Nchọpụta nke neuroplasticity nke opioid nke opioid nke dopaminergic neurons na mpaghara ikuku na-emetụta utom na ụgwọ ọrụ opia (2014)

IHE: The Nnyocha DeltaFosB anyị na-ekwukarị ihe niile echebara na nucleus accumbens (ụgwọ ọrụ ụgwọ), wee chọpụta na mmekọahụ na-eme njem otu usoro ụbụrụ dị ka meth & cocaine. Site na omumu ihe omumu site na otu onye nyocha (Ngwá Ọrụ Na-ahụ Maka Ọrịa na Ọgwụ Na-eme Omume na Ihe Ndị Na-emepụta Ngwá Ọrụ Na-emekarị Ihe na ΔFosB dịka Onye Mgbasa Ozi Dị Ukwuu (2013)):

Ya mere, ụgwọ ọrụ nke okike na ọgwụ abụghị naanị na-agbakọta n'otu ụzọ ahụ, ha na-agbakọta na otu ndị ogbugbo molekụla, yana ikekwe n'otu akwara ahụ na Nucleus Accumbens, iji metụta ikike na-akpali akpali na "ịchọ" ụdị ụgwọ ọrụ abụọ ahụ

Ihe na-ewepụ: meth, cocaine, na mmekọahụ niile na-eme otu ihe ahụ dị mkpa n'otu mkpụrụ ndụ nerve na ụlọ ọrụ ụgwọ (nucleus accumbens), ihe ọ bụla ha nwere ike ime n'ụzọ dị iche iche na ụbụrụ. Nke a na-eme ka okwu ahụ na-ekwu na ụgwọ ọrụ anụ ahụ na ọgwụ ọjọọ dị iche na usoro na mmetụta.

Ọmụmụ ihe ọhụrụ a nyochare ihe mmekọahụ na-eme na VTA. VTA bụ ebe mkpụrụ ndụ akwara na-emepụta dopamine na-amalite - ha na-agbanyekwa na ngwongwo na-ebuwanye ibu, cortex dị n'ihu, na amygdala. Ihe bụ isi bụ VTA bụ isi iyi (isi iyi) nke ọtụtụ dopamine. Lee foto 2 a nke sekit ụgwọ ọrụ: Pic1, Pic2

Ndị nchọpụta chọpụtara na inwe mmekọahụ (njedebe) na-eme ka sel ndị dị na VTA kwụsịtụ nwa oge (na ụmụ nwoke). Ahụike sel na dendrites ghọta ihe isi awọ nke ụbụrụ. Nke a bụ kpọmkwem ihe heroin riri ahụ na VTA (Ọ bụghị otu oge iji heroin, ma na-adịghị ala ala heroin eji). Rịba ama na otu shrinkage a nke sel VTA na-eme na ogwugwu heroin.

Mkpịsị nke cell sistemụ na-adịgide adịgide na-adịru ma ọ dịkarịa ala ụbọchị 7. Mgbanwe ndị gbanwere site na mmekọahụ enweghachiri na 30 ụbọchị, ma ndị nchọpụta na-enyocha ụbọchị 1, 7, na 30.

Mbelata nke mkpụrụ ndụ cell na ị inụ ọgwụ ọjọọ heroin na-eme ka obere dopamine na ụbụrụ na-ebuwanye ibu - ma ọ bụ ihe anyị na-akpọ deensitization. Ndị nnyocha ahụ nyere morphine ahụ na ụmụ oke iji nyochaa nzaghachi ha (mgbe ha nwesịrị mmekọahụ), mana ọ nweghị ihe mere. Oge ụfọdụ oke dị ka morphine ahụ dị ukwuu, mana ebe a ka ọ dịkwaghị ka ọ dị nwa oge. Na nkenke, oke ụgwọ ọrụ ụgwọ ọrụ na-adịghị anabata ọkwa dị ala nke heroin. Ndị nchọpụta kwubiri na a ga-achọ ọgwụ dị elu iji kpata mmeghachi omume oke "nkịtị".

Na mkpokọta - Mmekọahụ (nwa oge) na-eme otu ihe ahụ na VTA dị ka ihe riri ahụ na heroin: ịda mbà nke dopamine na-emepụta ahụ mkpụrụ ndụ akwara. Nke a na - eduga obere dopamine na ụlọ ọrụ nkwụghachi ụgwọ, yana obere nzaghachi maka ọgwụ ọjọọ - ọ ga - ewe opekata mpe ụbọchị 7 maka ụbụrụ oke ka ọ gbakee.

 

J Neurosci. 2014 Jun 25;34(26):8825-36. dị: 10.1523 / JNEUROSCI.0133-14.2014.

Ndị na-akụ ụta KK1, Coppens CM2, Gwa LN3, Fuller J2, Van S2, Frohmader KS2, Laviolette SR2, Lehman MN4, Coolen LM5.

nkịtị

Ngwongwo nke ndi mmadu na ndi ozo eji eme ihe ndi mmadu na-achikota n'uzo mgbochi ma megharia usoro ozo nke ikuku plastic na acumbens accumbens. Ogologo oge ikpughe na opiates na-adọta plasticity na neurot dopaminergic nke mpaghara mmebi (VTA), nke na-achịkwa ụgwọ ọrụ nke morphine.

N'ebe a, anyị na-anwale ụbụrụ ndị na-eme ka mwepụ nke opioids dị na VTA na-akpata mgbanwe morphological nke VTA dopamine sel na oke oke, nke na-eme ka o doo anya okwu ogologo oge nke mmetụ ahụ na-eme ka ị nwee mmekọahụ.

Mbụ, ahụmahụ mmekọahụ belata VTA dopamine amalite 1 na 7 ụbọchị, ma ọ bụghị 30 ụbọchị mgbe ikpeazụ ngwugwu nnọkọ. A na-egbochi mmetụta a na naloxone tupu oge ọ bụla ọ bụla; ya mere, VTA dopamine cell plasticity bụ dabere na omume nke endogenous opioids.

N'aka nke ya, a na - ejikọta plasticite VTA na ụgwọ ọrụ opiate, dị ka ụmụ nwoke nwere mmekọahụ na - enweghi mmasị maka 0.5 mg / kg morphine.

Ọzọ, e kpebisiri ike ma ọ bụ opioid na-akwado mgbasa ozi mmekọahụ na ncheta na ụmụ nwoke ejiri naloxone na-eme n'oge ahụmahụ mating, ma ọ bụ n'usoro ma ọ bụ intra-VTA. Naloxone anaghị egbochi mmemme mbụ nke mmekorita nke mmekorita nwoke na nwanyị na-emekọ oge ugboro ugboro, ma ọ bụ ebe a na-etinye ọnọdụ maka ịlụ di na nwunye. Otú ọ dị, ọgwụgwọ naloxone kwadoro okwu ogologo oge nke mmemme na-akpali akpali nke mmekorita nwoke na nwanyị na ịmalite ime ihe na mpaghara mesolimbic nke etinyere site na njikọ ndị nwere nsogbu na-ejikọ mating.

Akwukwo ihe ndia na egosiputa na opioids a na-acho ugbua n'oge eji eme ihe na-eme ka uzo di na VTA dopamine nehu na-adi ike maka uto morphine na ncheta ogologo oge maka ezi omume.

 

Okwu Mmalite

Ụdị nkwụghachi ụgwọ okike na-agbazi site na usoro mesocorticolimbic (Meisel na Mullins, 2006; Hoebel et al., 2009; Frohmader et al., 2010a; Pitchers et al., 2010a; Nwa na al., 2011; Blum et al., 2012). Iji ọgwụ ọjọọ eme ihe na-akpata mgbanwe ntanetị n'ime usoro ihe a, bụ nke na-atụnye ụtụ na mmepe na ngosipụta nke iji ọgwụ ọjọọ eme ihe (Hyman et al., 2006; Nestler, 2012). Anyị kpebisila ike na inwe ahụmahụ na-akwụ ụgwọ ọrụ, ya bụ, ahụmahụ mmekọahụ na oke nwoke, na-ebutekwa plasticity nke na-adịghị ahụkebe (nucleus accumbens) (NAc), gụnyere ọnụọgụ dendritic mụbaa (Pitchers et al., 2010a) na deltaFosB (Pitchers et al., 2013). N'aka nke a, plasticity nke a na-enwe mmekọahụ na-adị oké egwu maka mmetụta nke ahụmahụ mmekọahụ na mmekọ ụkwụ, gosipụtara dị ka mmemme nke ibido na omume nke omume mmekọahụ (Pitchers et al., 2010b, 2012, 2013). Ọzọkwa, inwe mmekọahụ na-agbanweghachi omume na psychostimulants, gụnyere ntinye uche nke ọrụ locomotor na ụgwọ ọrụ bara uru (Frohmader et al., 2010a; Pitchers et al., 2010a, 2013).

Na NA bụ otu ihe dị n'okpuru ala nke eriri dopaminergic na mpaghara mmepụta ahụ (VTA). VSA dopamine neurons na-arụ ọrụ n'oge oge aging na ikpuchi anya na njirimara dị iche iche na-egosi ụgwọ ọrụ ego (Balfour et al., 2004; Frohmader et al., 2010a), site na peptide opioid (EOP) opioid na-atụgharị uche -binding at receptors μ-opioid (MORs; Matthews na German, 1984; Johnson na North, 1992; Klitenick et al., 1992; Ikemoto et al., 1997; Balfour et al., 2004). N'ihi ya, ikpughe ihe ndị na-ekwu banyere mmekọahụ na-eme ka a hapụ ntọala EOP na VTA dopamine-cell, bụ nke na-eme ka mkpali na-akpali agụụ mmekọahụ (Mitchell na Stewart, 1990; van Furth et al., 1995; van Furth na van Ree, 1996) na ntọhapụ dopamine na NAc (Fiorino et al., 1997).

