Li-opiate-Li na le Mahlaseli a Melemo le a Mahlaseli a Ventral Tegmental Area le Locus Coeruleus Catecholamine Neurons (2012)

Cold Spring Harb Perspect Med 2012 Jul; 2 (7): a012070. Doi: 10.1101 / cshperspect.a012070.

  1. Eric J. Nestler

+ Boikarabello ba Mongoli

  1. Lekala la Fishberg la Neuroscience le Friedman Brain Institute, Mount Sinai School of Medicine, New York, New York 10029
  2. Lengolo: [imeile e sirelelitsoe]

inahaneloang

Boithuto ba ho feto-fetoha ha methapo ea methapo bo khothalletsoang ke lithethefatsi tsa opiate bo bohlokoa ka ho khethehileng kajeno kaha ba fuoe lengolo le pharaletseng la ho sebelisa litlhaloso ntle le ho ngola. Le ha ho tsebahala ho hongata ka ts'ebetso e matla ea lithethefatsi tse joalo tsamaisong ea methapo, mosebetsi o mongata o ntse o le ho utloisisa ka botlalo litlamorao tsa bona tse sa foleng. Mona, re shebana le liphetoho tse tšoarellang halelele tse etsahalang likarolong tse peli tsa boko ba catecholaminergic tse arolelanang boits'oaro bo fapaneng ba ts'ebetso: li-neurons tsa sebakeng sa "ventral tegmental" (VTA) dopaminergic neurons, tsa bohlokoa bakeng sa moputso oa lithethefatsi, le locus coeruleus (LC) noradrenergic neurons, ea bohlokoa bakeng sa 'mele ho its'epa le ho tlohela. Re shebana le liphetoho lipolitiking tsa cellular, synaptic, le sebopeho libakeng tsena tsa boko tse fanang ka ts'ebetso ea ho its'epaha le ho lemalla. Ho utloisisa lits'ebetso tsa limolek'hule tsa polasetiki ena ea opiate e tla ba bohlokoa bakeng sa nts'etsopele ea mekhoa e metle ea ho lemalla lithethefatsi tsa opiate mohlomong le lithethefatsi tse sireletsehileng bakeng sa tšebeliso ea meriana.

Ka lebaka la thepa ea bona ea "analgesic" e matla, lithethefatsi tsa opiate li 'nile tsa sebelisoa ka makholo a lilemo. Li-Opiates li kenyelletsa likhomphutha tse nkiloeng ho opium poppy tse kang morphine le codeine, hammoho le lintho tse ngata tsa maiketsetso tse kang heroin, oxycodone le hydrocodone. Molemong oa tlhahlobo ena, re shebisisa liketso tsa morphine le heroin, kaha tsena e bile tsona tse ithutoang haholo tsamaisong ea mohlala. Leha ho na le katleho ho phekoleng bohloko bo boholo, ho na le mathata a tebileng a ts'ebeliso ea opiate ea nako e telele, ho kenyelletsa mamello, ho itšepa 'mele le bokhoba ba tahi (Ballantyne le LaForge 2007). Ts'ebeliso e mpe ea lithethefatsi tse fanoang ke ngaka, 'me ka ho khetheha e kokobetsa bohloko ba opereishene, e eketsehile haholo lilemong tsa morao tjena ho batho ba baholo le ba bacha ba US (Compton le Volkow 2006; Manchikanti et al. 2010). Ts'ebeliso ea bongaka ea opiates e boetse e phahame haholo ka ha kalafo ea mathata a bohloko a sa foleng e se e le bohale haholo (Ka 2007). Le ha ho ka phehisanoa ka melao-motheo ea kalafo e sa feleng ea bohloko le ho ba le ts'oaetso e fetang kapa tlasa ts'ebeliso ea lithethefatsi tsa opiate (Masimo 2011), ha ho na potso ea hore tšebeliso e mpe ea opiate e baka li-neuroadaptations tse lebisang liphellong tse sa rateheng.

Ho itšetleha ka 'mele le bokhoba ba opiate ho kile ha nkuoa ho hokahane; leha ho le joalo, lits'ebetso tsena joale ho lumeloa hore li tsamaisana le methati le lipotoloho tse kahare ho bokong (Koob le Le Moal 2001). Ho itšetleha ka 'mele ho bonahatsoa e le matšoao a fosahetseng a' mele (mohlala, ho ruruha, bohloko ba ka mpeng, lets'ollo) ha moriana o felisoa. Ho lemalla, kapa "ho itšetleha ka lithethefatsi" joalo ka ha ho hlalositsoe ke Diagnostic and Statistical Manual of Mental Dis shida, ho na le tšusumetso e kholo ea bophelo bo botle le tlhahiso mme o tsebahala ka ho qobelloa ho batla le ho sebelisa lithethefatsi leha ho e-na le litlamorao tse mpe. Karolo, empa eseng kaofela, ea tlatsetso ena ea tlatsetso e kanna ea bonts'a "ho itšetleha ka kelello," ke hore, matšoao a mabe a maikutlo a bang teng nakong ea ho tlohela lithethefatsi.

Thutong ena, re tšohla se tsejoang ka polasetiki ea "neuroadaptations", kapa e amanang le polasetiki, tse hlahang libakeng tse peli tsa boko tse nang le catecholamine neurons, tse phethang likarolo tsa bohlokoa tlatsong ea ts'ebetso ea ts'ebeliso ea ts'ebetso le ts'ehetso ea 'mele, ka ho latellana: dopaminergic neurons ka har'a midbrain ventral tegmental sebaka (VTA) le li-neuron tsa "Noradrenergic" kahare ho pontine locus coeruleus (LC). Puisano ena e tsepamisa maikutlo ho mefuta e meraro ea polasetiki ea opiate e kentsoeng libakeng tsena: liphetoho tsa polasetiki tsa synaptic-tse phehellang phetisetsong ea glutamatergic le GABAergic synaptic (Mofuta le Nugent 2011b; Lischer le Malenka 2011); cellular plasticity-homeostatic changes in intracellular signaling cascades (Williams et al. 2001; Nestler 1992, 2004); le mekhabiso ea polasetiki-liphetoho tsa nako e telele ho "neuronal morphology"Russo et al. 2010). Ho tsebahatsa li-molek'hule tsa mefuta ena e meraro ea polasetiki bokong ba "catecholaminergic neurons" e sebetsa e le mohlala oa polasetiki e kentsoeng linthong tse ling tsa bohlokoa tsa neural tsa ts'ebeliso ea lithethefatsi mme e tla ba senotlolo sa ho ntlafatsa litlhare tse ntlafatsang bakeng sa lithethefatsi tsa opiate le lithethefatsi tse ntle tsa opiate bakeng sa analgesia.

