi-NAc yeempuku ze-transgenic overexpressing eyona ndlela imbi ye-CREB. Esi siphumo sasinxulumene nokuncipha kokuziphatha kokuphelelwa lithemba kwi-paradigm ye-LH. Ngokungaguquguqukiyo, uhlolisiso lwakutshanje luye lwanikela ingxelo yoko Pdyn ukuwisa (ngentetho yentsholongwane kwi-NAc ye-anti-Pdyn I-hairpin emfutshane i-RNA) iyancipha ukuziphatha okudakumba kuvavanyo lwe-FS (46).
Ngaphandle kweempendulo zomzwelo ezisisiseko, idatha ibonisa ukuba umsebenzi we-dynorphin / KOR inkqubo inokwenziwa ngoxinzelelo. Uxinzelelo olubukhali, kodwa olungagungqiyo, lubonakaliswe ukwazisa i-CPA exhomekeke kwi-KOR (89). Kwakhona, ukubonakaliswa okuphindaphindiweyo kuxinzelelo lwe-FS kuvelisa impembelelo efana ne-prodepressant eyayivaliwe ngumchasi we-KOR nor-BNI, kwaye wayengekho Pdyn Iimpuku ze-KO (90). I-Dynorphins yaphinda yaboniswa ukuba imodareyithe imeko ephindaphindiweyo yoxinzelelo oluxhomekeke kuxinzelelo (37). Iimpuku eziqeqeshelwe ukudibanisa ivumba elinikiweyo kunye noxinzelelo lweFS zaliphepha ngamandla elo vumba. Le ndlela yokuziphatha yokuphepha ayizange ibonwe kwi Pdyn I-KO iimpuku, kwaye yavalwa kwiimpuku ze-WT ngonyango lwangaphambili kunye nomchasi we-KOR. Ngokufanayo, umxholo odityaniswe ngokuphindaphindiweyo nokushukuma kweenyawo wawuchasene neempuku ze-WT; kodwa kwakhona, esi siphumo sasingekho Pdyn Iimpuku ze-KO, kwaye zithintelwe ngumchasi we-KOR kunyango lwangaphambili. Okubalulekileyo, ababhali babonise ukuba ukukhutshwa kwe-corticotropin ekhuphayo (CRF) kwinkqubo ye-nervous central kusenokwenzeka ukuba sesona siganeko siphambili esijongene noxinzelelo-olunyanzeliswa ukuqesha inkqubo ye-dynorphin / KOR. Iziphumo zibonise ukuba inaliti yenkqubo yeCRF yabangela i-KOR phosphorylation, njengoko kutyhilwe kusetyenziswa i-antibody ye-phospho-KOR. Ngaphaya koko, i-CPA ebangelwa luxinzelelo (ilinganiswe yinaliti ye-systemic okanye ye-intracerebroventricular yeCRF okanye iCRF2-receptor agonist Urocortin III) wayengekho kwi Pdyn KO iimpuku, kwaye ivinjwe nor-BNI pre-unyango. Ukulandela ukuvezwa koxinzelelo, ukusebenza kwe-KOR, kunye ne-phosphorylation ichongiwe kwizakhiwo ezininzi zobuchopho, kubandakanya i-amygdala ye-basolateral, i-hippocampus, i-dorsal raphe, i-VTA, kunye ne-NAc. Lilonke, ezi datha zibonisa ukuba imiba yedysphoric yoxinzelelo ibonakaliswa ngokubonakalayo xa iCRF ivuselela ukukhutshwa kwedynorphin, ivelisa ukusebenza kwe-KOR (37).
Uxinzelelo yinkqubo yefiziyoloji entsonkothileyo enexabiso eliguqukayo, kodwa enokuthi iqalise iziganeko ze-pathological ngexesha loxinzelelo olude kunye noxinzelelo olugqithisileyo. Kutshanje, ukusebenzisana phakathi koxinzelelo kunye ne-KOR kuye kwaphandwa kusetyenziswa imodeli entsonkothileyo kunye ne-ethologically efanelekileyo yokudakumba. Ngokwendalo, ukujongana ngezikhondo zamehlo phakathi kwezilwanyana ezikhethekileyo kunokubangela iziphumo ezibalulekileyo malunga nolawulo lwemithombo, ukufikelela kumaqabane, kunye nezikhundla ekuhlaleni. Umzekelo, umhlali-umngeneleli wokoyiswa kwentlalontle iparadigm (91) imodeli yendalo ebonakaliswe ngobudlelwane obunamandla obungalindelekanga kwaye obungenakuphepheka, ngaloo ndlela ibangela iimpawu ezifana ne-anhedonia ezifana nokunciphisa ukuthanda ngokwesondo kunye nokunciphisa ukhetho lwe-sucrose (52). UMcLaughlin kunye noogxa baba ngabokuqala ukuveza indima ye-dynorphins kunye ne-KOR ekutshintsheni imiphumo yoxinzelelo lwentlalo (92). Iigundane ezivezwe ngokuphindaphindiweyo kwintlalontle ngaphezu kweentsuku ze-3 zibonise uphawu lokutshatyalaliswa kwempendulo ye-postural, kunye nokunyuka kwe-nociceptive threshold, okanye i-analgesia ebangelwa uxinzelelo (i-SIA, ebonwe kwi-assay yokurhoxiswa komsila). Yomibini le miba ithintelwe kwiimpuku eziphathwe ngaphambili kunye nomchasi we-KOR, okanye ezingenayo Pdyn ufuzo. Olunye uphawu olubalulekileyo lwemodeli yokoyiswa kwezentlalo kukuba iziphumo zalo zibonisa ukuhluka okuphezulu phakathi kwabantu, zombini kwiimpuku kunye naphakathi kweempuku ezizalwayo, kangangokuba izilwanyana zinokwahlulwa ngokwesiqhelo zibe ngamaqela anokuchaphazeleka kunye nokomelela (93). Ngalo mgca, ngokutsho kukaBérubé et al. (94), amanqanaba okubonakaliswa kwee-dynorphins kwi-NAc ahluka phakathi kweempuku ze-Sprague-Dawley ezibuthathaka kunye nezomelele. Ukunyuka kwamanqanaba e-dynorphin mRNA (elinganiswe yi-qPCR) afunyenwe kwi-ventral striatum yeempuku ezithintekayo (iqokobhe le-NAc, lihambelana nedatha yeempuku zangaphambili), ngelixa amanqanaba anyukayo ngokumangalisayo abonwa kwi-dorsal striatum yabantu abangaguqukiyo, ecebisa ukuba ukulawulwa kwe-DA kunye imo ye-dynorphin kunye ne-KOR inokuba nzima kunokuba bekulindelwe. Izifundo ezongezelelweyo ziya kuba yimfuneko ukuqhubela phambili ukuxhasa le ngcamango. Ngokwahlukileyo, olunye uphononongo luchaze ukuba akukho tshintsho kumanqanaba e-dynorphin kwi-VTA okanye i-NAc yeegundane ezoyisiweyo eluntwini ze-Long-Evans.95). Ukungavisisani phakathi kwezi zifundo zibini kunokuchazwa ziintlobo ezahlukeneyo ezisetyenzisiweyo, okanye ukungabikho komahluko phakathi kweempuku ezinokomelela kunye nezichaphazeleka kwi-Long-Evans kuphononongo lwamva. Inqaku, uNocjar et al. (95) ifumene i-dynorphin-A eyanciphayo, kunye ne-orexins eyanciphayo A kunye ne-B, kwi-hypothalamus yeegundane ezoyisiweyo. Ke ngoko, umgaqo odityanisiweyo womsebenzi we-VTA DA neurons zezi peptides zimbini zichaseneyo zinokulamla ukoyiswa-okuxhomekeke kwi-KOR-exhomekeke kwintlalontle, kwaye kube nokwenzakala kulandela ukoyiswa eluntwini.