Ịmepụta ugboro ugboro na opiates dị iche iche na-akpata mgbanwe morphological na VTA (Mazei-Robison et al., 2011; Mazei-Robison na Nestler, 2012), belata ogo nke VTA dopamine neurons (Sklair-Tavron et al., 1996; Spiga et al., 2003; Chu et al., 2007; Russo et al., 2007; Mazei-Robison et al., 2011), ụda ndị na - adịghị edozi ahụ na -Beitner-Johnson et al., 1992), ụba excitability nke dopamine sel, ma belata axoplasmic iga na dopamine mmepụta na NAc (Beitner-Johnson et al., 1992; Mazei-Robison et al., 2011). Ihe ndị a VEM dopamine neuron na - eme ka morphine ụgwọ ọrụ na - enwe ndidi ma bụrụ ndị na - adịgide adịgide ka ha na - agbanye n'ime ọnwa nke ọgwụ abstinence (Russo et al., 2007). O doro anya na ọ bụrụ na plasticity na VTA dopamine neurons pụrụ iche na omume nke opiates ma ọ bụ ma ọ bụrụ na ha na-emepụta site na ntọhapụ nke EOP n'oge àgwà na-akwụghachi ụgwọ àgwà.

N'ebe a, anyị na-anwale nkwupụta ahụ na nhụghachi ụgwọ ọrụ nke anụ ahụ na-akpata nkwụnye ume yiri nke ahụ sitere na opiates, ma si otú a, nke ahụ na-agbakọta na usoro plastik nke dị oké egwu maka ụgwọ ọrụ ụgwọ ọrụ na ụgwọ ọrụ ụgwọ ọrụ. Anyị na-anwale ma ahụmahụ mmekọahụ na oke ụmụ nwoke na-ebelata nhazi nke VTA dopamine neurons site na usoro dabere na omume EOP na VTA. Ọzọkwa, anyị na-enyocha ma mgbanwe EOP na-emepụta na VTA dopamine neurons na-eme ka nkwalite mmeghachi omume na-akwụ ụgwọ ma na-egosi nsụgharị nke ume iji na-achọpụta ụgwọ ọrụ nkịtị, ebe ọ na-eme ka e nwee ohere ịgafe ụgwọ ọrụ morphine.

Akụrụngwa na ụzọ

Animals

Enwetara ụmụ nwoke toro eto na Sprague-Dawley (200-225 g) site na Charles River ma nọrọ na abụọ n'ime ụlọ ọkụ na 12 h ìhè / ọchịchịrị gbara na nyocha niile (ọkụ na 10: 00 AM ma e wezụga maka nnwale morphine , kpochapụ na 5: 00 PM). E nwere nri na mmiri ad libitum ma n'oge a na-anwale ule. A na - eji ovariectomized ụmụ nwanyị na-etinye aka na 5% 17-β-estradiol benzoate capsules SILASTIC (1.98 mm nke dị n'ime, 0.5 cm n'ogologo, Dow-Corning). A na-elekọta 500-0.1 h tupu a nwalee iji mee ka ị nweta mmekọahụ. Usoro nile nke University of Western Ontario na Mahadum Nlekọta Ụmụ anụmanụ nke Mahadum nke Michigan kwadoro usoro niile, ma soro Kansụl Kanada maka Nlekọta Ụmụ anụmanụ na National Institute of Health nke na-agụnye ụmụ anụmanụ na-eme nchọpụta.

Oge oge nke VTA dopamine amalite ogo mgbanwe

Nhazi oge ọ bụla.

Iji mụọ oge nke mgbanwe na dopamine neuron amalitela na VTA, a na-egbu ụmụ anụmanụ ndị nwere mmekọahụ na nke na-adịghị mma na 1, 7, ma ọ bụ 31 d (n = 5-8 kwa otu) mgbe ụbọchị ikpeazụ nke mating (ahụmahụ) ma ọ bụ njikwa (onye nwere uche). Ndị otu nwoke na nwanyị nwere mmekọahụ na-eme ka ha nwee mmekọahụ mgbe ha na-enwe mmekọahụ, yana ọnụ ọgụgụ nke ọnụ na-ezukọ maka nnọkọ ise (nkezi nke 5 maka otu ọ bụla), ma ọ bụghị iche na ọnọdụ ọ bụla nke inwe mmekọahụ.

Oge mkparịta ụka.

E kenyere ụmụ nwoke na-amaghị nwoke na nwanyị na-enwe mmekọahụ abụọ n'ime ụzọ abụọ a na-anwale: nwoke ma ọ bụ nwanyị inwe mmekọahụ ma ọ bụ nwee mmekọahụ. A na - ahapụ ụmụ anụmanụ na - enwe mmekọahụ ka ha nwee ike ịbanye ugboro ise na ụbọchị ọmụmụ ya na ụmụ nwanyị na - anabata ihe na ntanye ule rectangular (60 × 45 × 50 cm) ruo mgbe ngosi nke ejaculation ma ọ bụ ruo 1 h (nke ọ bụla bịara na mbụ). Ejichachara ngwangwa nke 70% ethanol mechakwara kwụnye ihe ndina ọhụụ n'etiti oge ngwugwu. Mmekọahụ na-eme n'oge ọchịchịrị (2-6 h mgbe mmalite nke ọchịchịrị). Naanị ụmụ anụmanụ ndị ejikọtara n'oge ọ dịkarịa ala anọ n'ime oge ise ịlụ nwoke na-ewere na ha nwere mmekọahụ ma tinye ya na nyocha. E weere oge niile gbasara mmekọ ahụ na omume nke mmekọahụ. Ọnụ ọgụgụ nke mpempe akwụkwọ (M) mgbochi (IM), mgbago ugwu (ML, oge site na mmalite nke nwanyi na ugwu mbụ), mgbochi ime ihe (IL, oge site na mmalite nke nwanyị na-ebido na mbụ), na njedebe ejaculation (EL; oge site na mbụ mgbochi ejaculation) e dere (Agmo, 1997). A na-etinye ụmụ anụmanụ Naive n'ọgba ule dị ọcha maka 1 na mgbe ọ bụla ha na ụmụ nwoke na-enwe mmekọahụ na-abanye n'otu ọnụ ụlọ ahụ, nke mere na ha na-ekpughere ísì ísì dị anya, na ụdị nsogbu dị iche iche na ihe nchekwa gburugburu ebe obibi dika ụmụ nwoke nwere ahụmahụ.

Ịmebanye aha na-emetụtaghị ya.

A na-eji anụ sodium pentobarbital (270 mg / kg, ip) tinye ya na 50 ml nke 0.9% saline, tinyere 500 ml nke 4% paraformaldehyde na 0.1 m sodium phosphate buffer (PB). E wepụrụ nsị na postfixed maka 1 h na ọnụ ụlọ okpomọkụ (RT) n'otu nhazi ahụ, wee mikpuo ya na 20% sucrose na 0.01% sodium azide na 0.1 m PB maka nchekwa na 4 ° C. Ebibiri ngalaba nke coronal na 35 μm na microtome na-egbuke egbuke (H400R, Microm) ma gbakọtara na usoro anọ dị na nchịkwa cryoprotectant (30% sucrose, 30% ethylene glycol na 0.1 m PB) wee debe na 20 ° C. A na - eme mkpọtụ nile na RT site na mkparịta ụka dị nro na mmiri mmiri na - ejiri 0.1 m PBS, pH 7.35, n'etiti incubations. E gosipụtara akụkụ nke 1% H2O2 maka 10 min iji laa n'iyi peroxidases, wee kpochie maka 1 h na ngwọta incubation (PBS +: PBS nwere 0.4% Triton X-100; Sigma-Aldrich) na 0.1% ọgwụ nje buvine (Jackson Immuno Research Laboratories). Na-esote, a na-etinye akụkụ ya n'otu abalị na RT na nru tyrosine hydroxylase (TH) -antibody (1: 20 000; Millipore). Mgbe a na-emepụsị ihe mgbochi nje, a na-etinye akụkụ ya na profagated goat anti-souruse (NDNUX); N'ikpeazụ, a na-asacha ngalaba na 555 m PB, na-agbakwunye na slit nke Superfrost Plus, nke a mịrị amị, ma kpuchie ya na gelvatol nke na-agụnye 1-diazabicyclo (100) octane (DABCO; 30 mg / ml, Sigma-Aldrich; Lennette, 1978).

Nchịkọta data: ịmalite ibido ogo.

Edere ihe oyiyi nke ndị na-ahụ maka immunoreactive (IR) na VTA na 40 × magnification na atọ rostral na ọkwa nke caudal (Balfour et al., 2004). Enweghị ọdịiche dị n'etiti mkpụrụ ndụ dị iche iche. A na-enyocha ụbụrụ ndị na-emepụta TH-IR na-eji amata ImageJ (National Institute of Health). A tụrụ akụkụ, perimeta, na okirikiri dị ka akọwapụtara site Sklair-Tavron et al. (1996). A na-enyocha mkpụrụ ndụ 25 dịka anụ ọhịa (gụnyere ngwakọta 3 VTA) na naanị sel ndị nwere ngwongwo anya doro anya gụnyere. A na-agụta anụ ọhịa ọ bụla, ebe a na-ahụkarị, perimeta, na okirikiri. Maka nyocha usoro onyonyo, e jiri ụzọ ANOVA mee ihe (ihe kpatara: ahụmahụ mmekọahụ (nwoke ma ọ bụ nwanyị nwere mmekọahụ) na oge (1, 7, ma ọ bụ 31 d) post hoc jiri ya na-eji usoro Holm-Sidak mee ihe na 0.05 dị mkpa.