LITLHAKISO TSA BOPHELO

Background

VTA e ithutile ka bophara ts'ebelisong e mpe ea lithethefatsi e fuoe karolo ea eona ea mantlha moputsong. Dopamine (DA) li-neurons tsa projeke ea VTA ho ea libakeng tse ngata tsa boko ho kenyelletsa le li-nucleus accumbens (NAc), moo kokelo e eketsehileng ea DA e hlokometsoeng ho arabela sehlopha ka seng sa lithethefatsi tse hlekefelitsoeng (Di Chiara le Imperato 1988). Leha ho le joalo, le ha li-neuron tsa DA e le karolo e hlahelletseng (∼60 %-65%) ea noute ea mothapo o pharalletseng, ho na le phapang e kholo ea selefouno, e nang le karolo ea bohlokoa ea li-neurons tsa GABA (30 %- 35%) hammoho le litlhaloso tsa glutamatergic neurons ( 2% –3%) (Swanson 1982; Nah-Roberts et al. 2008; Sesack le Mohau 2010). DA le Gaba neurons kahare ho mpa ea bohareng ba 'mele, ka kakaretso, projeke ka ho tšoana (medical to lateral) ka meaho e meholo ea tlhahiso e nang le NAc, preortal cortex (PFC), le amygdala (AMY) (e hlahlobuoe haholo ka Sesack le Mohau 2010) (Feie. 1). Liphatlalatso tsa mantlha ho VTA li kenyelletsa litlatsetso tse thabisang ho tsoa ho PFC, pedunculopontine le hamoraoodorsal tegmentum (PPTg le LDT), hammoho le meaho e meng e mengata e sa tsoa hlalosoa (Geisler et al. 2007). Tlatsetso ea inhibitory ho VTA ha e hlalosoe hantle, empa lipallo tsa NAc, ventral pallidum, le mesopontine rostromedial tegmental nucleus (RMTg) li tlalehiloe (Sesack le Mohau 2010). Patlisiso ho fihlela joale e shebane haholo le li-neuron tsa DA ho VTA, haholo-holo tse projeke e eang ho NAc, ka lebaka la karolo ea bohlokoa ea projeke ena moputsong (Nestler 2004).

Setšoantšo sa 1.  

Cartoon ea karolo e kholo ea boko ba methapo e bonts'a VTA le LC le merero ea bona e meholo le e sebetsang. DAergic (e khubelu) le GABAergic (putsoa) li-neurons tsa projeke ea VTA ho ea ho li-limbic and cortical and and kupokea glutamatergic (black-dash, PFC) le tlhahiso ea GABAergic (blue-dash, NAc, VP). Noradrenergic neurons (e putsoa) e LC ea kahare ho libaka tse ngata tse kenyeletsang HIPP le PFC mme e amohela ho kenya glutamatergic ho tsoa PGi. Maelefatso: AMY, amygdala; HIPP, hippocampus; LC, locus coeruleus; NAc, li-bokelle tsa nucleus; PFC, cortex ea pele; PGi, nucleus paragigantocellularis; VP, ventral pallidum; VTA, sebaka se khubung ea moea.

Liphetoho tse bakoang ke li-Acpi Opiate tse Lebisitsoeng ho Mosebetsi oa Neuronal

Ho fanoa ka bokhoni ba morphine o hlobaetsang ka har'a VTA ea ho etsa hore DA e ntšoe kantle ho NAc (Le et et al. 1991), mosebetsi o mongata o lekotse litlamorao tse mpe tsa opiates ho VTA. Acid morphine e eketsa lebelo la ho thunya ha li-neuron tsa DA ho VTA (Gysling le Wang 1983). Phello ena e kopantsoe bonyane ka karolo ho tlangoa ha morphine ho Gi / o-coupled μ-opioid receptor (MOR) ho li-neuron tsa GABA tsa lehae, ka tsela eo e fokotsa ts'ebetso ea bona le tokollo ea GABA e latelang ho li-neuron tsa DA le ho baka ho senngoa ha li-neuron tsa DA (Johnson le North 1992). Leha ho le joalo, ho toloka boholo ba mosebetsi oa pele oa elektrophiki ho thatafalitsoe ke bopaki bo bonts'ang sebopeho se haufi le sebopeho sa VTA DA le Gaba neurons (ka boholo, morphology, le thepa ea motlakase) (Margolis le ba bang. 2006), ho hlakisa tlhoko ea ho khetholla li-neurons tsa VTA tse ithutileng ka mokhoa o hlakileng haholoanyane (mohlala, ka immunohistochemistry, ts'ebeliso ea litoeba tsa bongoli ba GFP, jj.), ntlha e tla tšohloa ka botlalo hamorao tlhahlobisong ena. Mona, re shebana haholo le li-opiates tse sebetsang e le li-agonists ho MOR ho VTA, joalo ka morphine, kaha lithethefatsi tsena li hlahisa litlamorao tse atisang ho ithutoa tšimong ea tlhekefetso ea lithethefatsi. Leha ho le joalo, hoa tsebahala hore κ-opioid receptors (KOR) e boetse e hlahisoa ho li-neurons tsa VTA DA, le hore ts'ebetso ea li-receptors tsena e ka thibela ka kotloloho sekhahla sa ho thunya ha methapo ea DA (Margolis le ba bang. 2003), mohlomong ho kenya letsoho ho sithabetseng ha litlamorao tsa kappa agonists. Bokhoni ba li-opiate ba ho hlahisa tšebetso ea tšebetso ea methapo ea kutlo ea VTA DA le ho thibela tšebetso, le melemo e khahlisang le e khahlisang, ea makatsa, 'me moelelo ona oa "yin-yang" le karolo ea li-pioide tsa endiogen moputsong li lokeloa ho ba mohopolo oa ho ithuta nakong e tlang.

Acute Opiate-E Khantšitse Synaptic Plasticity

Ntle le liphetoho mosebetsing oa neuronal, ho na le litlaleho tse ngata tsa polasetiki ea synaptic e susumetsoang ke opiates e mpe. Joalo ka koae le lithethefatsi tse ling tse hlekefelitsoeng, ente e le 'ngoe ea morphine e fumanoe ho eketsa karolelano ea α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) ho N-methyl-D-aspartic acid (NMDA) maqhubu a thabisang a li-postynaptic currents (EPSCs) lihora tse 24 kamora ts'ebetso, e lumellanang le tšebeliso ea nako e telele ea nako e telele (LTP) ea li-glutamatergic synapses ho li-neurons tsa DA (Saal et al. 2003). Haufinyane, ho boetse ho tlalehiloe hore ho abjoa hape hoa hlobaetsang morphine induces receptor (AMPAR) ho VTA ka mokhoa o ts'oanang le cocaine, haholo-holo kenyelletso ea li-AMPAR tse se nang GluA2 (Brown et al. 2010). Brown et al. e bone lenane le eketsehang la tokiso le cytoplasmic GluA2 AMPAR ha e arabela moriana o hlabang, phello e hlahisoang hape ke ts'usumetso e tobileng ea li-neuron tsa DA ho VTA sebelisa polelo ea boikhethelo ea Channelrhodposin 2 (Brown et al. 2010), e amang ka kotloloho mosebetsi oa DA / ho supa kahare ho VTA ho molawana oa glutamatergic. Lintlha tsena li lumellana le mosebetsi oa pejana oa hore GluA1, empa eseng GluA2, ho tšetleha ho hoholo ho VTA ho etsa hore liphoofolo li tsebe boits'oaro bo botle ba morphine bo ts'oarellang le bo khotsofatsang (Carlezon et al. 1997).

Li-opiates tse sebetsang le tsona li susumetsa polasetiki ho GABAergic synapses ho VTA. Ho hlohlelletsa matla a maqhubu a phahameng ho fumanoe ho etsa hore ho buuoe ka thata ho LTP litsing tsa GABA (LTP)GABA) ho li-neurons tsa VTA DA, phello e itšetlehileng ka ts'ebetso ea li-postynaptic NMDA receptors (NMDAR) le tokollo ea nitric oxide (NO) joalo ka len asosa le khutlang ho tsoa ho li-neurons tsa DA (Nugent le al. 2007). HONA ha joale ho eketsa mosebetsi oa "cyanyase" oa "cycase" ka har'a Gaba neuron, o lebisang ho lokollotsoeng ha GABA le LTPGABA. Tekanyetso e le 'ngoe ea morphine e sitisa PDPGABA ka ho kena-kenana le papali ea NO-GC-protein kinase G (PKG), e bakang tahlehelo ea taolo e tloaelehileng ea thibelo (a hlokometse lihora tse 2 le tse 24 kamora ho entoa, empa eseng matsatsi a 5) (Nugent le al. 2007, 2009; Niehaus et al. 2010). Kahoo, tšitiso ea LTPGABA e fana ka mochine o mong bakeng sa bokhoni ba opiate e hlobaetsang ho eketsa tšebetso ea methapo ea methapo ea VTA DA.