Siye saxoxa ngaphambili (iCandelo loku-1) ukuba i-KOR inokubonisa njani ukwahlulahlula kweeseli zasekuhlaleni kuzo zonke iindawo ezimbini ze-VTA DA neurons ezijonge kwi-NAc okanye kwi-PFC. Ingxelo yakutshanje ibonisa ukuba oku kuchithwa kwe-anatomical kunokuba nokubaluleka ekuqondeni imiphumo yokutshatyalaliswa okungapheliyo kwentlalo. Chaudhury kunye nabalingane (96) ibonise ukuba ukuvinjelwa okukhethiweyo kwe-VTA DA neurons ejoliswe kwi-NAc okanye kwi-PFC, ngokulandelanayo, ikhuthaze ukomelela okanye ukuba sengozini yokutshatyalaliswa ngokuphindaphindiweyo kwentlalo. Ngenxa yokukhethwa kwendawo yeselula, kuyahenda ukucinga ukuba i-KOR inokulamla iimpawu ezinjenge-prodepressant ezibangelwa kukuvinjelwa kwendlela ye-VTA-PFC ye-DA.
Ukongeza kwisignali ye-DAergic, iziphumo ezitsha zibonisa ukuba ukuhanjiswa kwe-5-HT kunokuthi kumodareyithwe yi-KOR kuxinzelelo- kunye neemodeli ezisekelwe entlalweni zokudakumba. Imifuniselo ye-Electrophysiology (97, 98) ekuqaleni kubonise ukuba i-KOR ilawula i-5-HT neurons kwinqanaba le-dorsal raphe nucleus (DRN), eyona nto iphambili ye-5-HT yengqondo. Okubalulekileyo, iimvavanyo zokuhlangula zibonise ukuba ukubonakaliswa kwakhona okukhethiweyo kwe-KOR kwi-DRN ye-KOR KO iigundane kwanele ukubuyisela i-CPA eyenziwa ngokuxiliswa kwe-agonist ye-KOR kwi-NAc (38). Ngokudibeneyo neziphumo zangaphambili, ezi ziphumo zibonisa ukuba i-KOR kwi-PFC, kunye ne-KOR echazwe yi-neurons ekhoyo kwi-DRN, ejolise kwi-NAc (enokuthi ibe yi-5-HT neurons), iyimfuneko kwaye yanele, ngokulandelanayo, kwintetho. ye-KOR agonist-induced aversion. Kwinqanaba leemolekyuli, ukoyiswa kwentlalontle kwaboniswa ukuba kuqalise i-phosphorylation ye-KOR kunye ne-p38α kinase kwi-DRN (14). Ukuqeshwa kwe-p38α kwi-5-HT neurons kubalulekile, njengoko ukuphepha okubangelwa ukoyiswa kwentlalo kwapheliswa kwiigundane ze-cKO apho i-p38α isuswe ngokukodwa kwi-serotonin transporter (SERT) -i-neurons ebonisayo (p38α-cKOI-SERT). I-phosphorylated p38α yona ikhuthaza ukuhanjiswa kwe-SERT kwi-membrane yeplasma, ngaloo ndlela inyusa i-5-HT yokuphinda ithathelwe ingqalelo kunye nokuthintela ukuphepha kwentlalo. Ukurekhoda kwe-Electrophysiological kwizilayi zobuchopho (40) Kwakhona kubonise ukuba ukusebenza kwe-KOR kunciphisa i-excitability ye-DRN 5-HT neurons ngeendlela ezimbini: i-pre-synaptic inhibition ye-glutamatergic inputs, kunye ne-post-synaptic stimulation ye-G-protein-gated inwardly rectifying channels potassium (GIRKs). Ukubonakaliswa okuphindaphindiweyo kuxinzelelo lwe-FS kuphazamisa i-post-synaptic, kodwa kungekhona i-pre-synaptic, iziphumo zokuvula i-KOR. Okubalulekileyo, inhibition ebangelwa uxinzelelo lwe-KOR-mediated GIRK currents yapheliswa kwi-p38α-cKO.I-SERT iimpuku. Ekugqibeleni, ubungqina bakutshanje bubonisa ukuba ukulawulwa kwe-KOR ye-DA kunye ne-5-HT neurons inokuguqulwa kwinqanaba le-NAc ukuvelisa i-dysphoric kunye ne-depressive-like effects. Uxinzelelo oluphindaphindiweyo lwe-FS lunyusile ngokukhetha ukubonakaliswa komphezulu weseli ye-SERT kwi-ventral striatum, kodwa hayi kweminye imimandla evavanyiweyo (i-dorsal striatum, i-hippocampus, i-PFC, i-amygdala, okanye i-DRN). Le mpembelelo yoxinzelelo kwi-SERT yathintelwa yi-pharmacological blockade ye-KOR yokubonisa kwi-NAc, kodwa kungekhona kwi-DRN (16). Ewonke, amava acinezelayo abonakala efumana i-CRF-dynorhin-KOR-p38α-GIRK yokubonisa i-cascade ngaphakathi kwe-DRN 5-HT neurons, kunye nokusebenza kwe-KOR kwi-NAc. Olu hlengahlengiso lwemolekyuli lukhokelela kulawulo oluphezulu lwe-SERT kwi-NAc, kwaye ekugqibeleni luchaphazela umsebenzi we-DA ukuvelisa iimpawu zokuziphatha. Ingaba ukubonakaliswa okufanayo kwe-DRN kukwabandakanyeka kwiintsilelo ezinxulumene nemvakalelo yexesha elide, ngakumbi kumxholo wokuvezwa okungapheliyo kwiziyobisi zokusetyenziswa kakubi (Icandelo 3), akukacaciswa.
Ukongeza kwiisekethe ze-5-HT kunye ne-DA, ezinye iindawo ezinokubakho zokulawulwa kwemood exhomekeke kwi-KOR ngokukodwa ziquka i-hippocampal neurogenesis kunye nokuhanjiswa kwe-noradrenergic (NA). Enye ingxelo yafumanisa ukuba kwiimpuku, i-antidepressant-efana nefuthe lomchasi we-KOR nor-BNI (99) ezinxulumene ne-hippocampus, kunye nakwezinye izakhiwo (umzekelo, i-cortex yangaphambili, i-amygdala, i-hippocampus, kunye ne-endopiriform cortex), kunye namanqanaba okwanda kwe-mRNA ye-BDNF, i-neurotrophic factor controlling synaptic plasticity kunye neurogenesis. Uphononongo olongezelelweyo luyafuneka ukuze uqonde ngcono ukufaneleka kolu nxibelelwano lwe-KOR/BDNF.
I-Kappa Opioid Receptor kwi-Interface of Depression and Addiction
Siye sashwankathela indima ye-KOR kulawulo lweenkqubo zomvuzo (Icandelo 1), kunye nokumodareyitha kweempendulo zoxinzelelo kunye namazwe achaphazelekayo (Icandelo 2). Ngokusekwe kule datha, amaqela aliqela asandula ukuphonononga ukuba i-KOR inokulamla njani unxibelelwano phakathi kokulutha kunye nokudakumba. Ubudlelwane phakathi kwezi ziphazamiso zimbini bunokuba bu-bi-directional: abakhobokileyo babonisa umngcipheko oqinileyo wobomi boxinzelelo okanye ukudakumba, ngelixa, ngokuchaseneyo, izigulana ezidakumbileyo zihlala zisebenzisa iziyobisi ukuze zizenzele ngokwazo iimpawu zoxinzelelo. Yomibini le miba ngoku iyaqwalaselwa kwimizekelo yezilwanyana.