Mgbanwe VTA na-abụghị nke dopamine

Oge bi na na na na na.

Iji chọpụta ma a ga-enwe mmekọahụ mgbe a na-eme kwa ụbọchị na-eme ka ọ dịkwuo ala, na-achọpụta na ọ na-ebelata na TH-IR neuron soma size, VTA dopamine neurons nke ụmụ anụmanụ na mated mgbe ise biweekly mating sessions e nyochara. Oge a na-ekwu okwu dị ka akọwapụtara n'elu, ma karịa oge 2.5. A chịkọtara Brains 7 d mgbe ọhụụ ma ọ bụ njikwa ikpeazụ.

Ịmebanye aha na immunoperoxidase.

Tụkwasị na nke a, a nwalere ya ma ọ bụ iji usoro mmepụta ihe nke ọma na immunoperoxidase na nchọpụta chromogen, ga-enyekwa ohere iji hụ mgbanwe mgbanwe nke TH-IR. A na-eme nsị na nhazi anụ ahụ dị ka akọwapụtara n'elu. Ịnagide ọgwụgwọ na 1% H2O2 na PBS +, a na-etinye akụkụ ya n'otu ntabi anya na RT na polyiclonal tyrosine hydroxylase (TH) -antibody (1: 20 000; Millipore). Mgbe a na-eme ka a ghara ikpochapụ nje virus, a na-ejikọta akụkụ ya na IgG Igwe WWP (1 h, 1: 500 na PBS +; Laboratories Vector), avidin-biotin-horseradish peroxidase (1 h, ABC elite; 1: 1 000 na PBS ; Laboratories Vector), na 3,3'-diaminobenzidine tetrahydrochloride (10 min, 0.02%, DAB; Sigma-Aldrich) mejupụtara sulfate nickel na (0.02% na 0.1 m PB) na hydrogen peroxide (0.015%). A na-asacha akụkụ nke ọma na 0.1 m PB iji kwụsị mmeghachi omume ma wụnye n'elu Superfrost coded tinyere ihe ngosi iko (Fisher) na 0.3% gelatin na ddH2O. Mgbe mmiri gwụsịrị, ihe nkedo ọ bụla jupụtara na DPX mounting (dibutyl phthalate xylene, Sigma-Aldrich).

Nchịkọta data: ịmalite ibido ogo.

E nyochara mkpụrụ ndụ TH-IR maka mpaghara, gburugburu, na okirikiri dịka akọwara n'elu. Na mgbakwunye, enyocha mkpụrụ ndụ TH-IR na substantia nigra (SN), na otu ngalaba ahụ ejiri mee nyocha maka mkpụrụ ndụ VTA TH-IR. Na mmechi, nyocha nke VTA na sel SN-IR, a na-atụgharị ngalaba site na iji cresyl violet na sel ndị na-abụghị TH-IR na-eji otu ụzọ ahụ akọwara n’elu. E jiri ọdịiche dị n'etiti ndị nwere ọgụgụ isi na ndị nwere ahụmahụ jiri ihe nwata akwụkwọ nwere nku abụọ t nyocha nke nwere 0.05 dị mkpa.

Mmetụta nke naloxone na mbelata nke dopamine amalitela na-ahụmahụ

Iji chọpụta ma MOR na-ekere òkè n'inwe mmekọahụ - emee mgbanwe na dopamine na-amalitewanye ogo, a na-egbochi MOR n'oge omume mmekọahụ. Ọkara nke anụ ọhịa ahụ nwetara ahụmahụ mmekọahụ, ebe a na-edozi ọkara nke ọzọ ma nọgide na-enwe mmekọahụ rụrụ arụ. E kwere ka ụmụ anụmanụ nwere ahụmahụ nwee ike ịlụ na 5 ụbọchị ndị ọzọ. N'ime ndị nwere mmekọahụ na ndị na-amaghị ihe, a na-emeso ụmụ anụmanụ na ndị Naloxone antagonist na MOR na-enweghị nchebe (10 mg / kg, sc; Sigma-Aldrich, nke na-agbasa na 0.9% saline) ma ọ bụ salin 30 min tupu ịmalite nwanyị (ahụmahụ) ma ọ bụ tupu ejikwa ya (onye nzuzu); site n'inwe ihe omuma anọ: saline (naive Sal), nke na-enwe mmekọahụ nke naloxone (Naive NLX), saline nwere mmekọahụ (Exp Sal), naloxone na-enwe mmekọahụ (Exp NLX; n = 5-8 kwa otu). Ngwọta Naloxone enweghị mmetụta dị ịrịba ama na ọnọdụ ọ bụla nke inwe mmekọahụ, na nke ọ bụla n'ime 5 d, na naloxone- na ìgwè ndị na-agwọ saline bụ otu ahụ na ahụmahụ mmekọahụ. A na-egbu ụmụ anụmanụ niile site na ntanye intracardial 7 d mgbe oge mgbakọ ikpeazụ. Ngalaba, immunohistochemistry, na nyocha data (ụzọ abụọ ANOVA; ihe: ahụmahụ mmekọahụ na ọgwụgwọ ọgwụ) maka nhazi dopamine amalitere dịka akọwapụtara n'elu.

Morphine na-etinye mmasị

Nlekọta ahụmahụ.

Na mbụ, Russo et al. (2007) gosiri na morphine na-adịghị ala ala na-ebute ndidi na ụgwọ ọrụ nke morphine. Ebe ọ bụ na ahụmahụ mmekọahụ na ọrịa morphine na-adịghị ala ala na-eme ka mbelata dị otú ahụ na-eme ka ọ dịkwuo ogo nke dopamine neurons na VTA, a na-anwale njirimara arụmọrụ nke mgbanwe mmekọahụ na-emetụta ule morphine maka ugwo morphine. A kewara ụmụ anụmanụ ndị nwere mmekọahụ na ndị na-adịghị ahụkebe ka ha bụrụ òtù dị iche iche dị iche iche dị iche iche (isii)n = 9-13 kwa otu) na-adabere na omume mmekọahụ (onye na-enwe mmekọahụ ma ọ bụ ahụmahụ) na morphine dose (0.5, 5.0, ma ọ bụ 10.0 mg / kg, ip) ma nwalere maka ebe nchekwa ọnọdụ nke morphine (CPP).

Morphine-CPP.

Nlekọta mere 1 d mgbe oge ngwụsị ikpeazụ na otu dị iche iche jikọtara maka mmekorita nwoke na nwanyị n'oge nnọkọ ntụrụndụ ikpeazụ. Ụdị CPP ahụ e ji mee ihe bụ nke pretest, ụbọchị nkwonkwo, na ntinye ule, na ngwa dabere Tenk et al. (2009). Na nkenke, ngwa CPP (MED Associates) nwere ụlọ atọ dị iche iche. N’agbata oge ọ bụla, ejiri ngwa ngwa 70% ethanol kpochaa ngwa ahụ iji belata ihe ngosi na-esi ísì ụtọ. Iji chọpụta ihe ndị masịrị gị, e mere pretest mgbe a na-enye ụmụ anụmanụ ohere ịnweta ngwa niile maka minit 15. Dịka otu, ụmụ anụmanụ egosighi mmasị dị ukwuu maka otu ọnụ ụlọ, mana anụmanụ ọ bụla nwere ntakịrị mmasị mbụ. Oke ndị gosipụtara mmasị dị ukwuu maka otu n'ime ụlọ (> ọdịiche 200 s n'etiti oge ejiri n'ime ụlọ ọ bụla; 5% nke anụmanụ) n'oge pretest ewepụghị na ọmụmụ ihe ahụ. N'oge nkwonkwo, ejikọtara ọgwụ na nke mbụ ma ọ bụ na-enweghị mmasị na ụlọ site na iji usoro a na-achọghị iche (Tzschentke, 2007) na ụmụ anụmanụ na-etinye aka na ụlọ nke 30 min. Ejiri anụ saline (ip) na-agba ụmụ anụmanụ n'ụtụtụ (9: 00 AM na 12: 00 PM) ma jikọta ya na ụlọ saline-paired (njikwa). N'ehihie (1: 00-4: 00 PM), a na-etinye ụmụ anụmanụ na morphine (ip, 0.5 mg / kg, 5.0 mg / kg ma ọ bụ 10.0 mg / kg; morphine sulfate kwụsịrị na 0.9% saline, Johnson Matthey) ma kpochapụ ya gaa na ụlọ morphine. A na-edozi ụmụ anụmanụ ụbọchị abụọ. N'echi (3 d mgbe ụbọchị ikpeazụ nke ngwongwo) a na-eduzi post-ule, nke yiri nke pretest. Maka nyocha nchịkọta akụkọ, oge ejiri na morphine na-etinyere na oge nlele mgbe e jiri ya tụnyere oge eji nọrọ n'ụlọ saline na-esote mgbe a na-enyocha ụmụ nwoke ma ọ bụ ụmụ nwanyị nwere ahụmahụ n'ime ụdị usoro ọ bụla na-eji eriri ọnụ t ule. p E weere 0.05 dị ka ihe ndekọ ọnụ ọgụgụ. Ndị ọzọ na-achịkwa nke ụmụ anụmanụ na ndị nwere anụ ahụ nwetara saline na ime ụlọ abụọ na nke a na-emeghị eme dị ka njikwa na-adịghị mma. Enweghị ọdịiche dị n'etiti oge ejiri mee n'etiti ụlọ maka otu otu.