Haufinyane tjena ho hlalositsoe mofuta o mong oa VTA GABAergic plasticity: khatello ea maikutlo ea nako e telele ea li-synapses tsa GABAergic ho li-neurons tsa DA (LTDGABA) (Moruti le Nugent 2011a). E sebelisa tšusumetso ea maqhubu a tlase (LFS), e tsitsitseng ea LTDGABA ka har'a lisele tsa DA ho hlahisitsoe seo, ho fapana le PDPGABA, e hlahisitsoe ka postynaptically mme e sa itšetleha ka NMDAR. Tšusumetso ena e ne e boetse e sa itšetleha ka ho saena hoa endocannabinoid, empa e ne e thibetsoe ke dopamine D2 receptor (D2R) antagonist sulpiride. Ka ho khahlisang, ente e le 'ngoe ea morphine e ne e lekane ho thibela LFS-induction LTDGABA Lihora tse 24 kamora tšebetso, a fana ka tlhahiso ea hore morphine e ka laola polasetiki ea GABA ho VTA (Moruti le Nugent 2011a).

Chronic Opiate-E Khantšitse Synaptic Plasticity

Leha liphetoho tse kopaneng le tse etsahalang ka lebaka la opiate e mpe li bonts'oa hantle, liphetoho tse sa feleng ha li joalo. Ho fihla joale, ke ba 'maloa haeba lithuto leha e le life li hlahlobe liphetoho ho gluatamatergic kapa GABAergic polasetiki mabapi le tsamaiso ea opiate e sa foleng. Sena se kenyelletsa ho hloka tsebo ea hore na ho na le phapang ea taolo e sebetsanang le taolo ea lithethefatsi e sebetsang, tlhahlobo ea bohlokoa e fuoeng mosebetsi oa morao-rao o bonts'ang hore ho phehella hoa PDP ho VTA ea liphoofolo tse sa sebeliseng tsamaiso ea koae (ho fihlela likhoeli tse 3) hoa etsahala. ke feela ka ho pepesehela khokahano ea koae (Chen et al. 2008).

Leha ho le joalo, hoa tsebahala hore morphine e sa foleng, e tšoanang le morphine e mpe haholo, e eketsa tšebetso ea methapo ea DA. Litlalehong tsa vivo tse latelang morphine e sa foleng e bontša ho eketseha ha sekhahla sa ho thunya ha basal le ho phatloha ho hoholo ho khutlisetsang nakong ea ho tlohela (Georges le al. 2006). Sena se fapane le mosebetsi oa nakong e fetileng o boneng ho fokotseha ho sa feleng ha mosebetsi oa DA ho litlelase tse tlositsoeng morphine (Diana et al. 1995, 1999). Lebaka le leng le ka 'nang la baka phapang ena ke mokhoa oa tsamaiso o sebelisitsoeng. Mohlala, ba Georges et al. Boithuto bo sebelisitse "subcutaneous (sc)" e tsitsitseng ea pellet paradigm, e bonts'itsoeng e na le profilodynamic profil e fapaneng le e sa foleng ea ntseng e eketseha ea litekanyetso tsa paradigm e sebelisitsoeng ho Diana et al. lithuto. Joalokaha ho tlalehiloe pejana (Fischer et al. 2008), 24 hr ka mora pellet ea ho qetela ea morphine, methapo ea mali ea morphine ha e fokotsehe, e lula e tsitsitse ka tlhoro (∼3000 ng / ml), ha mohlala oa ente e sa foleng o hlahisa tlhoro e phahameng haholo (∼10,000 ng / ml) ho 1 hr, ka maemo a madi a ka tlase ho 100 ng / ml kamora 4 hr mme e sa tsotelloe ke 12 hr. Phetoho ea sekhahla sa ho thunya sa DA se bakiloeng ke ho tlohela morphine o sa foleng, ekaba ho khutlela molemong oa motheo kapa ho fokotseha ka tlase ho tlase, ho bonahala ho ipapisitse le liphetoho phetohong ea GABA. Ho khaotsa ho tsoa morphine o sa foleng ho eketsa GABA inhibitory postsynaptic currents (IPSCs) le GABA lokolloa ho VTA DA neurons (Bonci le Williams 1997), phello eo haufinyane ho fumanoeng e itšetleha ka ho ts'oaroa ha MOR hape le cyclic adenosine-5'-monophosphate (cAMP) signaling (Madhavan et al. 2010).

Motho e mong ea ka bakang liphapang lipakeng tsa lithuto ke heterogeneity ea VTA ha e bapisoa le LC (joalo ka ha ho hlalositsoe ka tlase). Ha ho na feela ho rarahana ha mefuta e mengata ea lisele tse ngata (haholo-holo GABA vs. DA), empa phetisetso ea mefuta ea lisele le eona e fapana le rostral-caudal VTA axis (Feie. 2). Ka ho khetheha, karolo ea DA ho ea Gaba neurons e phahame haholo ho subostions ea VTA ea Rostral (IFN, RL) ha e bapisoa le subregions tsa caudal (PN, PIF) (Nah-Roberts et al. 2008). Phapang ena e sebetsa hantle phetohong ea boitšoaro bo susumetsoang ke morphine. HSV-GluA1 overexpression e ile ea eketsa boitšoaro ba moputso oa morphine ka ente ho rostral VTA, athe e hlohlelletsa boitšoaro bo nyarosang ho CAD ea VUD, phello e boetse e bonoa mabapi le boteng ba bongata ba protheine ea cAMP-Karabelo-e tlamang protein (CREB) kapa phospholipase C gamma (PLCγ) (Carlezon et al. 2000; Bolanos et al. 2003; Olson le al. 2005). Phapang ena e ka bonoa ho limolek'hule le, ha morcine e sa foleng ea karabelo ea cAMP (CRE) -mediated transcript ho DA neurons ka har'a rostral le caudal VTA, empa e ne e bonoa feela ka li-neurons tse seng tsa DA ho rostral VTA (Olson le al. 2005). Boithuto ba Ultrastological bo netefatsa phapang e joalo ea rostral-caudal, 'me li fana ka tlhahiso ea ho rarahana ha mofuta oa kalafo le tlhahiso. GluA1 e ile ea eketseha ka bobeli tyrosine hydroxylase (TH) -positive (DAergic) le TH-negative (mohlomong GABAergic) dendrites ho parabrachial (PBP) VTA ka ente e le 'ngoe ea morphine. Ka lehlakoreng le leng, ka morphine e sa foleng, ho bile le keketseho ea GluA1 sebakeng sa paranigral (PN) VTA ho kenyelletsa sebaka sa PBP (Lane et al. 2008).

Setšoantšo sa 2. 

Ho rarahana ha cellular le projeke ka har'a VTA. Karolo ea li-neuron tsa DA (tse khubelu) ho GABA (buluu) li fapana pakeng tsa subnuclei ea VTA e nang le DA e phahameng: Litekanyetso tsa GABA tse bonoang maemong a holimo a rostral tse kang rostral linear nucleus (RL) ha li bapisoa le subnuclei e eketsehileng ea caudal e kang paranigral (PN) le parainterfascicular ( PIF) libaka. Ntle le moo, merero ea neuronal ea DA e fapana ho fapana le VTA e nang le libaka tse latelang tsa morao-rao tse kang parabrachial nucleus (PBP) e kenang ho NAc lateral shell (Lat Sh), athe libaka tsa kalafo tse kang PN li na le lipakanyo tse fapaneng tse kenyeletsang amygdala (AMY), preortalal cortex (PFC) , Mantlha ea NAc, le khetla ea medc ea NAc (Med Sh). Mosebetsi o lekanyelitsoeng o hlahlobile tšebetso ea neuronal ea GABA; ho na le bopaki bo bong ba hore li-neurons tsa GABA tse rostral PBP li na le projeke e matla ho PFC, athe ho na le li-neurons tse fokolang tsa PBP tsa DA tse projeke ho PFC, empa projeke e kholo ea David PBP; hona ho fana ka maikutlo a hore projeke ea PBP-PFC ha e hlalosoe feela tikolohong, empa e boetse e tobile ka neuronal-subtype (Lammel et al. 2008). (Lipalo tsa lisele tse sebelisitsoeng li tsoa Nah-Roberts et al. 2008 mme likhakanyo li tsoa lithuto tsa ho ngola mabitso ka Lammel et al. 2008.)