Ukukhathazeka koxinzelelo, ukuphinda ubuyele, kunye nokuvela kweempawu zokudakumba kubantu abakhobokileyo
Ukuphinda-phinda okubangelwa luxinzelelo ngexesha lokukhobokisa
Iimodeli ze-rodent ze-CPP kunye nokuzilawula kweziyobisi zisetyenziswe kakhulu ukuphanda izinto ezahlukeneyo ezibangela ukuphinda ubuyele, okanye ukuqaliswa kwakhona kokuziphatha kokufuna iziyobisi. Ukulandela ixesha le-conditioning ephindaphindiweyo, okanye ukuzilawula kweziyobisi ngokuzinzile, izilwanyana ziphinda zibonakaliswe kwi-CPP okanye kumagumbi asebenzayo ngokungabikho kweziyobisi, ukwenzela ukuba ukufuna iziyobisi kunye nokuphendula kwezixhobo kungasayi kuqiniswa kwaye kunyamalale ngokuqhubekayo, inkqubo ebhekiswayo. njengokuphela. Okubalulekileyo, emva kokuba ukutshabalala kuphunyeziwe, ukubuyiswa kwakhona kunokuvuswa ngokuphinda kubonakaliswe (okt, "priming") kwiziyobisi zokusetyenziswa kakubi (ukubuyiselwa okubangelwa yiziyobisi), okanye ngokuvezwa kwi-stressor ebukhali (ukubuyisela uxinzelelo olubangelwa uxinzelelo). Ngokwesiqhelo, amava acinezelayo amele izinto ezinkulu zomngcipheko wobomi bokuvela koxinzelelo (100) kwaye uyakhobokisa (101) iingxaki. Ukongezelela, iziyobisi zokuxhatshazwa zingabangela imiphumo ye-neurobiological kunye nokuziphatha kweentlobo ezahlukeneyo zoxinzelelo, ezinokuthi zibe nemiphumo yeziyobisi zokuxhatshazwa kwisangqa esibi (jonga ngezantsi ukubuyisela uxinzelelo lwe-CPP) (102). Ke ngoko, umlutha kunye noxinzelelo zisebenzisana ngokuqinileyo, kwaye iindlela ezisisiseko ze-neurobiological zimele izinto ezinegalelo kwi-comorbidity phakathi kokulutha kunye ne-psychopathology enxulumene noxinzelelo.
Ngokusekelwe kubungqina obukhoyo obubandakanya i-KOR kwimiphumo yoxinzelelo (Icandelo 2), abaphandi baqhubela phambili behlolisisa indima yale receptor ekubuyiseleni uxinzelelo. Lilonke, iziphumo zibonisa ukuba ukusayinwa kwe-KOR kulamla ngokunzulu ukubuyiselwa okubangelwa uxinzelelo kwiindidi zeziyobisi zokuxhatshazwa. Kwiimpuku, unyango lwangaphambili kunye nomchasi we-KOR (mhlawumbi i-JDTic okanye i-nor-BNI) lunciphise kakhulu uxinzelelo-olwenzelwa (i-footshock), kodwa hayi i-cocaine-induced, ukubuyisela i-cocaine self-administration (41). Kwiimpuku, iziphumo ezifanayo zafunyanwa kuzo zombini uxinzelelo- kunye nokubuyiselwa kweziyobisi okubangelwa yi-cocaine kuvavanyo lwe-CPP [usebenzisa umchasi omtsha we-KOR we-peptidergic osebenza ixesha elifutshane (103)]. Ngaphaya koko, ukuvezwa kuxinzelelo olubukhali okanye oluphindaphindiweyo lubuyisele i-cocaine CPP kwi-WT, kodwa hayi kwi-KOR okanye Pdyn Iimpuku ze-KO, okanye zilandela uthintelo lwe-pharmacological KOR (104). Uxinzelelo kunye ne-KOR zikwanxibelelana kwinqanaba le-cocaine-context associative conditionings: uxinzelelo lwaziwa ngokwesiqhelo ukwenza i-cocaine ye-CPP, kwaye esi siphumo silingiswa yinkqubo ye-KOR activation (105). Ke ngoko, i-KOR ilamla uxinzelelo / ukusebenzisana kwe-cocaine ngexesha lokuqala lokuvezwa kweziyobisi, kunye nokulandela ukuphela.
Ngokuhambelana nedatha ye-cocaine, iindlela zofuzo kunye ne-pharmacological zibonise ukuba ukubuyiswa okubangelwa uxinzelelo lokusetyenziswa kwe-ethanol ngokufanayo kuxhomekeke kwi-dynorphin kunye ne-KOR kuzo zombini i-CPP kunye ne-paradigms yokuzilawula.106). Ezi ziphumo zixhasa uluvo lokuba i-KOR yi-agent e-pro-addictive ngexesha lokuvezwa koxinzelelo, ngokungafaniyo nesenzo sayo sokuthintela kwiipropati ezibukhali zokuqinisa iziyobisi zokusetyenziswa kakubi (bona iCandelo 1). Njengoko kuya kuxutyushwa ngezantsi, ukucacisa le ngqungquthela ebonakalayo kuya kufuna ukumisela ngokucwangcisiweyo ukuba ngabaphi abantu base-KOR abaqeshwe kuyo yonke ingqondo emva kweziganeko zoxinzelelo (kunye nokulandela ukukhululwa kwe-CRH ephakathi kunye ne-systemic corticosteroids), kunye nendlela le miqondiso ebangelwa uxinzelelo eyahluke ngayo kwi-activation ye-KOR. ngeedynorphins ezingapheliyo okanye i-systemic pharmacological agents) kwizilwanyana ezingenalutho, ezingenaxinzelelo.
Kwinqanaba le-neuro-anatomical, okufunyenweyo kuwo wonke amachiza amaninzi okuxhatshazwa kunye neendlela zoxinzelelo zicebisa ukuba ukubuyiselwa okubangelwa uxinzelelo lokufuna iziyobisi kuxhomekeke kunxibelelwano oluninzi phakathi kwe-KOR kunye neenkqubo ze-monoaminergic, kunye nezakhiwo ezininzi ze-forebrain limbic. Kwi-DRN, iziphumo zihambelana nedatha ekhankanywe ngaphambili kwi-KOR exhomekeke kwi-CPA. Ukubuyiselwa kwe-cocaine ye-cocaine CPP kwapheliswa emva kokucinywa kwe-p38α kwi-5-HT neurons, njengoko kubonisiwe kusetyenziswa i-p38α-cKO.I-SERT iimpuku (14). Kumxholo wokulutha kwe-nicotine, uxinzelelo lwe-FS olubangela ukuba kusebenze ukubonakaliswa kwe-dynorphin / KOR kuboniswe ukwenza i-nicotine CPP (20), umphumo onokuthi uthintelwe ngokufakwa kwe-nor-BNI kwi-amygdala. Kwisakhiwo sokugqibela sobuchopho, uphononongo lwakutsha nje luye lwaqala ukutyhilwa, zeziphi ii-neurons ezibonisa i-KOR (jonga ngezantsi). Izifundo ezongezelelweyo ziya kuba yimfuneko ukuvavanya apho i-KOR-positive amygdala neurons ithumela i-projections, kwaye ingaba i-dysregulation ye-nicotinic receptors, iithagethi ze-nicotine ngokuthe ngqo, zenzeka kule ndawo okanye kwenye indawo yobuchopho emva kokuvezwa koxinzelelo.