Mmetụta naloxone na-arụ ọrụ n'usoro na mmemme na-akpali akpali nke omume mmekọahụ

Nlekọta ahụmahụ.

Ahụmahụ mmekọahụ na-ebute mmezi nke omume mmekọahụ nke a na-echekwa maka ọbụlagodi ọnwa 1 (Pitchers et al., 2012). Iji nyochaa mmetụta nke igbochi MOR maka mmemme nke mmekorita nke mmekọahụ, ụmụ anụmanụ na-ahụ maka mmekọahụ na-enweta maloloxone ma ọ bụ saline tupu oge ise na-emekọ mating (n = 12 ọ bụla) dịka akọwara n'elu. N'izu otu mgbe ọ gachara, a na-enyocha ụmụ anụmanụ niile mgbe a na-ahapụ ụmụ anụmanụ niile ruo mgbe ejaculation ma ọ bụ ruo 1 h. Enweghị ọgwụgwọ naloxone ma ọ bụ ọgwụ saline tupu e mee ya n'ụbọchị nyocha ikpeazụ. A na-atụle njedebe nke mating iji chọpụta ma naloxone emetụta ma ọ bụ mmekorita nwoke na nwanyị na-enwe mmemme nke ụbọchị ahụ (ụbọchị 1 vs 5) ma ọ bụ mmezi nlekọta a (ụbọchị 5 vs ule) site na iji ụzọ abụọ ANOVA [ihe: ọgwụgwọ (saline versus naloxone ) na ụbọchị (ụbọchị 1, ụbọchị 5, ma ọ bụ ule)] na usoro Holm-Sidak maka post hoc atụnyere. Maka ule onyonyo niile, p E weere 0.05 dị ka ihe ndekọ ọnụ ọgụgụ.

Ihe nchịkwa ndị ọzọ

Naloxone Systemic na ule ule.

Iji gosi na omume mmekọahụ gbanwere n'oge ikpeazụ nke ule na-adabere na enweghi naloxone, anyị na-elekọta maloxone ma ọ bụ saline na ụbọchị nyocha ikpeazụ nke anụ ahụ na ụmụ anụmanụ ndị natara na ngwunye na naloxone mgbe ha nwetara ahụmahụ mmekọahụ. N'ụzọ doro anya, ụmụ anụmanụ niile natara ọgwụ naloxone (10 mg / kg, sc) 30 min tupu ejikọta n'otu ejaculation n'oge 5 ụbọchị. N'ụbọchị 7 nke nyocha n'oge ikpeazụ, ihe dị ka ọkara ụmụ anụmanụ natara ọgwụ ogwu nke naloxone (10 mg / kg, n = 7) ma ọ bụ saline (n = 6) 30 min tupu ewebata nwanyi nabatara. A na - ahụ ma na - edekọahụ mmekọahụ. A na-atụle njedebe nke mating iji chọpụta ma naloxone emetụta ma ọ bụ mmekorita nwoke na nwanyị na-enwe mmemme nke ụbọchị ahụ (ụbọchị 1 vs 5) ma ọ bụ mmezi nlekọta a (ụbọchị 5 vs ule) site na iji ụzọ abụọ ANOVA [ihe: ọgwụgwọ (saline versus naloxone ) na ụbọchị (ụbọchị 1, ụbọchị 5, ma ọ bụ ule)] na usoro Holm-Sidak maka post hoc atụnyere. Maka ule onyonyo niile, p Ewere 5% dị ka ihe ndekọ ọnụ ọgụgụ.

Mmetụta nke naloxone na okwu mkpirikpi nke ime ka enwe mmekọahụ.

A nwalere mmetụta nke naloxone (10 mg / kg, sc) n'oge a na-emegharị ahụ na omume mmekọahụ na-esote mgbe a na-anwale ule ikpeazụ nke nyocha, nke e mere nanị 1 d mgbe emesịrị (saline, n = 5; naloxone, n = 4).

Ngosipụta nke naloxone systemic.

Iji chọpụta ma ọ bụ ugboro ugboro na-agwọ ọrịa naloxone na-akpata nhụsianya nke omume mmekọahụ 7 d mgbe emesịrị ọgwụgwọ ikpeazụ, ụmụ anụmanụ na-enweghị isi na-enweta ụtụtụ naloxone kwa ụbọchị (10 mg / kg, sc) ma ọ bụ saline injections na ụbọchị ndị na-esochi tupu nyocha Xingum ma ọ bụ saline ọgwụ. N'ime ule ikpeazụ a, ụmụ anụmanụ anaghị enweta ọgwụ ọ bụla. A hụrụ omume mmekọahụ ma dekọọ dị ka akọwapụtara n'elu. A na-eji njigide nke mating tụnyere ndị otu na-eji emeghi ego t ule. Maka ule onyonyo niile, p Ewere 5% dị ka ihe ndekọ ọnụ ọgụgụ.

Naloxone Systemic na ụgwọ ọrụ mmekọahụ.

Otu uzo enwere ike isi metụta ihe naloxone na ngosiputa nke ndozi omume nmeko nwoke na nwanyi bu naloxone na egbochi ihe mmadu na eme gi. Iji nwalee ihe a nwere ike ime, atụmanya CPP ahụ bụ maka omume mmekọahụ ozugbo naloxone ma ọ bụ ntụtụ saline n'ime ụmụ nwoke na-enwebeghị ahụmịhe mmekọahụ tupu ha enwee ya. Usoro CPP yiri nke a kọwara n’elu maka morphine-CPP, gụnyere pretest, ụbọchị oyi, yana ule post.

Omume mmekorita nwoke na nwanyi di na nwunye ya na ndi ulo ya. N'ọnọdụ a na-enweghị atụ, anụmanụ ọ bụla natara ọgwụ naloxone (n = 12) ma ọ bụ saline (n = 11) 30 min tupu ị nweta ohere maka nwanyi nabatara. Ogologo oge nke nnọkọ ntụrụndụ bụ ~13 min. Otu nkeji mgbe ejaculation, e debere anụ ahụ n'ime ụlọ iri abụọ maka 30 min. N'ọnọdụ ụra nke ọzọ, ụmụ anụmanụ natara ọgwụ ogwu maloxone ma ọ bụ saline (ọ bụla ha nwetara tupu ha agaa), ma tinye ha n'ime ụlọ a na-akwụghị ụgwọ maka 30 min. Na-esote, a na-eduzi nyocha post, dị ka pretest. Iji chọpụta nhọrọ ime ụlọ, oge e ji etinye ọnụ na ọnụ ụlọ a na-eme abụọ mgbe a na-egosipụta pretest na post-test. Maka nyocha nke onyonyo, jikọtara ọnụ t E jiri ule mee ihe iji tụnyere nchọta na mgbanwe dị iche iche, na oge na ọnụ ụlọ a jikọtara ọnụ n'oge pretest na post-test iji chọpụta ma enwere CPP dị mkpa maka omume mmekọahụ. p E weere 0.05 dị mkpa.

Mmetụta nke naloxone intra-VTA banyere mmemme nke mmekorita nke mmekọahụ

Nlekọta ahụmahụ.

Iji chọpụta ma ihe EOP mere kpọmkwem na VTA, ọ bụ maka mmetụta nke ahụmahụ mmekọahụ - kpatara mgbanwe n'arụmdi na nwunye, ụmụ anụmanụ na-enwe mmetọ na mpaghara nke naloxone ma ọ bụ saline n'ime VTA n'ihu izu ise nke ụtụtụ. Ụdị nhụjuanya dịka ihe nyocha nke naloxone. E kwere ka ụmụ anụmanụ nwere ahụmahụ nwee ike ịlụ n'oge 5 ụbọchị dị iche iche ruo mgbe otu ejaculation ma ọ bụ ruo 1 h. Nkeji iri na ise tupu ewebata ụmụ nwanyị na-anabata ihe, ụmụ nwoke na-enweta nhụjuanya nke ọ bụla na naloxone (10 μg / μl site na yamisphere; 0.5 μl volume; na-agbasasị na 0.9% saline) ma ọ bụ saline (0.5 μl permis). Ejiri microinjections bilateral dị na ntanarị nke 0.5 μl / min na oge 1 min wee soro 1 min ọzọ na-ejikwa eriri mmiri na-agbagharị ebe maka mgbasa ozi. Ejiri ya na cannula na-ekpuchi ya. Otu izu mgbe ụbọchị ikpeazụ nke oge aghara (ụbọchị ule), ụmụ anụmanụ niile na-ejikọta ọzọ na ejaculation na-enweghị ntanye nke naloxone ma ọ bụ saline. Nyocha 3A na-akọwa atụmatụ imepụta. A na-eduzi nyocha data dịka akọwapụtara na nyocha naloxone.

Ịwa ịwa ahụ.

A na-ejide ụmụ irighiri ihe ndị na-ejiri intraperitoneal (0.1 ml / kg) nke ketamine (0.87 mg / ml) na xylazine (0.13 mg / ml), ma tinye ya n'ime ngwá ọrụ kopf. Ejila obere oghere ntanetị nke 21 (Plastics One) belata site na obere oghere dị na okpokoro isi na ụbụrụ na VTA na -4.8 mm AP, ± 0.75 mm ML si bregma na -7.8 mm DV site n'elu okpokoro isi Paxinos na Watson (2013). A na - eji katịkị nwere ahụike na - eme ka a na - ejikọta ya na klọb atọ nke na - etinye ya na okpukpu atọ. E nyere ụmụ anụmanụ nkwụsị nke izu 2, a na-edozi kwa ha kwa ụbọchị iji mee ihe nhazi na usoro ogwu a na-eji n'oge ule omume.