Phapang lipakeng tsa li-neuron tsa VTA DA, tse ipapisitseng le sebaka sa bona sa tlhahiso, li khahliloe haholo haufinyane, kaha ho se ho thehiloe hantle hore thepa ea motlakase ea li-neuron tsa DA e fapana ka ho lekanya. Vta DA neurons e kenelletseng NAc e na le I e nyane haholoh hona joale ho feta li-neuron tse rerileng ho basolateral amygdala (BLA) (Ford et al. 2006), 'me ho na le phapang lipapatso kahare ho NAc ka boeona, ka li-neurons tsa DA tse hlahang ho NAc hamorao khetla e bonts'a phahameng haholoh hona joale ho feta li-neurons tsa DA tse sebelisoang ho NAcLammel et al. 2011). Nako ea ts'ebetso (AP) ea nako ea li-neurons tsa DA le eona e fapana ka ho latellana, ha li-neuron tsa projeke tsa DA li na le nako e telele haholo ea AP, ha nako ea ProC ea proon neuron AP e le khuts'oane, mme li-neurons tsa DAY tse sebelisang DAY li na le nako e khuts'oane haholo (Margolis le ba bang. 2008). Habohlokoa, karabelo ho li-opiate e boetse e bonahala e fapana ho VTA ho latela mofuta oa projeke: Li-neurons tsa DA tse rerang NAc li arabetse ho feta ho lingaka tsa KOR ho feta li-neuron tsa projeke tsa BLA, athe phello e fapaneng e ile ea bonoa bakeng sa ho arabela ho agorist ea MOR / delta (DOR). , e bileng le phello e kholo ho li-neurons tse hlahisang BLA (Ford et al. 2006). Sena se fetoletsoeng ho litlamorao tsa phetoho ea mopresidente le bohareng, joalo ka setsebi sa kelello sa KOR se bakile thibelo e kholo ea GABAA IPSCs ea li-neurons tsa DA e qala ho ea BLA, ha ho ne ho e-na le thibelo e kholo ea boemo ba leholimo ea KORB IPSC ka li-neurons tse hlahisang NAc (Ford et al. 2006). Ntle le moo, haufinyane ho hlokometsoe hore modumo ea li-synapses tse thabisang ho li-neuron tsa DA e fapana ho latela projeketso (Lammel et al. 2011). Lammel le basebetsi-mmoho (2011) e fumane hore karolelano ea AMPA / NMDA e eketsehile ka koae ho li-neuron tsa DA tse bolelang hore li na le NAc, empa eseng ho li-neuron tsa DA tse neng li qalile ka PFC. Leha ho le joalo, karolelano ea AMPA / NMDA e ile ea eketseha liseleng tsa DA tse neng li qala ho fihla ho PFC ka lebaka la ts'usumetso e matla (ente ea hindpaw formalin), e leng tšusumetso e ileng ea boela ea bonoa ho li-neurons tsa DA tse rerileng kameho ea morao ea NAc, empa e le sieo ho li-neurons tsa DA tse kenang ho NAc medial shell-e bontšang heterogeneity e arabelang kahara likarolo tse tlase tsa sepheo sa morero ona (Lammel et al. 2011). Ka ho hlakileng lithuto tsena li bonts'a hore kutlwisiso e phethahetseng haholoanyane ea liphetoho tsa synaptic tse etsahalang ka bobeli le tse sa foleng tsa opiate li tla hloka ho kenyelletsa tlhahisoleseling mabapi le tlhahiso ea li-neuron tsa DA tse ithutoang. Nts'etsopele ea maano a neuron- le projeke e ikhethang e tla thusa ho hlakisa litaba tsena, ka ho lumella ho feto-fetoha ho ikhethang sebakeng sena se phahameng.

Opiate-E kentsoe Sebopeho sa Maiketsetso le Cellular

Kameho ea ts'ebetso ea polasetiki e kentsoeng ke lithethefatsi ho liphetoho tsa synaptic le boits'oaro e shebiloe haufinyane (Russo et al. 2010). Boholo ba lithuto tsa polasetiki ea sebopeho ho tla fihlela joale li hlahlobe liphetoho tsa lesapo la mokokotlo kapa dendritic branching ea li-neuron libakeng tsa sepheo sa VTA, empa laboratori ea rona e fuputse phetoho e ngoe hape ea sebopeho ho arabela taolong ea opiate e sa fetoheng, phetoho ea boholo ba VTA DA neuron soma. Re qalile ho hlokomela hore tikoloho ea "manonyeletso" ea "V" DA "e fokotseha ka ∼25% ha e arajoa ka nako e telele, empa e seng taolo e mpe haholo. (Sklair-Tavron et al. 1996). Phello ena e ne e ikhethile bakeng sa li-neuron tsa DA ho VTA, ha lisele tse nang le TH-negative (mohlomong GABAergic) ha lia ka tsa fetoloa. Ntle le moo, phetoho ena e ka koaloa ke systemic naltrexone, ho fana ka maikutlo a hore ho saena MOR ho ne ho hlokahala, 'me ts'oaetso ea lehae e hlahisitsoeng ke boko ea Vot le eona e thibetse ho fokotseha, ho fana ka maikutlo a hore ho fokotseha ha lentsoe la neurotrophic ho ka baka phetoho ea morphological. Habohlokoa, phokotso ena ea boholo ba li-neuron soma ea VTA DA e bonoa ka tsamaiso e sa feleng ea heroin le morphine (Russo et al. 2007), ka har'a liprothokholi tse itlhommeng pele le tse itaolang (Spiga et al. 2003; Chu et al. 2007; Russo et al. 2007), le ho mefuta eohle, joalo ka ha re sa tsoa tšoaea phello ena ho litoeu tsa panya le linthong tsa postmortem ho tsoa ho batho ba hlekefetsang bahale ba batho (Mazei-Robinson et al. 2011). Lithuto tsa ho latela ha li fumane bopaki ba lefu la kotsi ea methapo ea VTA DA kapa likotsi (Sklair-Tavron et al. 1996; Russo et al. 2007) le hore fokotseho ea boholo ba lisele e tsoela pele matsatsi a 14 ka mor'a tsamaiso ea morphine e sa foleng, empa e khutlela morao ka matsatsi a 30. Liraka tsa nako ena li fana ka mamello (Russo et al. 2007), moo tšebeliso ea lithethefatsi khafetsa e theolang phello e ntle ea lithethefatsi 'me e lebisa ho nyoloheng ha tšebeliso ea lithethefatsi, joalo ka batho (O'Brien 2001).