Ukusebenzisana okusebenzayo phakathi kokudluliselwa kwe-NA kunye nenkqubo ye-dynorphin / KOR nayo inegalelo ekubuyiseleni okubangelwa uxinzelelo lokufuna iziyobisi. Izifundo ze-anatomical ekuqaleni zibonise ukuba i-KOR ibonakaliswe kumacandelo amaninzi eselula ngaphakathi kwe-LC, eyona nucleus yobuchopho ye-NA. Ukukhanya kunye ne-electron microscopy ibonise ukuba i-KOR ihambelana ngokubonakalayo kunye ne-vesicular glutamate transporter kunye neCRF (107), kunye ne-preprodynorphin (108), kwiitheminali ze-axon zeLC. I-KOR iphinda ibonakaliswe yi-LC NA neurons, njengoko i-KOR immunoreactivity ifunyenwe kwiinkqubo ze-TH-positive somatodendritic.108). Ukurekhodwa kwe-Electrophysiological kubonise ukuba ukusebenza kwe-KOR kwi-LC kuzinza kuthintele ukusebenza kwe-neuronal okuphunyeziweyo ngokugaya imincili, okanye i-CRF-positive, amagalelo. Ngokwahlukileyo, ukusebenza kwe-KOR akuzange kube nefuthe kwimisebenzi ye-LC neurons ezenzekelayo (107), ecebisa ukuba i-agonists ze-KOR zifuna kakhulu ii-KOR zangaphambili ze-synaptic phantsi kweemeko ze-basal. Kwinqanaba lokuziphatha, ukusebenzisana kwe-KOR / NA kutshanje kuphandwe kumxholo we-heroin self-administration (109). Inaliti ye-systemic ye-Yohimbine yayisetyenziselwa ukubuyisela ukuphindaphinda, ngokusekelwe kwipropati yale khompawundi ukuze kusebenze i-axis ye-HPA kunye ne-NA neurons (esebenza njengomchasi kwi-α2 NA inhibitory autoreceptors). Iziphumo zibonise ukuba i-Yohimbine ivelise ukubuyiselwa okubalulekileyo kwiigundane zokulawula, kodwa kungekhona kwiigundane eziphathwe kwangaphambili kunye ne-KOR antagonist nor-BNI. Ngenxa yokuba olu pho nonongo lusebenzise ulawulo lwenkqubo ye-Yohimbine kunye ne-nor-BNI, kunzima ukugqiba ukuba ngaba iziphumo ezibonisiweyo zibangelwa i-KOR blockade kwi-LC, okanye kwenye indawo yobuchopho, emva kokusebenza kwe-Yohimbine-induced ye-stress system (enokuthi ikhokelela ekwandeni Ukukhululwa kweCRF kunye nedynorphin). Enye ingxelo yamva nje isasaze ezi ndlela ngesisombululo esingcono se-anatomical, ithatha ithuba lemodeli elula yokuziphatha ye-KOR agonist-induced reinstatement ye-cocaine CPP (39). Ukuvinjelwa kwe-KOR ngokukhethiweyo kwi-LC ngokuyinxenye kuthintele ukubuyiselwa kwe-KOR-induced reinstatement. Ngokungaguquguqukiyo, ukuhlangula i-KOR kwi-LC ye-KOR KO iimpuku ngokuyinxenye ibuyisele i-KOR exhomekeke kwi-CPP yokubuyisela. Njengezinye iisekethe ze-monoaminergic (110, 111), umsebenzi we-physiological we-NA neurons uxhomekeke kwii-subtypes ezininzi ze-receptor, kubandakanywa inhibitory α2-i-autoreceptors kunye ne-post-synaptic β1– kunye no-β2-i-heteroreceptors. Iiarhente ezikhethiweyo ze-pharmacological zazisetyenziselwa ukubonisa ukuba inhibition ye-NA neurons (α2-i-receptor agonist), okanye i-blockade yesenzo se-NA kwi-post-synaptic β1-abamkeli (β1-antagonist), zombini i-KOR-induced reinstatement enokwenzeka. Ezi ziphumo zibonisa imodeli apho uxinzelelo- kunye ne-KOR-mediated inhibition ye-NA neurons inegalelo ekubuyeleni kwakhona, kwaye ihambelana nedatha yangaphambili ebonisa ukuba ukusebenza kwe-LC KOR ekuhlaleni kunciphisa umsebenzi we-neuronal. Okubangela umdla kukuba, zombini i-cocaine-eyenziwe ukubuyiselwa kwe-cocaine CPP, kunye ne-KOR-induced CPA, ayizange ichatshazelwe bubuchule bokusayinwa kwe-NA, icebisa ukuba umdlalo we-KOR/NA ngokukhethayo ulamla imiba enxulumene noxinzelelo lokufuna iziyobisi. Kuphononongo olukhankanywe ngaphambili, i-Yohimbine iphinde yabuyela umva ngelixa ithathwa njenge-activator yazo zombini i-axis ye-HPA kunye ne-NA neurons. Ukudibanisa zombini izifundo, umntu unokuqikelela ukuba ezi ziphumo zokuqala zokuvuselela i-Yohimbine zinokulandelwa kwaye ekugqibeleni zichaswe yi-CRF- kunye ne-KOR-induced inhibition ye-LC NA neurons, ekhokelela ekubuyeleni kwakhona. Okokugqibela, le datha iphakamisa imibuzo eliqela kwizifundo zexesha elizayo: ingaba ii-CRF-receptors kunye ne-KOR zisebenzisana njani kwiLC? Ziziphi iindlela zokubonisa iimolekyuli eziqeshwe kwii-neurons ze-LC ezilandela ukusebenza kwe-KOR, kwaye ngaba zifana nezo zichazwe kwi-DRN? Zeziphi izakhiwo ze-forebrain ezinempembelelo ekusebenzeni kwe-LC KOR?
Kutshanje, iplastikhi ye-synaptic iye yavela njengelinye inqanaba lohlalutyo ukuqonda ngcono ukubuyiselwa kwe-KOR-mediated yokufuna iziyobisi. Ngokusekelwe kubungqina obudlulileyo bokuba: (i) uxinzelelo luphazamisa amandla exesha elide (LTP, uhlobo lokuphucula ixesha elide kwi-synaptic transmission phakathi kwee-neurons ezimbini) kwi-VTA, kwaye (ii) i-KOR ilawula indlela ye-mesolimbic (Icandelo 2) , ingxelo yakutshanje ihlolisise i-KOR yokuguqulwa kwe-LTP kwi-VTA njengomsebenzi woxinzelelo (112). Iziphumo zibonise ukuba i-systemic pharmacological blockade ye-KOR ithintele ukunyanzeliswa kwe-LTP kwi-GABAergic synapses (LTP).GABA), kodwa kungekhona ukunyanzeliswa koxinzelelo lwe-synapses ye-excitatory, ngaphakathi kwe-VTA. Ukusebenza kwe-KOR kwi-VTA kwakwanele ukulinganisa umphumo woxinzelelo, kunye nokuvimbela i-LTPGABA kwi-DA neurons. Okubalulekileyo, ukungena kwe-intra-VTA nor-BNI, phambi kuxinzelelo lwe-FS, yaboniswa ukunqanda ukubuyiselwa okubangelwa luxinzelelo lokuzilawula kwe-cocaine. Iqela elifanayo labaphandi libonise ngakumbi i-kinetics yoxinzelelo / i-KOR interplay (113) ngokujonga i-KOR kunye ne-glucocorticoid receptor (GR), esebenzayo ngexesha lamava oxinzelelo kunye ne-systemic endogenous release of corticosteroids. Ukulandela uxinzelelo lwe-FS, i-GR yaqeshwa okwethutyana (ngexesha le-1), ngelixa ubuncinci iintsuku ze-4 zokuvula i-tonic ye-KOR yayiyimfuneko ukulamla iziphumo ezihlala ixesha elide zoxinzelelo kwi-LTP.GABA kwi-DA neurons. Ngokungaguqukiyo, ivalela umqondiso we-KOR emva Uxinzelelo lwe-FS luthintele ukubuyiselwa kokuzilawula kwe-cocaine. Ehlabathini lonke, ezi zifundo zimbini zibonisa ngamandla ukuba i-GR- kunye ne-KOR-ixhomekeke kwi-LTPGABA kwi-DA neurons ilamla ngokubalulekileyo ukubuyiswa koxinzelelo lokufuna iziyobisi. Ngokusekwe kule datha, kubonakala ngathi kwiimodeli zokuphendula koxinzelelo kunye nokulutha, iinkqubo ezahlukeneyo zeplastiki zinokuthi zenzeke kwimimandla emininzi yobuchopho emva kokusebenza kwe-KOR.