Nyocha nkwenye site na Cannula.

A na-enyocha ebe ntinye nke cannula site na iji ọgwụ na-edozi ahụ iji kwenye na VTA ka ezubere. Naanị ụmụ anụmanụ nwere ebe kwesịrị ekwesị gụnyere nchịkọta (nchịkọta nke ikpeazụ: saline nwere ahụmahụ n = 8; Naloxone nwere ahụmahụ n = 6). Enwere umu ozo ato ndi nabatara na-VTA naloxone injections na-eduga n'èzí VTA ka ha gbakọtara n'otu otu ogbugba ogbugba. A na-enyocha ìgwè ahụ ejiri edozi iche iche iji rụọ ọrụ dịka njikwa ihe atụ na Mann-Whitney U anwale ule iji tụnyere omume na ụbọchị nyocha ikpeazụ na ndị naloxone na ụmụ nwoke nwere ahụ saline.

Ihe gbasara ihe omimi nke ihe jikọrọ ya na okwu

Nlekọta ahụmahụ.

E gosipụtara ihe ngosi na oghere nke ụmụ nwoke nwetara ahụmahụ mating na-eme ka malite ọrụ MOR na VTA na ọrụ ntanetị na VTA na NAc (Balfour et al., 2004). N'ihi ya, gburugburu ebe obibi na-arụ ọrụ dị ka ihe na-egosi na ọ bụ ụgwọ ọrụ mmekọahụ. Nnyocha a na-amụ ugbu a nwalere ma ọ bụ ịmalite MOR n'oge enwere mmekọahụ ga-achọ maka ịmalite ịmalite ịmalite ime ihe. Naloxone ma ọ bụ Saline na-edozi 30 min n'usoro ihe eji eme ihe na ntinye na ntinye na ntinye nke nwanyi nke na-anabata ya ma ọ bụ tupu ntule nke na-etinye ntinye n'ime oghere na-enweghị njide nke nwanyi gburugburu ebe obibi; Ya mere, e kere ìgwè anọ na-eme nchọpụta: Salve Naira, Naive NLX, Exp Sal, na Exp NLX. Otu izu mgbe nke ikpeazụ gasịrị, ọkara nke ụmụ anụmanụ na nke ọ bụla nọ na-ekpughere ọnụ ụlọ ahụ (ndị ikom na-emepụta nwoke: ndị nwere mmekọahụ na-ejikọta ọnụ) ma ọ bụ na-ejide ube (ụmụ nwoke na-amaghị nwoke: nonsalient / neutral cues), ebe ọ bụ na ọkara ahụ adịghị ekpughe nyocha ọ bụla ma kama ịnọgide n'ụlọ n 'ụlọ (iji chọpụta akara ngosi akara). Ihe omuma a nke mepụtara 8 otu: Nri Sal-No Cue, Naive Sal + Cue, Naive NLX-No Cue, Naive NLX + Cue, Exp Sal-No Cue, Exp Sal ​​+ Cue, Exp NLX-No Cue, Exp NLX + Cue (n = 4 onye nke ọ bụla ma ọ bụghị Nchịkọta NLX-No Cue, n = 3). A na-eme ka ụmụ anụmanụ bie 10-15 min ka ha ghara ikpughe. A na-ewepụ anụmanụ ndị na-achịkwa n'ụlọ ha ma na-efesa ha n'otu oge.

Immunohistochemistry.

A na-eduzi akụkụ na immunohistochemistry dịka akọwara n'elu. N'ebe a, anyị na-eji mpempe akwụkwọ polyclonal rabbit megide p42 na P44 MAP Kinases ERK1 na ERK2 (PERK; 1: 4 000; Technology Cell Signaling Technology). A na-ejikarị akwụkwọ ndị a na-ede akwụkwọ (Roux na Blenis, 2004; Murphy na Blenis, 2006; Frohmader et al., 2010b). Ọzọkwa, nkwụsị nke onye bụ isi na-egbochi mmechi niile na ụbụrụ nke ụbụrụ nke ụbụrụ na-ekpughe ìgwè abụọ na mpempe akwụkwọ kwesịrị ekwesị.

Nyocha data.

A gụrụ mkpụrụ ndụ (-IR) na-emeghe immunoreactive (ụbụrụ) n'ọtụtụ ụbụrụ ụbụrụ na-eji igwefịfụfụ na-emepụta mkpụrụ nke a na-etinye na ya. Leica Microscope DMRD: NAc [isi (C) na shea (S); 400 × 600 μm; ihe ntanetị nke prefrontal coriex; mPFC; mpaghara na-eme ka a na-ahụ anya (ACA); prelimbic cortex (PL); infralimbic cortex (IL); 600 × 800 μm onye nke ọ bụla], kọmitii-etinyeam (CP; 800 × 800 μm), na amygdala akwa (BLA; 900 × 1200 μm; Balfour et al., 2004; Frohmader et al., 2010b; Pitchers et al., 2010b). A gụrụ akụkụ abụọ maka ụbụrụ ụbụrụ na ọnụ ọgụgụ nke mkpụrụ ndụ na mpaghara ntụle nke nchịkọta ahụ dị ka ọnụ ọgụgụ nke sel kwa mm2. A na-atụle ọnụ ọgụgụ abụọ ahụ maka anụmanụ maka nchịkọta nke otu ụzọ. Ọnụ ọgụgụ nke ndị otu n'ime ndị na-enwe mmekọahụ ma ọ bụ ndị na-amaghị ihe mere ka e jiri ya tụnyere ụzọ abụọ ANOVA [ihe: ọgwụgwọ ọgwụ (NLX ma ọ bụ Sal) na cue (cue ma ọ bụ enweghị ihe)] gbasoro post hoc tụnyere iji nyocha Holm-Sidak ma ọ bụ Mann-Whitney nyochaa ebe o kwesịrị ekwesị na ọkwa dị mkpa p <0.05. Na ngwugwu NAc nke ụmụ anụmanụ nwere ahụmahụ mmekọahụ, enwere omume siri ike banyere mkpa ihe kpatara ya, ya mere, e jiri ntụnyere ha abụọ tụnyere saline (Sal-No Cue) na saline cue (Sal + Cue) naanị.

Foto.

E weghaara foto di iche iche site na iji kamera CCD (Macrofire, Optronics) nke gbakwunyere na Leica microscope (DM5000B) na ntọala igwefoto edozi. Edere foto na Adobe Photoshop 9.0 software. Agbanweghị foto ọ bụla ma e wezụga n'ihi mgbanwe nke nchapụta na ọdịiche.

Results

Mmekọahụ na-emetụta mgbanwe VTA dopamine sel

Ahụmahụ mmekọahụ na-eme ka a ọnụ na VTA dopamine amalite size (Fig. 1A-C). Ahụmahụ mmekọahụ na-ebelata ebe na njedebe nke sel nke VTA TH-IR (mpaghara: F(1,31) = 23.068, p <0.001; perimeta, F(1,31) = 18.225, p <0.001). Enwekwara mmetụta dị mkpa dị mkpa n'oge (mpaghara: F(2,31) = 6.377, p = 0.005; nhazi, F(2,31) = 4.389, p = 0.021) na mmekọrịta dị ịrịba ama dị n'etiti ahụmahụ na oge (mpaghara: F(2,31) = 5.284, p = 0.011; nhazi, F(2,31) = 4.347, p = 0.022). Ntụkọ abụọ na-egosi na mpaghara na perimeta nke mkpụrụ ndụ TH-IR dị mfe belata 1 na 7 d mgbe ụbọchị ikpeazụ nke omume mmekọahụ na ụmụ anụmanụ na-enwe mmekọahụ ma e jiri ya tụnyere njide ndị na-adịghị mma nke mmekọahụ [Fig. 1B, ebe: p = 0.002 (1 d), p <0.001 (7 d); C, ebe: p = 0.009 (1 d), p <0.001 (7 d)]. Mmetụta nke omume mmekọahụ na-agbasasị mgbe oge nke ụgwọ ọrụ abstinence na-esochi dị ka soma soma nke TH-IR neurons laghachiri na ntọala 31 d mgbe ikpeazụ mating nnọkọ (Fig. 1B, ebe: p = 0.798; C, ebe: p = 0.785). Achọpụtaghị mmegharị ahụmahụ nke mmekọahụ na mpaghara ọ bụla nke oge (Fig. 1D). VTA dopamine amalitelata nha nke na-adabere na nkwụsị ụtụtụ kwa ụbọchị, dị ka ahụmahụ mating n'oge ise bi na nwunye na-enwe mmekọahụ na-emepụta ka a na -Fig. 2A,B, E-H, ebe: p = 0.004; nkeji: p <0.001). N'ụzọ dị iche, ahụmịhe mmekọahụ emetụtaghị TH-IR soma size na substantia nigra (Fig. 2C, M-J, ebe: p = 0.13; nkeji: p = 0.16) ma ọ bụ gbanwee nke ọma na VTA na-abụghị TH-IR neurons (Fig. 2D, E-H, ebe: p = 0.46; nkeji: p = 0.45).

Nyocha 1. 