Ka lebaka la hore BDNF e ka pholosa phetoho e sa feleng ea morphine e kentsoeng, re ne re batla ho hlahloba hore na methapo e fokotsang methapo ea methapo ea methapo e tsamaeang ka polokeho ea polasetiki ena. Leha ho na le khang ea hore na maemo a BDNF ka boeona a fetotsoe ho VTA ho latela taolo ea opiate e sa foleng.Numan le ba bang. 1998; Chu et al. 2007; Koo et al. 2010), melaoana e tlalehiloe litseleng tse tharo tse kholo tsa ho theoha BDNF: PLCγ, phosphatidylinositol 3'-kinase (PI3K), le minogen-activated protein kinase (MAPK) (Russo et al. 2009). Morphine e sa foleng e eketsa ts'ebetso ea tsela ea PLCγ (Wolf le al. 1999, 2007), e fokotsa ts'ebetso ea tsela ea PI3K, joalo ka ha e lekantsoe ke insulin receptor substrate-2 (IRS2) le maemo a phospho-AKT (Wolf le al. 1999; Russo et al. 2007; Mazei-Robinson et al. 2011), hape e eketsa ho saena ha MAPK, joalo ka ha e lekantsoe ke ho eketseha ha phosphorylation le ts'usumetso ea tšebetso ea protheine e amanang le extracellular-kinase (ERK) (Ortiz le al. 1995; Behow et al. 1996; Liu et al. 2007). Re sebelisa overexpression ea bongata bo pakeng tsa bongata ba kokwanahloko, re fumane hore ke phetoho e sa feleng e susumetsoang ke morphine ho lets'oa la PI3K e kenyang phetoho ea morphological: Ho pepeta ho hoholo ha IRS2 (IRS2dn) kapa AKTdn e ne e lekane ho fokotsa boholo ba soma ea VTA, ha mokhoa o hlakileng oa mofuta oa hlaha oa IRS2 o ne o thibela ho fokotseha ho matla ha morphine o bakiloeng le ho ts'oaroa ho hoholo ha mofuta oa AKT (AKTca) (Russo et al. 2007; Mazei-Robinson et al. 2011). Ho fapana le moo, ho tebisa maikutlo ho feta ha PLCγ kapa ERK ho ne ho sa lekana ho fetola boholo ba sapa ea VTA DA (Russo et al. 2007). Habohlokoa le ho feta, ho tšetšetha ka matla ha IRS2 ho bile ho khona ho thibela mamello ea moputso oa morphine, ho beha karolo ho sebopeho sa polasetiki ho karabelo ea boitšoaro.

Mosebetsi oa rona oa morao-rao o fana ka maikutlo a hore phetoho ena ea sebopeho e kanna ea hokahana haholo le liphetoho tse etsahalang ke lingaka tse sa foleng. Hoa tšoana le thutong ea vivo ea Georges et al. ho tšohliloe ka holimo, re fumane hore sekhahla sa ho thunya VTA DA se ile sa eketseha ka nako e le ngoe eo boholo ba soma bo fokotsehang ho litoeba tse pepesitsoeng ke morphine o sa feleng. (Mazei-Robinson et al. 2011).

Leha ho le joalo, re fumane hore tlhahiso ea DA ho NAc, joalo ka ha e lekantsoe ke vivo cyclic voltammetry, ehlile e fokotsehile, e fana ka maikutlo a khefutso ho ts'ebetso e tloaelehileng le tlhahiso ea "mesolimbic" potoloho.

Re boetse re tšoaea sephetho sena mme ra fumana hore IRS2dn overexpression ho VTA, e lekaneng ho fokotsa boholo ba DA soma, e fokotse tlhahiso ea DA ho NAc mme le eona e fokotse polelo ea tse 'maloa K+ seteishene se kenella, ka tsela e ts'oanang le morphine e sa foleng.

Boitekong ba rona ba ho fumana litsela tse tšoaeang liphororo tse tlohang IRS2 / AKT tse kopanyang moruro o sa feleng oa morphine, re ile ra hlokomela ka mokhoa o makatsang hore sepheo sa "mamamalian lengo" la rapamycin (mTOR) tataiso ea 1, mTORC1) , ha e le hantle e ile ea eketsoa ke morphine e sa foleng. Ho fapana le moo, re bone ho fokotseha ha matšoao a mTOR tata 2 (mTORC2), ao re ileng ra tsoela pele ho a bontša ho hlokahala ebile ho lekane bakeng sa liphetoho tse susumetsoang ke morphine ka boholo ba soma le ts'ebetso ea neuronal. Ka ho khetheha, re fumane hore overexpression ea rapamycin-insensitive molekane oa mTOR (Rictor), protheine ea bohlokoa ea mTORC2, e ne e lekane ho thibela ho theoha ha boholo ba soma hape e thibetse keketseho ea sekhahla sa ho thunya ha neuron ho DA ka tsela ea selefouno: ke lisele tsa DA feela ho VTA tse hatellang Rictor ho feta tse neng li le boemong ba ho thunngoa, athe lisele tsa DA tse haufinyane li ne li ntse li supa keketseho. Sena se fana ka maikutlo a hore ho supa liphetoho tse kenelletseng ho li-neuron tsa DA ho ka kena lipakeng liphetoho tse tlisoang ke lingaka tse sa foleng, mohlomong ka ho fetola modumo ea AKT ea GABAA maqhubu (Krishnan et al. 2008) kapa polelo ea K+ menyetla (Mazei-Robinson et al. 2011) (Feie. 3). Joalo ka IRS2 overexpression, re fumane hore phetoho ea ts'ebetso ea mTORC2 e tsamaellane le boitšoaro ba moputso oa morphine, kaha mesebetsi e fokotsang mTORC2 e fokotsehile morphine conditioned place preference (CPP), ha ts'ebetso ea MTORC2 e ne e lekane ho kenya CPP tekong e tlase ea morphine e sa khanneng. sebaka boemo ba liphoofolo tse laoloang.

Setšoantšo sa 3. 

Morphine e sa foleng e fokotsa boholo ba soma ea VTA DA leha ho le joalo e eketsa thabo ea neuronal, athe phetisetso ea DA ho NAc e fokotsehile. Litlamorao tsa morphine ke tsela e sa arabeloang haholo ea moputso, e leng, mamello ea moputso. Pholoso ea tlase ea IRS2-AKT signaling (e putsoa) ho VTA mediates litlamorao tsa morphine o sa foleng ka boholo ba soma le thabo ea motlakase; litlamorao ho thabo li kopantsoe ka GABA e fokotsehilengA maqhubu le khatello ea K+ polelo ea seteishene. Morphine-indedu-regulation ea tšebetso ea mTORC2 ho VTA e bohlokoa bakeng sa liphetoho tsena tsa morphine le morphological le mmele hammoho le mamello ea moputso. Ho fapana le mTORC2, morphine e sa foleng e eketsa tšebetso ea mTORC1 (e khubelu), e sa bonahaleng e susumetsa ka kotloloho litloaelo tsena tse susumetsoang ke morphine. Morphine e sa foleng e boetse e fokotsa tlhahiso ea DA ho NAc, hammoho le ho fokotsa makala a dendritic le palo ea methapo ea methapo ho li-spiny GABA neurons tse bohareng tsa NAc, le ho hatella ho feta ho saena ho tloaelehileng ha DA ho potolohong ea mesolimbic.