Ngokubanzi, inkqubo ye-dynorphin / KOR ibandakanyeka ngokubalulekileyo ekubuyeleni kwakhona kwiimpawu zezilwanyana ezahlukeneyo kunye neziyobisi zokuxhatshazwa, ngokusebenzisana okuyinkimbinkimbi kunye ne-5-HT, i-DA, kunye ne-NA yokubonisa. Ngaphantsi kweemeko ezisisiseko, ukusebenza ngokukrakra kwe-KOR kuvimbela ukuqiniswa kweempawu zokusetyenziswa kakubi kweziyobisi (Icandelo 1). Ngokwahlukileyo, idatha ye-rodent icebisa ukuba ebantwini, ukuqeshwa kwe-KOR ngexesha loxinzelelo lwamava obomi kunokulamla ukubuyiselwa kokufuna iziyobisi kubantu abakhobokileyo abazama ukurhoxa kwichiza, kwaye ke kunokuba negalelo ekugcinweni komlutha.
Ukuvela kweempawu zokudakumba kubantu abanomlutha
Ukomelezwa koxinzelelo-reactivity ngexesha lokuvezwa ixesha elide, kunye nokuziyeka, iziyobisi zokusetyenziswa gadalala zinegalelo ekuveleni kweempawu ezidakumbisayo, ezinokuthi emva koko ziguquke zibe ziimeko ezingapheliyo ngaphandle kokuphazamiseka kokulutha.
Ukuchaneka okungapheliyo kwiziyobisi zokusetyenziswa kakubi kubonakaliswe ukwenza umqondiso ongapheliyo nge-KOR. Ukuvezwa okuphindaphindiweyo kwe-cocaine kwandisa ukugxila kweedynorphins kwi-striatum kunye ne-substantia nigra kwiimpuku (114). Ngokufanayo, ukuzilawula kwe-heroin ixesha elide kukhokelele ekwandeni Pdyn ukubonakaliswa kwigobolondo le-NAc kunye ne-nucleus ephakathi ye-amygdala, ngaphandle kwempembelelo Ipenki, i-gene efaka i-enkephalin opioid peptides esebenza ngokufanelekileyo kwi-MOR kunye ne-DOR (115). Utywala obungapheliyo buye badibaniswa nokunyuka kwentetho ye-dynorphin kunye nokukhululwa kwi-NAc (116, 117) kunye ne-amygdala (118). Njengoko sele kukhankanyiwe, ukunyuka kwe-dynorphin kwi-NAc kunokwenzeka ukuba kwenzeke ngendlela ye-cAMP-CREB yokubonisa.119). Ngokufanelekileyo, iziyobisi zokuxhatshazwa zonyusa ukukhutshwa kwe-DA kwi-NAc, ekhokelela ekuphuculweni nasekusebenzeni ixesha elide kwe-DA D1-receptor, i-receptor ukuba izibini zivuselele i-G.s-iiproteni. Oku kwandisa ukwakheka kwe-cAMP ye-intra-cellular, kwaye kwandisa i-CREB ebophelelayo kwizinto zayo zokuphendula ze-genomic, ezikhokelela ekubonakalisweni okwandisiweyo kwe Pdyn ufuzo. Ezi zinto zifunyanisiweyo zixhaswe ebantwini abakwimimandla ye-cortical yangaphambili ethi, efana ne-NAc, ifumane indawo yokuhlala exineneyo ye-DA. Kuphononongo oluvavanya izicubu zasemva kokufa ukusuka kwi-14 alcoholics ngokuchasene ne-14 yolawulo olusempilweni, yanda. Pdyn I-mRNA kunye ne-dynorphin peptides A kunye ne-B zabonwa kwi-dorsolateral PFC, kunye nokunyuka kwe-KOR mRNA kwi-cortex ye-orbito-frontal, kanti, akukho tshintsho lufunyenweyo kwezinye iipeptide ze-opioid kunye ne-receptors.120) kule mimandla.
Ngenxa yomsebenzi wayo onamandla we-prodepressant-like (Icandelo 2), ukwanda kokubonakaliswa kwenkqubo ye-dynorphin / KOR emva kokuvezwa ixesha elide kwiziyobisi zokuxhatshazwa kuye kwabandakanyeka kwiimpawu eziphazamisayo zokuyeka ngokukhawuleza, kunye nokuvela kweempawu zokudakumba ngexesha elide. izigaba zokurhoxisa okanye ukuziyeka. Impembelelo embi iqhuba ukusetyenziswa kweziyobisi (i-hypothesis "yokuzinyanga"), ngaloo ndlela kuqiniswa ukufuna iziyobisi kunye nokuba negalelo kubungqongqo bomlutha. Ukongeza, ukuphazamiseka ngokweemvakalelo okubangelwa ziziyobisi kunokukhokelela, kubantu abasesichengeni, kuxinzelelo oluvela ngokuzimeleyo kusetyenziso gwenxa lweziyobisi. Kwiimodeli zeempuku, ukurhoxa ngokungxamisekileyo ekuvezweni kwe-ethanol okungapheliyo kunxulunyaniswa nemeko yeemvakalelo ezimbi [jonga imizekelo kwiRef. (121-124), kubandakanywa iimpawu zokuziphatha ezidla ngokuchazwa njengexhala- (125) okanye ezinxulumene nokudakumba (126)]. Kusenokwenzeka ukuba yomibini le milinganiselo yempendulo yeemvakalelo iyasebenzisana (127-129), kunye nokuziphatha okubangelwa kukurhoxa kunokubangela i-symptomatology yoxinzelelo. Kwiigundane, ukuxhomekeka kwe-ethanol kunokusekwa ngokuvezwa okungapheliyo kunye nokunyanzeliswa kokutya kwi-ethanol liquid diet (125) okanye kumphunga we-ethanol (130). Kwiimpuku zeWistar (125), ukuxhomekeka kubonakaliswe njengokuziphatha okuphuculweyo okufana nokuxhalaba (njengoko kuhlolwe kuvavanyo oluphakanyisiweyo kunye novavanyo lwe-maze) ngexesha lokurhoxiswa ngokukhawuleza, kwaye esi siphumo savalwa ngonyango lwenkqubo kunye ne-KOR antagonist nor-BNI. Kissler et al. (130) Kwakhona waqaphela ukuba ukuhoxiswa ngokukhawuleza kwi-ethanol-dependence associates kunye nokwanda kokuzilawula ngotywala, kunye nokwanda kwe-22-kHz vocalizations ultrasonic, emele "indlela yokuziphatha esemthethweni ecalula ngokulula iimeko ezichasayo"(131). Olu tshintsho lokuziphatha oluhambelana nokunyuka kwe-Dynorphin-A immunoreactivity kwingingqi ye-capsular ye-amygdala ephakathi (CeA) kunye nokwandisa i-agonist-ivuselelwe i-G-protein coupling ye-KOR [njengoko ilinganiswe kusetyenziswa i-classical [35S]-GTPγS indlela (132)]. Ukuvalwa kwe-KOR kwi-CeA kwaboniswa ukukhusela ukunyuka kwe-ethanol ukuzilawula ngokuzimeleyo kwiigundane ezixhomekeke. Isiphumo solu qheliso lwendawo kwi-ultrasonic vocalizations ayizange ihlolwe; nangona kunjalo, kusenokwenzeka ukuba umqondiso we-CeA KOR unokuba negalelo kwimpembelelo embi emva kokuvezwa kwe-ethanol engapheliyo. Kwinqanaba lokujikeleza, indawo ye-KOR kwi-amygdala kunye nokufaneleka kwayo ngokomzimba kuye kwaqala ukuxatyiswa, kwaye iziphumo zamva nje zibonisa ukuba i-receptor ikakhulu ibeka kwiindawo ze-pre-synaptic terminals ze-GABAergic neurons.133). Ngokungaguquguqukiyo, ukulawulwa kwe-agonist ye-KOR kunye nomchasi kumalungiselelo esilayi se-amygdala