Endogenous opioid na-ebute mgbanwe dị ukwuu nke VTA dopamine neurons. A, Ihe nnọchiteanya nke VTA dopamine neurons si na ụmụ nwoke na ụmụ anụmanụ nwere ahụmahụ na-egosi Mbelata nke nha 7 d mgbe oge mgbakọ ikpeazụ. Ogwe mmanya, 5 μm. Akara data na-egosi na ahụmahụ mmekọahụ (Exp, Ogwe ojii) mere ka ọnụ ọgụgụ dị ntakịrị ebe (B; na μm2) na perimeter (C; ke μm) nke VTA dopamine sel, 1 d (Naive, Exp; n = 6) na 7 d (Naive, n = 5; Na-akọwa, n = 6), ma ọ bụghị 31 d (Naive, n = 6; Na-akọwa, n = 8) mgbe emechara agwakọta, ma e jiri ya tụnyere njikwa na-eme ka ndị mmadụ nwee mmekọahụ (Naive, ogwe ọcha). A na - ebelata mpaghara na 84% na ụmụ nwoke nwere ahụmahụ ma e jiri ya tụnyere njikwa nụ na 1 ma ọ bụ 7 d. A na-ebelata ọnụala na 91.6 na 90% na otu ahụmahụ dị iche iche tụnyere njikwa na 1 na 7 d resp. Enweghị mmetụta ọ bụla dị na akụkụ (D). Nke a dopamine cell plasticity na mpaghara (E) na perimeter (F) gbochiri naloxone (NLX, n = 8), ma ọ bụghị Saline (Sal, n = 7) ọgwụgwọ na oge aging, 7 d mgbe oge ikpeazụ na-agwakọta ma e jiri ya tụnyere njedebe nwoke na nwanyị (Sal, n = 5; NLX, n = 6). Ngosipụta data pụtara ± SEM; * na-egosi nnukwu ihe dị iche ma e jiri ya tụnyere njedebe nke inwe mmekọahụ na otu ụbọchị (B, C) ma ọ bụ jiri ya tụnyere ndị na-emeso ndị na-emeso ndị na-edozi ahụ na-agwọ saline na ụmụ nwoke na-enwe mmekọahụ naloxone (E, F).

Nyocha 2. 

Ahụmahụ mmekọahụ anaghị eme ka ọnụ ọgụgụ ndị na-eme ka ọ bụrụ nke na-adịghị mma ma ọ bụ VTA nondopamine neurons. VTA TH-IR neuron soma mpaghara (A; na μm2) na perimeter (B; ke μm) na ụmụ nwanyị na-acha ọcha (ndị ọcha) na anụ ahụ nwere ahụmahụ (nwa) nke na-enweta ahụmahụ site n'inweta ugboro abụọ kwa izu kama n'oge ụbọchị. Ngwá ọrụ THRA na-arụ ọrụ na mpaghara (C) na VTA non-TH-IR malitere mpaghara (D) na ụmụ nwoke na-amaghị nwoke (ndị ọcha) na ụmụ anụmanụ nwere ahụmahụ. Ngosipụta data pụtara ± SEM; * na-egosi nnukwu ihe dị iche ma e jiri ya tụnyere njikwa n'amaghị ama. Ndi nnochite anya ndi na-egosi TH-IR (aja aja) na VTA nke di na nwunye (E), na ahụmahụ (F) ụmụ nwoke. G, H, Ihe oyiyi di elu nke di neuron nke ahihia gosiri E na F otu. A na-egosi eriri mmiri Nissl na-acha anụnụ anụnụ na ihe oyiyi ndị a. Ndị nnọchiteanya na-egosi TH-IR neurons na SN nke mmekọahụ naive (I) na ahụmahụ (J) ụmụ nwoke. Akwụsị ụfe: E-J, 20 μm.

Mmekọahụ na-eme ka ọnụ ọgụgụ nke VTA dopamine neurons dabere na opioid ntinye ọrụ

Mbelata VTA dopamine neuron amalite ogo nke kpatara ahụmahụ mmekọahụ na-egbochi site na onye na-adịghị echepụta MOR naloxone, bụ nke a na-eme tupu oge ọ bụla. Nlekọta Naloxone tupu oge enwere ntụrụndụ nwere mmetụta dị ịrịba ama na mpaghara (F(1,22) = 4.738, p = 0.041) ma na-emekarị ka mmetụta dị ịrịba ama dị na ya (F(1,22) = 2.892, p = 0.052). Achọpụtara mmekọrịta dị mkpa n'etiti ahụmahụ na ọgwụgwọ naloxone maka mpaghara (F(1,22) = 5.578, p = 0.027) na perimeter (F(1,22) = 8.167, p = 0.009). Ntụkọ abụọ na-egosi na ahụmahụ mmekọahụ na saline-emeso ụmụ anụmanụ belata obere ebe na nkwụsị nke VTA dopamine neurons 7 d mgbe ọnụọgụ ikpeazụ nke oge tụnyere ndị na-emeso ụmụ nwoke na-emeso saline (ndị na-Fig. 1E, ebe: p = 0.018; F, ebe: p = 0.007). N'adịghị iche, ụmụ anụmanụ na-agwọ ọrịa naloxone nwere mmekọahụ na-adịghị iche na ụmụ nwoke na-edozi na-arịa ọrịa naloxone (Fig. 1E, ebe: p = 0.483; F, ebe: p = 0.330). Tụkwasị na nke ahụ, ọnụ ọgụgụ nke ụmụ anụ saline nwere ahụmahụ dị ntakịrị jiri aka ya tụnyere anụmanụ naloxone nwere ahụmahụ (Fig. 1E, ebe: p = 0.002; F, ebe: p = 0.002). Ebumnuche nke naloxone bụ kpọmkwem maka ahụmahụ mmekọahụ, dịka ọgwụgwọ nanị naloxone adịghị emetụta ụbụrụ TH-IR na-emeso ụmụ nwoke na-arịa ọrịa naloxone na-enwe mmekọahụ ma e jiri ya tụnyere njikwa nke saline (Fig. 1E,F). Ọzọkwa, mmetụta a nke naloxone na mbelata nke soma na-akpata abụghị n'ihi mmetụta nke naloxone na-enwe mmekọahụ, dịka ịkpa àgwà na-adịghị njọ dị n'etiti naloxone na ụmụ nwoke na-agwọ saline, ma e wezụga oge dị ogologo ịmalite ịlụ mating mgbe ejaculation (tinye oge nke ejaculation) na ụmụ nwoke naloxone na-emeso ụmụ nwoke n'oge nke mbụ na nke ise (na-emekọ oge ọnụ)p = 0.03 na p = 0.004, n'otu n'otu). Ma saline- na ụmụ nwoke naloxone na-emeso ya na ejaculation n'oge nke ọ bụla n'ime oge ise ịme nkata.

Ahụmahụ mmekọahụ - mepụtara uru morphine ụgwọ ọrụ

Mmetụta nke ahụmahụ mmekọahụ na VTA dopamine malite nha site na ihe nke EOP na VTA bụ ndị yiri ndị kọrọ maka exogenous opiates (Sklair-Tavron et al., 1996; Russo et al., 2007). Ya mere, a nwalere ya ma uru VA dopamine cell na-akpata bụ plasticity na-emetụta ụgwọ ọrụ maka opia morphine. N'ezie, ahụmahụ mmekọahụ kpatara morphine ụgwọ ọrụ nkwụsị, dịka mmetụta nke ndị na -Russo et al., 2007). Ụmụ nwoke na-enwe mmekọahụ enweghi ike ịmepụta CPP maka 0.5 mg / kg morphine dose; ma, ụmụ nwoke na-amaghị nwoke nwere mmekọahụ na-etolite CPP maka ọgwụgwọ a, dị ka egosipụtara site na iji oge dị ukwuu n'ime ụlọ nke morphine tụnyere ụlọ saline-paired mgbe a na-enyocha ya (Fig. 3; p = 0.039). Ma ndi otu di iche iche na ndi di iche iche enwere uche na ndi ozo di iche iche jiri otutu oge n'ile ha na nke morphine ma e jiri ya tụnyere okpukpu ahu nke saline nke di elu nke morphine: 5.0 mg / kg (Fig. 3; Naïve: p = 0.029; Gwa: p = 0.012) na 10.0 mg / kg (Fig. 3; Naïve: p <0.001; Gbaa: p = 0.002).

Nyocha 3. 

Mmetụta nke ahụmahụ mmekọahụ na ụgwọ ọrụ morphine. Oge eji saline- (sal) ma ọ bụ morphine-paired (Mor; 0.5, 5 ma ọ bụ 10 mg / kg bodyweight) ụlọ mgbe a na-esite n'azụ nyochaa na ntinye nwoke na nwanyị (Naive, n = 10-13) ma ọ bụ ahụmahụ (Exp, n = 9-13) ụmụ nwoke. Data dị ka pụtara ± SEM; * na-egosi oke dị iche ma e jiri ya tụnyere ụlọ Sal-paired n'ime otu anụmanụ. NS, Ọ bụghị ihe dị ịrịba ama.