Ha ho na monyetla oa hore phetoho ea boholo ba soma ke eona feela phetoho e hlophisitsoeng e entsoeng ke opiate e sa foleng ea VTA. Ka lebaka la palo e tlase ea mokokotlo oa dendritic le ho fokola ha dendritic ha lekala la li-neurc le spiny neuron le pakeng tsa likhoto li kile tsa pepesoa ke morphine e sa foleng.Robinson le Kolb 1999; Robinson et al. 2002), re lebelletse hore liphetoho tsa dendritic le tsona li etsahala ka har'a li-neuron tsa VTA DA. Lithuto tsa hona joale li ntse li tsoela pele ho supa phetoho ea morusu morphology, lekhalo le leholo tšimong, ha thuto e le 'ngoe feela ho fihlela joale e lekotse liphetoho tse susumetsoang ke lithethefatsi ho meaho ea li-dendritic tsa VTA. Phuputso ena e fumane keketseho ea dendritic spine density ho subtype e le 'ngoe ea VTA ha e arabela jekeng e mpe ea cocaine, subtype e tšoanang e bontšitsoeng e bonts'a keketseho ea NMDA / AMPA e eketsehang (Sarti et al. 2007). Lintlha tse tsoang mosebetsing oa rona o fetileng, bolelele ba lits'ebetso tsa VTA DA bo fokotsehile (∼30%) ho likhoto tse tšoaroang ke morphine e sa foleng (Sklair-Tavron et al. 1996), e tsamaellana le liphetoho tsa lefats'e tsa kaho ea VTA DA. Phetoho ena e ka thusa ho hlalosa ho fokotseha ha tlhahiso ea DA ho NAc kamora morphine e sa foleng, joalo ka ha re boletse pejana ho fokotseha ha lipalangoang tsa axonal le maemo a liprotheine tsa neurofilament ho VTA (Beitner-Johnson et al. 1992, 1993), ho fana ka maikutlo a hore morphine e sa foleng e boetse e ama sebopeho le tšebetso ea axonal. Ka lebaka la ho rarahana ha lebatowa le boiketsetso ho li-neurons tsa VTA DA tse boletsoeng ka holimo, ha joale re ntse re hlahloba hore na liphetoho tsena tsa sebopeho li kentsoe ka har'a setheo se itseng sa li-neuron tsa VTA DA li sebelisa li-tracers tsa fluorescent. Lintlha tsena e tla ba tsa bohlokoa ho utloisisa liphetoho le sebopeho sa elektroniki se hlahisoang ke li-opiates tse sa feleng le lipotoloho tse amehang tse amehang.

Joalokaha ho boletsoe pejana, lithuto tse 'maloa, tsa limolek'hule le tsa motlakase, li fane ka bopaki ba hore tsamaiso e sa fetoheng ea opiate e kenya tšebetsong tsela ea CAMP-CREB ho VTA (Bonci le Williams 1997; Olson le al. 2005; Madhavan et al. 2010). Hape, phuputso e entsoeng ka microarray e hlalositse liphetoho tsa lefats'e tsa mofuta oa gene tse hlahang VTA ha li araba morphine o sa foleng (McClung et al. 2005). Hona joale ho hlokahala mosebetsi oa ho hlalosa ka ho hlaka semelo sa li-neuroadaptations tsena le ho hlakisa litholoana tsa tsona tse sebetsang. Ntle le moo, le ha mosebetsi o mongata ho VTA o tsepamisitse maikutlo ho oproate-induro neaptadionations eo ho nahanoang hore e etsahala ho li-neuron tsa DA, ho bohlokoa ho hlahloba polasetiki e entsoeng ke lithethefatsi e hlahang ho "GABAergic neurons" ea VTA, e leng e 'ngoe ea lipheo tsa mantlha tsa ts'ebetso ea opiate ho sebakeng sena sa boko.

LECUS COERULEUS

Background

LC ke sebaka sa mantlha sa norepinephrine (NE) - se nang le li-neurons bokong (Dahlstrom le Fuxe 1965). Joalokaha ho hlahlojoa pele (Aston-Jones le Bloom 1981a; Aston-Jones et al. 1991b; Berridge le Waterhouse 2003; Van Bockstaele et al. 2010), LC ke senotlolo se kopanetsoeng, se kopanetsoeng, se nang le moea o fapaneng, se nang le li-neurons tse ikhethang tsa NE. Likenyelletso tse kholo ho LC li tsoa ho medullary nucleus paragigantocellularis (PGi) le li-nucleus prepositus hypoglossus, 'me liphetho tsa LC li atile ho kenyeletsa forebrain, cerebellum, brainstem, le lesapo la mokokotlo (Feie. 1) (Berridge le Waterhouse 2003). Ts'ebetso ea methapo ea methapo ea kutlo ea LC e lumellana haholo ha e le hantle ebile e le karabelo ho susumetso (Foote et al. 1980; Aston-Jones le Bloom 1981b; Aston-Jones et al. 1991a; Ishimatsu le Williams 1996). Li-neuron tsa LC li sebetsa ka boithatelo (Williams et al. 1991) mme ts'ebetso ea bona ea ts'ebetso e etsa hore NE e lokolloe libakeng tse 'maloa tsa bokapele ho kenyeletsa cortex le hippocampus. LC haholo e sebetsa joalo ka khubu ea "relay", e nang le polasetiki e fokolang e bonoang ho fihlela joale, le ha barekisi ba glutamate ba laola ts'ebetso ea LC, haholo ho tloha PGi (Ennis le al. 1992). Li-neuron tsa LC li hlahisa lihlopha tse tharo tsa mantlha tsa li-opioid receptors: MOR, DOR, le KOR ka ho ajoa ka mokhoa o hlakileng, leha ho le joalo, joalo ka VTA, puisano ea rona e lekanyelitsoe ho MOR, e sebetsang haholo ka kotloloho ho ts'epahalong le bokhobeng ba opiate.

Cellular ea Opiate-E Etselitsoeng

Le ha ho se na bopaki ba polasetiki ea setso ea synaptic (ke hore, LTP le LTD) ho LC, ho na le cellular e hlalositsoeng hantle ea cellular. Karolo e ikhethang ea LC ke hore likarabo tsa eona tse ngata tsa vivo ho li-opiate tse sa foleng li ka phetoa hape tsa ithutoa setsing se le seng (Nestler et al. 1994; Nestler le Aghajanian 1997; Nestler 2004). Ho tlangoa ha opiates (mohlala, morphine) ho MOR ho lebisa ho fokotseha hoa ts'ebetso ea adenylyl cyclase (AC) le ho saena hoa CAMP (Duman et al. Ka 1988). Ho tlangoa ka matla ha opiates ho MOR le hona ho fokotsa ts'ebetso ea pacemaker ea li-neuron tsa LC, haholoholo ka ho kenya tšebetsong protheine ea G kahare kahare-ho lokisa K.+ (GIRK) dikanale (Williams et al. 1982; Torrecilla et al. 2002). Leha ho le joalo, ka tsamaiso e sa foleng ea opiate, sekhahla sa ho thunya le cAMP e khutlisetsang ho motheo ka lebaka la taolo ea tsela ea CAMP, e bonts'a mamello (1978 ea Aghajanian; Duman et al. Ka 1988; Nestler le Tallman 1988; Guitart le Nestler 1989; Kogan et al. 1992; Ivanov le Aston-Jones 2001). Plastiki ena e susumetsoang ke tsamaiso ea opiate e sa foleng (ke hore, cAMP way up-regulation) e bonahala ka mokhoa o hlakileng ts'ebetsong ea ho tlosa opiate, ha sekhahla sa ho thunya ha li-neurons tsa LC se eketseha haholo hammoho le keketseho e kholo ea ts'ebetso ea cAMP, e bonts'ang ho itšetleha le ho tlosoa (Feie. 4) (1978 ea Aghajanian; Rasmussen et al. 1990).

Setšoantšo sa 4.  