yegundane, ngokulandelelana kwehle kwaye kwanda ukuhanjiswa kwe-GABAergic [ii-IPSC ezincinci, (21)]. Okothusayo kukuba, ezi khompawundi zimbini zifunyenwe zineziphumo eziguquguqukayo ezilandela iiseshini zemihla ngemihla zokuzilawula kwe-cocaine, kwaye ngokulandelelanayo ziye zabangela ukwanda kunye nokuncipha komsebenzi we-GABAergic. Ezi ziphumo zabonwa kuphela kwiimpuku eziye zanyusa ukusetyenziswa kwe-cocaine ngexesha elide (6 h) lokuzilawula, kodwa hayi kwiimpuku ezibonisa ukusetyenziswa kwe-cocaine okuzinzile ngexesha elifutshane (1 h). Ke ngoko, ngelixa ukuvezwa okungapheliyo kwiziyobisi zokusetyenziswa kakubi kunokubangela i-dynorphin / KOR ukusayina, kuyenzeka ukuba ukulahleka kolawulo lokuthatha iziyobisi kunokuguqula ngokuthe ngqo impembelelo ye-KOR kusebenze kwiisekethe ezithile ze-neuronal (njengoko kubonisiwe apha kwi-CeA) , ngokunokwenzeka ngenxa yotshintsho kwiintlobo zeeseli ezibonisa i KOR, okanye kwiselula yendawo ye KOR. Kwinqanaba lokuziphatha, i-CeA micro-infusion ye-nor-BNI yanciphisa isimilo esifana nexhala (kwi-paradigm ekhuselayo yokungcwaba) eyabonwa ngexesha lokurhoxa kwisitofu esinganyangekiyo, sovavanyo, kunye nesitofu se-cocaine. Ngelixa esi siphumo se-KOR blockade kufuneka kwakhona sivavanywe emva kokusetyenziswa kwe-cocaine ngokuzithandela, ezi ziphumo zibonisa ngokucacileyo ukuba ii-amygdala KORs zilawula iimpendulo zeemvakalelo ngexesha lokurhoxa kwe-cocaine.
Ngexesha lemijikelo ephindaphindiweyo yokunxila kunye nokurhoxa okubonisa ukuba likhoboka, ezinye iindlela zokusingqongileyo zihamba ngokuthe ngcembe zinxulumana nelizwe elichaphazelekileyo, kwaye ke zinokuvelisa iziphumo ezichaseneyo ngokuzimeleyo nakuphi na ukuvezwa kweziyobisi [kuquka neempawu zokurhoxa.134)]. Ngalo mgca, uBerger et al. (19) ibonise ukuba i-air-puff induced 22-kHz i-ultrasonic vocalizations inokwenzeka ngexesha lokuhoxiswa kwi-ethanol-dependence (eyenziwe yi-2-iveki yokunyanzeliswa kokunyanzeliswa komphunga we-ethanol), kwaye esi siphumo sasixhomekeke kwi-dose ngokuxhomekeke kwi-systemic KOR antagonism. Kwesinye iseti yovavanyo, ababhali banxulumanisa ivumba elingathathi hlangothi (ivumba le-almond), kunye neempawu eziphikisayo ze-systemic KOR activation. Okubangel 'umdla kukuba, ukuvezwa kwakhona kweli vumba elicwangcisiweyo kuboniswe ukwenza i-ethanol esebenza ngokuzilawula ngokuzimeleyo kwiimpuku ezingaxhomekekanga, kwaye esi siphumo savalwa yi-KOR systemic blockade. Ngokukwanjalo, ebantwini, ukuvezwa kwakhona kwimixholo edityaniswe ngokuphindaphindiweyo nefuthe elibi elibangelwa kukurhoxa kunokuvelisa imeko ye-dysphoric exhomekeke kwi-KOR kunye nokufuna iziyobisi, ngaloo ndlela kube negalelo ekugcinweni komlutha kunye nokuvela kweempawu zoxinzelelo.
Iziphumo zovakalelo lweziyobisi zokusetyenziswa kakubi zinwenwela ngaphaya kwesigaba sokurhoxa, esichazwa njengethuba apho ichiza licocwa emzimbeni. Uphononongo lwakutsha nje luvavanye utshintsho lwexesha elide oluxhomekeke kwi-KOR oluhambelana nokurhoxa kwi-ethanol.135). Iigundane zondliwa ukutya kotywala obumanzi kangangeentsuku ezingama-25-30, zisebenzisa ukuzilawula ngomlomo kwiparadigm yokukhetha iibhotile ezimbini. Iiveki ezintandathu emva kokususwa kwe-ethanol, ukuziphatha okufana nokuxhalaba (okulinganiswa ngokukhawuleza emva koxinzelelo lwe-20-min yokuzithiba, kwindawo ephakamileyo kunye ne-maze) ibe yinto enokwenzeka kwiimpuku ze-ethanol-abstinent. Esi siphumo sivalwe yi-nor-BNI pre-treatment 24 h phambi kovavanyo, ebonisa ukuba ukunyuka kwe-stress-reactivity yenkqubo ye-dynorphin / KOR inokuqhubeka ixesha elide kakhulu emva kokuvezwa kwe-ethanol yokuqala. Iqela lethu lisandula ukwandisa obu bungqina bukhulayo bokusetyenziswa kakubi kwe-opiate, kunye nokubandakanya i-KOR kukusilela ngokweemvakalelo ngexesha lokuyeka iziyobisi ixesha elide kwiimpuku. Siqale sabonisa ukuba ukuziyeka kwe-morphine kukhokelela ekuveleni kokunyuka kokuphelelwa lithemba kokuziphatha (kuvavanyo lokunqunyanyiswa komsila) kunye nokurhoxa kwintlalontle (136, 137). Zombini iintsilelo zichongiwe iiveki ezi-4, kodwa hayi iveki enye, emva kovavanyo olungapheliyo lwanikezela ngeedosi eziphezulu zemorphine. Ezingapheliyo ngelinye unyango kunye ne-antidepressant Fluoxetine (i-serotonin reuptake inhibitor ekhethiweyo) ngexesha le-4-iveki yokuyeka ukuyeka ukuguqulwa kweentsilelo ezibangelwa yi-morphine. Ngapha koko, i-5-HT metabolism (136) kunye nomsebenzi we-5-HT1A-receptor (138) zaye zachithwa ngexesha lokuyeka i-morphine, ngokukodwa kwi-DRN, ebonisa igalelo elibalulekileyo leendlela ze-5-HT. Ukomeleza le modeli, sibonakalise ipateni yekinetic eyahlukileyo kusetyenziswa iheroin (139): kwiiveki ze-4 zokuziyeka, ukuhoxiswa kwentlalo kuphela kwafunyanwa kwi-heroin-pre-treated mice; kwiiveki ze-7 zokuziyeka, esi sibonakaliso sokuqala sasihamba kunye nokunyuka kokuziphatha kokuziphatha (kuvavanyo lweFS). Okubalulekileyo, sibonise ukuba oku kuncipha kobudlelwane boluntu (okubonwa kuzo zombini i-morphine kunye ne-heroin abstinence) kuxhomekeke ekusebenzeni kwe-MOR kunye ne-KOR (139): le phenotype yayingekho: (i) kwiigundane ze-cKO, apho i-MOR yacinywa ngokukodwa kwi-DRN ngaphambi konyango lwe-heroin; kunye (ii) neempuku ze-KOR KO. Ukuqwalasela idatha yangaphambili kwi-5-HT kunye ne-DA yokunxibelelana kwinqanaba le-NAc kwiimodeli ze-CPA exhomekeke kwi-KOR kunye ne-cocaine CPP, into enomdla kukuba ukusebenzisana okufanayo kwe-monoamine kunokuba negalelo ekuphazamisekeni kweemvakalelo ngexesha lokuyeka i-opiate, ngokunokwenzeka ngeendlela ezifanayo ze-molecular cascades. .