Mmekọahụ na-eme ka mmekorita nke mmekọ ahụ na-adabere na ịmalite ọrụ nnabata

Ihe nchoputa nke a gosiputara na EOP na-eme ihe n'oge VTA n'oge 5 n 'oge mkparita uka oge nile na-eme ka plasticity nke VTA dopamine neurons nke yiri nmetuta nke morphine ma obu heroin onwe-administration (Russo et al., 2007; Mazei-Robison et al., 2011). Anyị na-atụle na VTA dopamine amalitelata nha dị oke egwu maka ụgwọ ọrụ nkuzi na kpọmkwem maka ahụmahụ mmekọahụ-emee ihe mmemme nke mmekọahụ omume na okwu nke mkpali na arụmọrụ. A nwalere echiche a site na igbochi MOR n'iji naloxone n'oge ịkọ mating ma nyochaa mmetụta dị na mmezi nke omume mmekorita nke mmekorita ahụ na-enwe mgbe ọ bụla n'ime oge ise ị ga-ahụ. A na-ewepụta data na Nyocha 4 maka oge nke mbụ na nke ise, dịka ndị a bụ data nke kachasị mma na-egosi na ahụmahụ na-eme ka mmemme ahụ nwee mmemme. Ọzọkwa, a na-anwale ihe ndị na-adịte aka nke ọgwụgwọ naloxone n'oge oge mmekọ ahụ na nhazi nke mmemme mmezi nke ahụmahụ, n'ime oge nyocha ikpeazụ nke 1 ka e mesịrị. Nyocha 4A na-egosi nhazi imepụta. E nwere mmetụta dị ịrịba ama dị na ntinye oge na mmemme nile nke omume nwoke na nwanyị (ugwu mgbaghara: F(2,55) = 11.286, p <0.001; intromission latency: Ekwensu F(2,55) = 8.767, p <0.001; ejaculation aka: F(2,55) = 10.368, p <0.001) na ọgwụgwọ naloxone na latencies iji gbagoo (F(1,55) = 6.585, p = 0.013) na intromission (F(1,55) = 7.863, p = 0.007). Ntụkọ abụọ na-egosi na ọgwụgwọ naloxone na-emetụta omume mmekọahụ n'oge mbụ enwere mgbakọ n'ihi na ụmụ anụmanụ naloxone nwere ụba nta karịa ka ha buru ibu (p = 0.002) na intromission (p = 0.002) ma e jiri ya tụnyere njikwa saline n'ụbọchị mbụ nke mating. Ihe a na - eme naloxone na - enwe mmetụta mmekọahụ ma ọ bụ na - ahụghị ya n'oge ọ bụla n'ime oge mmekọ ahụ (Isiokwu 1). Ọzọkwa, nchịkwa naloxone tupu oge ise ọbụla na-ejikọta ọnụ anaghị egbochi mmemme mbụ nke omume mmekọahụ na ahụmahụ mmekọahụ. N'ikwekọ na mmetụta na-eme ka ahụ nwee ahụmahụ mmekọahụ, ndị na-emeso saline gosipụtara oghere ndị na-ebelata adalata (Fig. 4B; p = 0.032) intromission (Fig. 4C; p = 0.033) na ejaculation (Fig. 4D; p <0.001) n'oge nke ise nke ise na-atụnyere na nke mbụ mating nnọkọ, nke gosipụtara mmezi nke omume mmekọahụ. N'otu aka ahụ, ụmụ nwoke ndị a na-agwọ naloxone gosipụtara obere oge dị ntakịrị iji gbagoo (Fig. 4B; p <0.001), njigide (Fig. 4C; p <0.001), na ejaculation (Fig. 4D; p = 0.017) na nke ise ma e jiri ya tụnyere ụbọchị mbụ. Ọzọkwa, ụmụ nwoke naloxone na-emeso ya adịghị iche na nchịkwa saline na nke ọ bụla n'ime umunya ahụ n'oge nke ise oge ịlụ.

Nyocha 4. 

Endogenous opioids na-arụ ọrụ dị oke mkpa na mmemme nke mmekorita nke omume mmekọahụ. A, Nlekọta ahụmahụ. B-D, Mmekorita mmekorita nwoke na nwanyi na - eme saline (Sal, white bars, n = 11) ma ọ bụ naloxone (NLX, black bars, n = 12) na nhazi usoro. Ngosipụta gosiri bụ ụda ugwu (B; Sekọnd), intromission (C; Sekọnd), na ejaculation (D; Sekọnd) na ụbọchị 1 na 5 nke ụbọchị ụbọchị asaa nke oge. Tụkwasị na nke ahụ, a na-egosi data maka ule nyocha ikpeazụ ahụ, 7 d mgbe oge nke ise ga-eme. A na-enye data dịka ihe dịka ± SEM; + na-egosi nnukwu ọdịiche dị n'etiti ụbọchị 1 na 5 n'ime ọgwụgwọ; * na-egosi nnukwu ọdịiche dị n'etiti ule ụbọchị na ụbọchị 5 n'ime ọgwụgwọ; # gosiri na ọdịiche dị n'etiti naloxone na saline dị iche iche n'ime ụbọchị.

Lelee okpokoro a: 

Ntọala 1. 

Ọchịchị Naloxone tupu enweghi mgbakọ na-arịwanye elu iji gbagoo na mwepụ naanị n'ụbọchị mbụ nke ịlụ

N'ụzọ dị iche, nchịkọta naloxone n'oge enwere mmekọrịta mmekọahụ na-eme ka nrụgide nke mmemme nke mmekorita nwoke na nwanyị nwee mmekorita nke ule ikpeazụ. A na-eduzi ụbọchị nyocha ahụ na 7 d mgbe oge mgbakọ ikpeazụ ga-adị na enweghị nkwụsị naloxone. Ndị ikom na-agwọ saline gosipụtara ahụmahụ a tụrụ anya ya-nke ga-eme ka mmemme nke mmekọahụ nwee mmekorita. N'ụzọ doro anya, ndị nne na nna na-arịgo elu, mwepụ, na ejaculation adịghị iche n'agbata oge nke ise na oge ikpeazụ nke ule (Fig. 4B-D). Ọ bụ ezie na ndị ikom naloxone na-emeso nnukwu mmụba na ogige iji rịgoo (Fig. 4B; p = 0.033), intromission (Fig. 4C; p = 0.036) na ejaculation (Fig. 4D; p = 0.049) n'ụbọchị ule na-atụle oge nke ise oge. Ozokwa, n'oge ule a, a hụrụ ụmụ anụmanụ naloxone ka ha jiri nwayọ nwayọọ nwayọọ karịa ụmụ nwoke na-emeso saline dị ka egosipụtara site na ogologo oge ịgbaghara ugwu (Fig. 4B; p = 0.017) na intromission (Fig. 4C; p = 0.043). Ya mere, ọgwụgwọ naloxone egbochiri nhazi ahụ, ma ọ bụghị nke mbụ, mmepe nke mmemme na-eme ka mmemme nwee mmekọahụ. Nchọpụta ndị a na-egosi ọrụ dị oke mkpa maka EOP-induced VTA dopamine neuron plasticity na okwu ogologo oge nke mmesi ike nke ụgwọ ọrụ ụgwọ ọrụ.

Enwere ọtụtụ nchịkwa nchịkwa ndị ọzọ iji chọpụta na mmetụta nke onye na-anabata onye na-akwado opioid na-egbochi nkwụsị nke nkwalite mmekọahụ na-adịte aka site na enweghi nchịkwa naloxone na ụbọchị nyocha ikpeazụ (Fig. 5A,B), bụ kpọmkwem maka ọnwụ nke ogologo oge, ma ọ bụghị nchịkọta okwu oge dị mkpirikpi nke mmezi mmemme (Fig. 5E,F), ọ bụghị n'ihi na ọ bụ nanị naloxone ka a na -Fig. 5C,D), ọ bụghị ụkọ ọrụ ego na-eme ka ụmụ nwoke na-arịa ọrịa naloxone kpatara (Fig. 5G,H). Nke mbụ, iji gosi na omume mmekọahụ gbanwere na nyocha ikpeazụ ahụ abụghị n'ihi na enweghi naloxone, ma naloxone ma ọ bụ saline nọ na-eme n 'ụbọchị ikpeazụ nke ule na-emetụta ụmụ anụmanụ ndị natara na ngwunye na naloxone mgbe ha nwetara ahụmahụ mmekọahụ (Fig. 5A). E nwere mmetụta dị ịrịba ama nke ụbọchị ụtụtụ na ụlọ ịgba nkịtị ka ọ dị elu (Fig. 5B; F(2,27) = 30.031, p = 0.038) na intromission (Isiokwu 2; F(2,27) = 10.686, p = 0.048). Enweghị mmetụta dị ukwuu nke ụbọchị ụtụtụ na njedebe ka ejaculation (Isiokwu 2; F(2,27) = 2.388, p = 0.109) Yiri nke a kọwara n'elu, ọgwụgwọ naloxone mgbe ị na-aga n'emeghị emetụta mmemme nke mmekorita nwoke na nwanyị n'oge mbụ enwere mmekọahụ. Ndị otu (saline na ndị naloxone na-emeso ya dị ka ndị a kwadoro site na ọgwụgwọ ha nwetara n'oge nyocha ikpeazụ ahụ, ma natara naloxone n'oge mgbochi) gosipụtara gosipụtara omume mmekọahụ na 5 ụbọchị ma e jiri ya tụnyere 1 nke ụbọchị ma gosipụ ụkọ nta karịa ka eburu nke mbụ (Fig. 5B; saline: p = 0.033; naloxone: p = 0.014) na intromission (Isiokwu 2; saline: p = 0.034; naloxone: p = 0.026). Ụmụ anụmanụ ndị natara maloxone ma ọ bụ saline na ngwụcha nke ule ikpeazụ nwere ogologo oge iji nweta ugwu (Fig. 5B; saline: p = 0.018; naloxone: p = 0.029) na intromission (Isiokwu 2; saline: p = 0.019; naloxone: p = 0.020) jiri ya tụnyere ụbọchị nke ise ahụmahụ ahụmahụ. Ya mere, nchịkwa nke naloxone ma ọ bụ saline na ule ule ahụ tupu oge agwakwa emetụtaghị mmetụta nke ọgwụgwọ naloxone n'oge mmemme mmekọahụ na nkwụsịtụ nke mmezi omume oge dị ogologo bụ nke e gosipụtara na anụmanụ ndị na-enwetaghị ọgwụ ọ bụla na ule ule ugbua nke ikpeazụ (Fig. 4).