Tlhahiso-leseling ea tseleng ea cAMP ho LC e le mokhoa oa ho mamellana le ho ts'epahalla. Top phanele, Opiates e sitisa ts'ebetso ea ts'ebetso ea cAMP (e bonts'itsoeng ke maemo a cellular a cAMP le phosphorylation ea protocol ea cAMP). Ka ponelopele e tsoelang pele ea ts'ebetso, ts'ebetso ea ts'ebetso ea tsela ea cAMP butle-butle ea hlaphoheloa, 'me e eketsehe maemo a holimolimo a taolo kamora ho tlosoa hoa opiate (mohlala, ka ts'ebetso ea opioid receptor antagonist naloxone). Liphetoho tsena tšebetsong ea tsela ea cAMP li tsamaisoa ka ho kenella ka li-cyclase tsa adenylyl (AC) le protein kinase A (PKA) mabapi le tsamaiso e sa fetoheng ea opiates. Ho kenyelletsoa ha li-enzyme tsena ho etsa hore ho hlaphoheloe butle mesebetsing ea tsela ea cAMP e etsahalang nakong ea ho pepeseha ha opiate (mamello le ts'ehetso) le ts'ebetso ea ts'ebetso ea cAMP e hlokometsoeng ka ho tlosoa ha opiate (ho tlosoa). Bottom phanele, Opiates e thibela li-neuron tsa LC ka ho eketsa ho tsamaisa ha K ho hlophisa bocha K+ mocha ka ho kopanya le li-subtypes tsa Gi / o hape, mohlomong, ka ho fokotsa Na+-itshetleha kahare hona joale ka ho kopanya le Gi / o le thibelo e hlahlamang ea AC, ho fokotsa maemo a ts'ebetso ea PKA, le ho fokotsa phosphorylation ea mocha kapa pompo e ikarabellang. Ho thibela tsela ea cAMP hape ho fokotsa phosphorylation ea liprotheine tse ling tse ngata, 'me ka hona, e ama mekhoa e meng e mengata ea neuronal. Mohlala, e fokotsa boemo ba "phosphorylation state" (CREB) ea phosphorylation, e hlahisang liphetoho tse ling tsa nako e telele mosebetsing oa LC. Tsamaiso e sa feleng ea morphine e eketsa maemo a ACI, ACVIII, PKA catalytic (katse.) Le subunits tsa taolo, le li-phosphoprotein tse 'maloa, ho kenyelletsa CREB le tyrosine hydroxylase (TH) (e bontšitsoeng ke metsu e khubelu). Liphetoho tsena li thusa ho fetoleng mofuta oa naha e lemaletseng lithethefatsi. Mohlala, thabo e makatsang ea li-neuron tsa LC e eketsoa ke ts'ebetso e ntlafalitsoeng ea tsela ea cAMP le Na+-e itšetlehileng ka hare hona joale, e tlatsetsang ho mamelleng, ho ts'epahallang, le ho khaola ho bontšoa ke li-neuron tsena. Up-regulation of ACVIII and TH is mediated via CREB, athe up-regulation of ACI le ea PKA subunits e bonahala e hlaha ka mochine o ikemetseng oa CREB o ikemetseng.

Liphetoho tsena li kopantsoe ka phepelo ea liprotheine tse 'maloa tse tšoaeang tseleng ea cAMP ho kenyelletsa AC1 / 8 (Matsuoka et al. 1994; Lane-Ladd et al. 1997; Zachariou et al. 2008), cAMP e itšetlehileng ka protheine kinase (PKA) (Nestler le Tallman 1988), CREB (Guitart le al. 1992; Shaw-Lutchman et al. 2002; Monghali Han et al. 2006), le liphutheloana tsa CREB ka bobeli ()Guitart le al. 1989; Akbarian le al. 2002). Li-opiates tse sa feleng li boetse li kenya polelo ea GIRK2 / 3 ho LC (Cruz et al. 2008) hammoho le mefuta e meng e mengata e joalo ka ha ho senotsoe ke tlhahlobo ea Microarray (McClung et al. 2005). Ho feta moo, haufinyane ho bonts'itsoe, ho sebelisa mohlala oa setso sa LC, hore ts'ebetso e eketsehileng ea motlakase ea LC neurons e hlahisoang ke opiates e sa foleng e bakoa ke ts'ebetso e tobileng ea MOR ho li-neuron tsa LC NE, e etsa hore ho be le mokhoa o makatsang oa homeostatic (Cao et al. 2010). Mokhoa ona o bonts'a karolo ea bohlokoa bakeng sa CREB mesebetsing ea pacemaker le keketseho ea morphine e susumetsang sekhahla sa ho thunngoa hoa LC (Monghali Han et al. 2006; Cao et al. 2010), phello e ileng ea boela ea bonoa ho litoeba ka ho kokota ha nts'etsopele ea CREB e ikhethileng ho li-neuron tsa NE (Parlato et al. 2010). Kamora nako, ts'ebetso ena ea ho thunya ha methapo ea LC, le tsela e laoloang ea CAMP-CREB, e sebelisang ho fofa ho eketsehileng, ho bontšitsoe lithutong tse ngata hore ho hlokahala ebile ho lekane ho nka matšoao a 'maloa a ho tlohela ha opiate ea' mele (Lane-Ladd et al. 1997; Punch le al. 1997; Monghali Han et al. 2006).

Leha boholo ba polasetiki e hlohlellelitsoeng opiate e hlalositsoeng mona e hlahisoa e le litakatso tsa methapo ea LC NE, ho na le bopaki bo bong ba hore morphine e sa foleng le eona e ka susumetsa ho kenya litlatsetso ho LC kaha ho na le keketseho ea khafetsa ea EPSC khafetsa lipakeng tsa litoeba tse tsoang ho morphine e tšoeroeng ke morphine (Torrecilla et al. 2008). Ntle le moo, ho na le keketseho ea ho nts'oa ha glutamate le aspartate ho LC ho vivo literekeng tse tlositsoeng morphine le ts'ebeliso ea lehae ea li-amino acid antagonists ho LC ka mokhoa o thibelang keketseho e tlisoang ke ho tlosoa hoa mosebetsi oa LC (Akaoka le Aston-Jones 1991; Aghajanian et al. 1994).

Phehisano e 'ngoe e ntse e le mabapi le hore na liphetoho tsa cAMP-CREB signaling ea LC le tšebetso ea methapo ea methapo ea kutlo ea LC li sebetsa. Mohlala, ho ruruha ha LC, kapa nts'etsopele ea ts'ebetso ea CREB ho li-neuron tsa LC NE, e sitoa ho fetola matšoao a ho tlohela (Christie le ba bang. 1997; Parlato et al. 2010). Ho fapana le hoo, re bonts'itse hore modumo oa ts'ebetso ea tsela ea cAMP kapa ea CREB ho LC ea liphoofolo tse kholo o lula a thibela boits'oaro bo bongata ba ho tlohela (Lane-Ladd et al. 1997; Punch le al. 1997; Monghali Han et al. 2006). Re lumela hore lintlha tse 'maloa tsa bohlokoa tse hlalosang liphetho tsena li fapane. Taba ea mantlha, LC ke e 'ngoe ea likarolo tse' maloa tsa boko tse bohlokoa bakeng sa ts'ebeliso ea opiate ea mmele le ho tlohela (Koob le Le Moal 2001). Ha ho makatse hore liphoofolo tse nang le li-LC tse se nang leseli li ntse li nts'etsapele matla a tebileng a ho its'etleha ka ho ts'epahala ho itšetleha ka likarolo tse ling tsa neural. Taba ea bobeli, ho utloahala haholo hore lisebelisoa tse ling tse sebelisoang ho thetsa tšebetso ea tsela ea CAMP ho LC (mohlala, infusion ea lehae ea baetsi ba PKA kapa li-inhibitors) li susumetsa barekisi ba glutamatergic sebakeng sena, bao le bona ba bonts'ang liphetoho tsa polasetiki (ho kenyeletsoa tsela ea cAMP ho nyoloha- regulation) kamora morphine o sa feleng (Nestler 1992; Christie le ba bang. 1997). Taba ea boraro, ho sa tsotellehe karolo e ka 'nang ea etsoa bakeng sa liphatlalatso tsena tsa glutamatergic, ha ho na potso ea hore polasetiki ea methapo ea kutlo ea LC NE e boetse e ameha, hobane ho ts'oaroa hoa CREB ho motho ea moholo LC (ho ke keng ha ama li-terminals tsa nerve tse amanang) ho sitisa thabo e atileng ea morphine ea LC NE li-neurons le ho amohela ho tlosoa (Cao et al. 2010; V Zachariou le EJ Nestler, unsubl.). Ho hloka matla ha CREB ho kokota ho tsoa litsong tsena tsa methapo ho litloholo tse nang le maemo a itseng (Parlato et al. 2010) e totobatsa likhakanyo tsa nts'etsopele tse kopantseng ts'ebeliso ea meetso ea pele ea ho khemisa le ho totobatsa bohlokoa ba ho sebelisa liphatsa tsa lefutso mohopolong o moholo o khetholloang ka botlalo ha o ithuta polasetiki ea batho ba baholo.