Umsebenzi obalulekileyo wophando lwexesha elizayo iya kuba kukuphonononga iimpendulo ezinjengeemvakalelo kumxholo wemodeli entsonkothileyo yokuziphatha okufana nomlutha. Kwimbono ye-phylogenic kunye nokuguqulela, kunye nokusebenzisa iiparadigms zokuzilawula, amaqela amaninzi akwazile ukudlulisela indlela ye-DSM-IV yokulutha kwi-reproducible, iziyobisi zokuziphatha ezingaqhelekanga, kubandakanya ukuvela kokunyanzeliswa kokufuna iziyobisi kunye nokuthatha iziyobisi nangona iziphumo ezibi. (140, 141). Siqikelela ukuba iipateni ezinjalo ezitenxileyo zokusela iziyobisi zinokukhokelela ekomeleleni nasekuphelelweni kwexesha elide ngokweemvakalelo kwiimpuku, kwaye zinokubonisa iimodeli ezingcono ze-comorbidity yeemvakalelo ezinxulumene nokuba likhoboka. Iindlela ezinjalo zikwanakho ukutyhila, kwindlela yokulinganisa, iimpawu zokuziphatha ezinokuthi ziqikelele nje inguqu ekusetyenzisweni kweziyobisi ezinyanzelekileyo (ezifana nokungxamiseka okuphezulu), kodwa kunye nomngcipheko wokukhathazeka ngokweemvakalelo.
Ngokudibeneyo, uncwadi olukhula ngokukhawuleza lwe-KOR luvuselele umdla omkhulu kuphuhliso lwabachasi be-KOR njengee-pharmacotherapies zoxinzelelo kunye nokuphazamiseka kokuxhalaba, kunye nokuphucula ukulawulwa koxinzelelo kunye nokunciphisa i-dysphoria kumxholo wokulutha. Nangona ezinye ii-ligands ze-KOR zingakhange zibonise iipropathi ezifanelekileyo ze-pharmacological, ezinye zibonakaliswe njengabaviwa abasebenzayo beziyobisi (142). Isishwankathelo, abachasi be-KOR banokuthi (i) bathintele uxinzelelo-olubangelwa ukusetyenziswa kweziyobisi, (ii) ukuthintela ukuphindaphinda okubangelwa uxinzelelo ngexesha lokuziyeka, kunye (iii) nokunciphisa iimeko zeemvakalelo ezingathandekiyo ngexesha lokurhoxiswa ngokukhawuleza kunye nexesha elide lokuziyeka. Nangona ukulandelwa kwexesha elide kunye nezifundo ezilawulwa kakuhle zingumngeni ngokwendlela kumakhoboka eziyobisi, ezi ziphumo zihambelana nengxelo yekliniki kubaxhaphazi be-opiate abadangeleyo yeziphumo eziluncedo ze-buprenorphine, umchasi we-MOR we-agonist / we-KOR (xa kuthelekiswa ne-methadone, i-agonist ecocekileyo ye-MOR) (23); Olunye uphononongo, nangona kunjalo, aluzange lufumane umahluko phakathi kwezi zixhobo zimbini (143). Uphando olunzulu kwi-pharmacology ye-KOR sele ivelise i-plethora emfutshane- [Zyklophin (103), LY-2456302 (144, 145)] kunye nabachasi bexesha elide (nor-BNI, GNTI, JDTic) (146). Izifundo zexesha elizayo ziya kufuneka zihlalutye ngononophelo iimpawu zazo zomqondiso ngokuxhomekeke kulwakhiwo olulufumanayo kunye ne-KOR, oko kukuthi, intsimi ethembisayo ye-agonism enomkhethe [jonga umzekelo kwi-Ref. (147-150)]. Iinkcukacha ezongezelelweyo zinokuvela xa kuthelekiswa umqondiso we-KOR kwiimpuku kunye neentlobo zabantu (151), okanye njengomsebenzi we-polymorphisms yemfuza (152-154). Kwakhona, ukubakho kwamva nje kokufunda i-KOR yabantu kwi vivo, usebenzisa i-PET-Scans nge-radiotracer 11C-LY2795050 (155), uyathembisa. Ngexesha elide, iindlela ze-pharmacogenomic ziyakwazi ukuqikelela iindlela zonyango ezijoliswe kumntu ngamnye kwi-KOR, kwaye ngoko ke ingaba yintloko kwimimiselo yeklinikhi esebenzayo.
Xa ukudandatheka kwandulela ukukhotyokiswa
Ukujongana neendlela ze-neurobiological ze-comorbidity phakathi kokudakumba kunye nokuba likhoboka, enye indlela ehambelanayo kwiimodeli zezilwanyana kukufunda ukuba amazwe afana noxinzelelo anokuthi enze njani iziphumo zokuziphatha kunye neepatheni zokusetyenziswa kweziyobisi zokuxhatshazwa (36, 156). Xa kuthelekiswa nobudlelwane be-causal obuchanekileyo obandakanyiweyo kwi-comorbidity, inkalo yamva ayizange ifundwe kakuhle, kwaye zimbalwa kakhulu izifundo eziphonononge indima enokwenzeka ye-KOR.
Kwesi sikhokelo, ubungqina obukhoyo bentonga abuhambelani, kwaye iimodeli ezisekelwe kuxinzelelo olungapheliyo zokudakumba ziye zanxulunyaniswa nokonyuka kweziphumo zeziyobisi zokusetyenziswa gadalala (ukuqonda iindlela zomvuzo ezinokuthi zihambelane ne-comorbidity yabantu) okanye ukuncipha kweziphumo. UKrishnan et al. (93) ibonise ukuba iimpuku ezinokuthi zichaphazeleke kwiziphumo ezingapheliyo zokoyiswa kwentlalo, eziphuhlisa iimpawu ezinjengoxinzelelo oluhlala ixesha elide, kubandakanya nokuncipha kokuthandwa kwe-sucrose kunye nokuphepha kwezentlalo, zikwabonisa i-CPP ebalulekileyo kwiidosi ze-cocaine ezingaqini kwiimpuku ezingoyiswanga, okanye ekoyisiweyo. kodwa iimpuku ezomeleleyo.