Kahoo, leruo la liteko tsa liteko le theha molao-motheo oa tsela ea cAMP-CREB e le mochine oa polasetiki ea homeostatic ea methapo ho li-neurons tsa LC NE ho nts'etsapele ts'epo ea opiate ea 'mele. Ho bohlokoa hape ho totobatsa bohlokoa ba nalane ea mosebetsi ona ho LC, joalo ka ha e ne e sebetsa e le mohlala oa liketso tsa nako e telele tsa opiates bokong: ho ipapisitse le lipatlisiso tsa pejana tsa LC, taolo ea cAMP-CREB tsela esale e bontšoa e le mokhoa o tloaelehileng oa mamello ea opiate, ho its'etleha, le ho khaola libakeng tse ngata tsa methapo ea methapo e bohareng le e sa sebetseng 'me kannete e emela e le e' ngoe ea mehlala e metle ea motheo ea ts'ebetso ea molek'hule ea lithethefatsi (Nestler 2001, 2004).

TLHALOSO EA PELE EA TLHOKOMELISO

Ho fihla joale, ha ho so ka ho ba le tlhaloso ea polasetiki ea sebopeho ho li-neuron tsa LC mabapi le tsamaiso ea opiate e sa foleng. Ha joale re ntse re hlahloba hore na ho na le liphetoho tsa boholo ba soma li-neurons tsena tse amanang le liphetoho tse bonoang ke li-neuron tsa DA ho VTA. Leha ho le joalo, lintlha tse peli tsa bopaki li fana ka maikutlo a hore mofuta ona oa phetoho o kanna oa se ke oa sebetsa ho LC. Taba ea pele, lipetlele tse tloaelehileng tsa axonal le maemo a liprotheine tsa "neurofilament" a ile a bonoa ho LC kamora lefu la morphine le sa foleng le fapaneng le VTA (Beitner-Johnson et al. 1992; Beitner-Johnson le Nestler 1993), ho fana ka maikutlo a hore tšehetso ea trophic ea sebopeho sa neuronal e kanna ea se amehe. Taba ea bobeli, ha re fumana hore palo e eketsehang ea ho thunya ke karolo ea bohlokoa phetohong ea soma, phapang lipakeng tsa taolo ea litheko ho LC le VTA e kanna ea ba tsa bohlokoa. Ka mantsoe a mang, VTA, e opaates ka mokhoa o hlakileng le ka mokhoa o sa lekanyetsoang oa ho thunya ha liseke le vivo, mme re bona palo e fokotsehileng ea sele e lekanang ka lebaka la keketseho ena ea sekhahla sa ho thunya. Tekanyo ena e ntseng e eketseha e ntan'o thatafala kapa e fokotsehe ka tlase ho liphoofolo tse tlisoang ke opiate. Hobane ho na le bopaki bo tsoang mosebetsing oa rona (Russo et al. 2007), le ba bang (Spiga et al. 2003), hore boholo ba soma bo boetse bo fokotsehile linakong tsa nako tsa morao-rao, ha sekhahla sa ho thunya se fokotsehile, e kanna ea ba keketseho ea pele ea sekhahla sa ho thunngoa e bohlokoa bakeng sa ho kenyelletsa kapa ho boloka phetoho ea morphological. Ka lehlakoreng le leng, ts'ebetso ea neuronal ea LC e fokotsehile haholo ke tsamaiso ea morphine, e khutlela mehatong ea motheo ea vivo ka tsamaiso e sa foleng, 'me e eketseha ka holim'a maemo a tloaelehileng feela a ho tlosoa ha opiate. (Tsena ponong ea vivo li fapana le se etsahalang litsong tsa methapo ea boko, moo sekhahla se ntseng se eketseha sa ho thunya le "cAMP-CREB -way -way regulation" se etsahala maemong a sa foleng a morphine a tšoeroeng [a itshetlehile], ntle le ho tlohela [Cao et al. 2010.) Lintlha tsena li fana ka maikutlo a hore, athe morphine e sa foleng e kanna ea se ke ea baka phetoho ea polasetiki ea sebopeho ho LC li-neuron ka vivo, ho itokolla ho morphine. Ho ts'ehetsa mohopolo ona, liphetho tsa lipatlisiso tsa rona tsa microarray tsa LC li fumane hore mefuta e 'maloa e kenyelletsang kholisong ea sele le sebopeho e fokotsehile kapa e sa fetohe ka morphine e sa foleng, empa ea eketseha ka ho khaotsa (McClung et al. 2005). Hoa tsebahala hore ho fokotseha ha nako e telele molemong oa ho thunya ha "LC neurons" ha hoa lekana ho fetola boholo ba soma, hobane CREB e tsoang ho LC NE neurons ha ea ka ea fetola boholo ba neuronal empa ea fokotsa mosebetsi oa basal (Parlato et al. 2010). Leha ho le joalo, hape ha re a ka ra bona phapang ea boholo ba mofuta oa VTA DA ha re hatella K+ mocha oa ho fokotsa sekhahla sa ho thunya (Mazei-Robinson et al. 2011), kahoo Parlato et al. Seo u se boneng ha se qobelle monyetla oa phetoho e susumetsoang ke morphine. Leha ho le joalo, ho lokela ho hopoloa hore mochine o arolelanang liphetoho lipakeng tsa ho thunya lipakeng tsa likarolo tse peli tsa boko o fapane haholo, o bile le liphetoho ho AKT signaling, GABAA maqhubu, le K+ polelo ea seteraeke e amehang ho VTA le cAMP-CREB ho supa e na le tšusumetso ho LC.

TLHOKOMELISO REMAKHE

Ka kopanelo, data e tsoang VTA le LC e bonts'a liphetoho tse rarahaneng le tsa bohlokoa ho li-synaptic, cellular, le sebopeho sa polasetiki tse arabelang litlamorao tse sa feleng tsa lithethefatsi tsa opiate bokong ba neurone le mefuta e meng ea li-neuronal libakeng tsena, tseo ka tšohanyetso li fetisang lithethefatsi moputso le ho itshetleha. Leha polasetiki e thehileng ts'ebetso e matla ea opiate libakeng ka bobeli, le ts'ebetso e sa foleng ea opiate ho LC, e tsebahala hantle, lithuto tsa nako e tlang lia hlokahala ho hlakisa polasetiki e etsahalang ka tsamaiso ea opiate e sa feleng ho VTA mabapi le phapang e bonoang ho mefuta e mengata ea sele le mehatong e mengata ea ho kenyelletsa esita le ea mofuta o le mong. Tsoelo-pele e joalo e tla kenya letsoho kutloisisong e ntle ea hore na li-opiates li susumetsa sebaka sena sa boko joang ho laola moputso 'me qetellong bo lemale. Kutloisiso e joalo ea liphetoho tse tšoarellang halelele tse susumetsoang ke li-opiate tsa VTA le LC ha li na ho ntlafatsa tsebo ea rona ea boits'epo ba ho itšepa le ho lemalla, empa hape e tla re thusa ho hlakisa ho kenella hoa bongaka.

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