Uxinzelelo oluphantsi olungapheliyo yenye imodeli yokudakumba, esekwe ekuvezweni okungalindelekanga kweempuku kwizixinzelelo ezininzi ezithambileyo, ngokwesiqhelo kwiiveki ze-4-8. Le modeli isetyenziswa kakhulu ngenxa yobuso bayo, ulwakhiwo, kunye nokuqikelelwa kwangaphambili (157-159). Esona siphumo sixhaphakileyo sokuziphatha kuvavanyo loxinzelelo oluthambileyo olungapheliyo (CMS) lukhetho oluncitshisiweyo (ngaphezu kwamanzi) kwisisombululo se-sucrose, okanye i-anhedonia. Le phenotype ye-anhedonic ibonakala ngathi yandisa kwiipropathi zokuqinisa iziyobisi zokusetyenziswa kakubi, njengoko i-CPP iyancipha ye-amphetamine (160) kunye ne morphine (161) kuye kwabikwa ngokulandela iCMS kwiimpuku. Okothusayo kukuba, akukho sifundo sikhoyo, kulwazi lwethu, kwiziphumo zeCMS kwiimpuku ze-KOR KO: ngaba inkcazo ye-KOR inokubakho kwiimpuku ze-WT ezicinezelekileyo? Kweziphi iindawo zengqondo? Ngaba iigundane ze-KOR KO ziya kukhuselwa kwimiphumo yoxinzelelo olungapheliyo? Ukujongana nesi sikhewu kuncwadi, u-Al-Hasani et al. kutshanje ihlolisise imiphumo yokubuyiselwa kwe-CPP yeendlela ezintathu ezixinzelelekileyo: i-CMS, "ukutshatyalaliswa kwentlalo engapheliyo" (indlela emfutshane ye-5 yeentsuku zokutshatyalaliswa kwentlalo), kunye noxinzelelo olulodwa lwe-FS olunzima.162). Iziphumo zibonise ukuba, njengoko bekuchaziwe ngaphambili, uxinzelelo olunamandla lunokwenza i-KOR-mediated ukubuyiselwa kwe-cocaine CPP. Ngokwahlukileyo koko, zombini i-CMS kunye noloyiso olungapheliyo lwentlalo lufunyenwe ukuthoba i-KOR exhomekeke kwi-agonist ukubuyiselwa kwe-cocaine kunye ne-nicotine CPP. Njengoko bekulindelekile, ukubuyiselwa kwe-cocaine okanye i-nicotine CPP akuzange kuchaphazeleke yi-CMS, ukongeza kubungqina bangaphambili malunga nentsingiselo ethile ye-KOR ekubuyeleni koxinzelelo. Ezi ziphumo ziphikisanayo zibonisa ukuba, ubuncinci kwiimodeli ze-rodent, i-CMS inokuba neziphumo ezikhuselayo okanye eziguquguqukayo ngokuchasene nokubuyela kwakhona kweziyobisi, ingcamango ehambelana kakubi ne-epidemiological kunye neziphumo zekliniki ebantwini.
Ngokubanzi, sicingela ukuba isimilo esifana ne-anhedonia elandela i-CMS okanye ukoyiswa kwexesha elide kunokunciphisa iipropathi zokuqinisa iziyobisi zokusetyenziswa gadalala (njengoko kuvavanywa kusetyenziswa iiparadigms zokhetho lwendawo yeziyobisi, ukuphela, kunye nokubuyela kwakhona), okunokwenzeka ukuba kubandakanye indlela exhomekeke kwi-KOR. . Kwangaxeshanye, i-anhedonia ebangelwa luxinzelelo inokubangela ukuvela kokunyanzeliswa kokuthatha iziyobisi ngexesha lokusetyenziswa ngokuzithandela kweziyobisi zokusetyenziswa kakubi, kungoko kuthanda ukungena kubukhoboka. Ukuphonononga oku kunokwenzeka, izifundo zexesha elizayo ziya kudibanisa ngokufanelekileyo iiseti ezimbini zeparadigms zokuziphatha eziphambili: i-CMS okanye ukoyiswa okungapheliyo kwezentlalo kuqala, kulandelwa kukuzilawula okwandisiweyo kwechiza. Ubuninzi beempuku ze-cKO ezikhoyo ngoku kufuneka bungqineke buluncedo ekuqondeni ngcono indima ye-KOR kwezi ndlela zidityanisiweyo zokugula.
Izalathiso zexesha elizayo kunye nesiphelo
Umceli mngeni omkhulu kwixesha elizayo iya kuba kukutyhila ulungelelwaniso oluguquguqukayo lwenkqubo ye-dynorphin/KOR njengoko imo kunye nokuphazamiseka komvuzo kuvela kwaye kuvela. Lo mbandela unokubaluleka okubalulekileyo kweklinikhi kuthathelwa ingqalelo ukunganyangeki kwezi meko zimbini. Ngokukodwa, ubungqina obukhoyo bubonisa ukuba i-KOR yenza ulawulo oluninzi kwii-monoamines eziphambili kwiigundane. Okubangel 'umdla kukuba, uphando lokulutha lubonisa ukuba ukubonakaliswa okuphindaphindiweyo kwiziyobisi zokuxhatshazwa kuphazamisa iindlela zokuphendula ezithintelayo phakathi kwe-monoaminergic nuclei, enokuthi idibanise ukungasebenzi kakuhle kwexesha elide.163, 164). Ingaba ezo ndlela zikwaphazamisa ukulawulwa kwemo ye-KOR yingcinga enomdla kumxholo we-comorbidity.
Ubungqina obuninzi kwintsimi ye-KOR kutshanje bubangele oogqirha ukuba benze izifundo zokucinga ngengqondo kunye nezilingo zeklinikhi (22). Kutshanje, isifundo sokuqala se-PET-Scan sisebenzisa umchasi we-KOR we-radioactive sikwazi ukubonisa ukuphazamiseka okukhulu kunye nokusasazeka kwe-KOR. kwi vivo ukufumaneka kwizifundo eziphethwe luloyiko kunye neempawu zedysphoric emva kokuvezwa kokwenzakala okukhulu (165). Ngelixa iziphumo zihambelana kakuhle nedatha yezilwanyana kwi-KOR kunye nendlela ye-mesolimbic, zikwacebisa ukuba eminye imimandla yobuchopho, ngoku iphononongwa kakubi kwiseto lwe-preclinical, inokubaluleka ngokulinganayo (umzekelo, i-thalamus kunye ne-insular cortex). Izifundo ezongezelelweyo ziya kufuneka ukuqhubela phambili ukuvavanya ukufumaneka kwe-KOR kumaqela abantu abadakumbileyo, abakhobokileyo, kunye nezifundo ezidibeneyo. Ekugqibeleni, ukusuka kwindawo yokujonga i-pharmacological, intsimi eguqukayo ngokukhawuleza ye-agonism ye-biased (okanye i-ligand-directed signaling) iphakamisa ithemba elikhulu kwi-KOR-targeting therapeutics (149). Injongo ephambili kwintsimi ye-G-protein-coupled receptors kukuchongwa kweendlela ezicacileyo zokubonisa ezinokuthi zisebenze ukulawula iimpendulo ezithile zokuziphatha. Kwixesha elizayo elingekude, ezo ndlela ziya kunceda ekuphuhliseni i-antidepressants ezisebenza njengabachasi be-KOR kwaye zingenazo iziphumo ezinokuthi zinxulunyaniswe nazo (umzekelo, i-hyperalgesia).
Ukuqukumbela, siye sashwankathela kuphononongo lwangoku uninzi lobungqina obuxhasa indima ye-KOR ekulawuleni umvuzo kunye nomoya. Siphinde sachaza indlela le receptor ibekwe ngayo ngokufanelekileyo ukulamla ukusebenzisana okuqinileyo phakathi kokuphazamiseka okuhlala rhoqo kunye nobunzima bengqondo, umlutha kunye nokudakumba. Lilonke, uphando lwangaphambili kwi-KOR lubonisa indlela izifundo ezinqamlezileyo kuzo zonke iimodeli zezilwanyana ezininzi ezinokuthi zichonge iindlela zobuchopho ezinegalelo kwiinkqubo ze-pathophysiological ze-transdiagnostic, kwaye ke ngoko zimele iithagethi eziphambili zonyango kulawulo lwe-comorbidity, enye yezona zinto zibalaseleyo zehlabathi engqondweni. impilo.
Ukuxabana kweNkcazo yeNzala
Ababhali bavakalisa ukuba uphando lwenziwe ngokungabikho naluphi na ulwalamano lwezorhwebo okanye lwezezimali olubhekiswa njengengxabano yenzuzo.
Imibulelo
Ababhali babulela uDkt Laura Fiori ngokufunda okubalulekileyo kombhalo wesandla. Lo msebenzi wawuxhaswa yi-Agence Nationale de la Recherche (ANR-Abstinence).
Ucaphulo