Nyocha 5. 

Endogenous opioids dị mkpa na okwu ogologo oge nke mmemme nke mmekorita nke inwe mmekọahụ. A, Nlekọta ule nke nnwale na mmetụta nke NLX ọgwụgwọ n'oge ule. B, Ugwu Ugwu na ụbọchị 1 na 5 nke ụbọchị ise nke ịkọ mating na nke ikpeazụ nke ule ngwakọ (Test) na-esote saline (isi awọ) ma ọ bụ naloxone (nwa). Ngosipụta data pụtara ± SEM. * na-egosi nnukwu ọdịiche dị n'etiti ụbọchị 1 na ụbọchị 5 n'ime ọgwụgwọ. # gosiri na ọdịiche dị n'etiti oge nyocha na ụbọchị 5 n'ime ọgwụgwọ. C, Ebumnuche ahụmahụ maka nnwale iji nyochaa mmetụta nke naloxone tupu ọgwụgwọ naanị n'enweghị ahụmahụ mmekọahụ na mmekọ ahụ. D, Ugwu nke ala na ule nyocha ikpeazụ, ụbọchị 7 nke na-eso 5 ụbọchị nke nnu saline ma ọ bụ naloxone na-enweghị nọn. Ngosipụta data pụtara ± SEM. E, Ebumnuche nke nnwale maka nnwale iji nwalee ma ọgwụgwọ naloxone emetụta ihe ngosi dị mkpirikpi nke ime ka omume mmekọahụ nwee mmekọahụ na-enwe mmekọahụ. F, Ogige nke ugwu na 1 ụbọchị na 5 ụbọchị nke ụbọchị ise nke oge ịlụ na ngwụsị nke nyocha ikpeazụ, 1 kwa ụbọchị 5 n'ihu saline (isi awọ) ma ọ bụ naloxone (nwa). Ngosipụta data pụtara ± SEM. * na-egosi nnukwu ọdịiche dị n'etiti ụbọchị 1 na ụbọchị 5 n'ime ọgwụgwọ. G, Nlereanya nke nnwale maka nnwale iji nwalee ma ọgwụgwọ naloxone gbochie mmetụta na-akwụghachi ụgwọ nke omume mmekọahụ. H, Oge a na-ejikọ ọnụ na ọnụ ụlọ (na sekọnd) n'oge pretest (ọcha) na post-ule (nwa) maka ụmụ anụmanụ na-anata maloxone ma ọ bụ saline tupu ịlụ. Ngosipụta data pụtara ± SEM; * na-egosi oke dị iche ma e jiri ya tụnyere pretest.

Lelee okpokoro a: 

Ntọala 2. 

E gosipụtara data ndị a na-ejide na njigide na ejaculation (sekọnd) site na nchịkwa nchịkwa e mere iji chọpụta na mmetụta nke MOR na-egbochi njedebe nke nkwalite mmekorita nke nwoke na nwanyị site na enweghi nchịkwa naloxone na nyocha ikpeazụ

Iji chọpụta ma ọ bụ naloxone ọgwụgwọ mgbe ejikọtara ya na inwe mmekọahụ ma ọ bụghị ugboro ugboro naloxone kwa nke mere ka enweghi mmekorita nke omume mmekọahụ na 7 d mgbe emesịrị ọgwụgwọ, ụmụ anụmanụ na-azụ atụrụ na-anata ma ọ bụ ise ojiji kwa ụbọchị nke naloxone ma ọ bụ saline injections tupu nyocha ule ikpeazụ nke 7 d mgbe e mesịrị (Fig. 5C). Achọpụtaghi ọdịiche dị ịrịba ama maka ihe ọ bụla dị n'etiti saline na naloxone pretreated groups (Fig. 5D; ugwu mgba; nkwụsị nkwụsị: saline 139.7 ± 40.3 na naloxone 121.83 ± 42.55; Ejaculation latency: saline 887.9 ± 70.0 vs naloxone 1050.8 ± 327.31). Ihe ndị a na-egosi na naanị naloxone adịghị ezu iji gbanwee omume mmekọahụ na-esote, dịka enweghi mmetụta nke naloxone naanị na VTA dopamine neuron plasticity.

Anyị na-eche na ọgwụgwọ naloxone mgbe ị na-enweta ahụmahụ mmekọahụ na-emebi okwu ogologo oge nke inwe mmekọahụ - na-ebute mmemme nke inwe mmekọahụ. Iji nyochaa nke a n'ihu, a nwalere mmetụta nke naloxone ọgwụgwọ n'oge enwere ụkwụ n'àgwà mmekọahụ mgbe ọ na-esote ule ikpeazụ, nke e mere nanị 1 d mgbe ọhụụ ikpeazụ (mmepụta ihe ngosi; Fig. 5E). E nwere mmetụta dị ịrịba ama dị ukwuu nke ụbọchị ụtụtụ n'elu ugwu (Fig. 5F; F(2,20) = 19.780, p <0.001) na intromission oge (Isiokwu 2; F(2,20) = 19.041, p <0.001). Enweghi mmetụta dị ịrịba ama nke ụbọchị na njedebe ejaculation (Isiokwu 2; F(2,20) = 3.042, p = 0.070). Dị ka akọwapụtara n'elu, ụmụ nwoke nile (n'agbanyeghị ngwọ ọrịa saline ma ọ bụ naloxone) gosipụtara mmemme nke mmekorita nwoke na nwanyi na oge omume mmekọahụ ise nke egosiputara site na mkpirisi umuntakiri ka ha di elu (Fig. 5F; saline: p = 0.002; naloxone: p = 0.018) na intromission (Isiokwu 2; saline: p = 0.006; naloxone: p = 0.009) na 5 ụbọchị a tụnyere 1 ụbọchị. N'otu aka ahụ, a gosipụtara omume mmekọahụ na-eme ka a mata na oge nyocha na-atụle ụbọchị 1 nke gosiri site na obere mkpirisi nta ka ọ dị elu (Fig. 5F; saline: p = 0.001; naloxone: p = 0.020) na intromission (Isiokwu 2; saline: p = 0.004; naloxone: p = 0.009). Nke ka mkpa bụ na ọgwụgwọ naloxone na-emetụtaghị ahụmahụ nwoke na nwanyị ma ọ bụrụ na ha enwee mmekọahụ mgbe a nwalere 1 d mgbe enwere mmekọahụ, na-adabere na ọgwụgwọ naloxone na ule ikpeazụ nke nyocha.

N'ikpeazụ, anyị nwalere ihe naloxone na-eweta mmetụta dị ogologo na ngosipụta nke omume mmekọahụ a na-eme ka ọ dị mma n'ihi ihe mgbochi naloxone na akụrụngwa na-akwụghachi ụgwọ nke omume mmekọahụ. Agbanyeghị, naloxone na-achịkwa ozugbo tupu mating emegharịghị ịgbanwe CPP maka mating (Fig. 5G), na-atụ aro na ọgwụgwọ naloxone agbanweghị ụgwọ ọrụ mmekọahụ. Ndị otu saline na ndị naloxone na-emeso otu CPP dị oke mkpa maka omume mmekọahụ dị ka egosipụtara site n'ịgbatịkwu oge ejirila na-enwe mmekọahụ na-arụkọ ọrụ ọnụ (Fig. 5H; saline: p = 0.038; naloxone: p = 0.002) n'oge ule nlele mgbe e jiri ya tụnyere pretest. Ya mere, naloxone adịghị etinye mmetụta ọjọọ ya na mmezi nke mmekorita mmekọahụ site na igbochi ụgwọ ọrụ nke metụtara mmekọahụ.

Inwe mmekorita nke nwoke na nwanyi na-adabere na omume EOP na VTA

Iji kwado na EOP na-eme kpọmkwem na VTA iji mee ka mmekọrịta nwoke na nwanyị nwee mmekorita oge dị ogologo, usoro nyocha ahụ e depụtara na Nyocha 3A emeghachiri na intra-VTA naloxone infusions kama usoro injections. Nsonaazụ dị ka usoro nlekọta usoro nke akọwapụtara n'elu. E nwere mmetụta dị ịrịba ama nke ụbọchị ụtụtụ na ihe niile gbasara mmekọahụ (Fig. 6A, ugwu ugwu: F(2,33) = 4.494, p = 0.019; B, njedebe na-agbaghasị: F(2,33) = 4.042, p = 0.027; C, ịgba aghara ejaculation: F(2,33) = 5.309, p = 0.010) na ọgwụ intra-VTA naloxone na nkwụsị na ugwu (F(1,33) = 7.345, p = 0.011) na intromission (F(1,33) = 6.126, p = 0.019). Naloxone intra-VTA anaghị egbochi mmemme mbụ nke mmekorita nke omume mmekọahụ na 5 d nke mating, dịka ụmụ nwoke na-emeso naloxone gosipụtara oghere ndị bekee ka ha dakwasị (Fig. 6A; p = 0.001), intromission (Fig. 6B; p <0.001), na ejaculation (Fig. 6C; p = 0.001) na 5 ụbọchị a tụnyere 1 ụbọchị. Ndị ikom naloxone na-emeso ndị dị iche na ụmụ nwoke na-emeso saline n'ụbọchị nke ise nke mating na nke ọ bụla n'ime ụlọ ọgwụ. Ngwọta naloxone intra-VTA, dịka nchịkwa usoro, mere ka ụba elu dị elu (Fig. 6A; p <0.001) na intromission oge (Fig. 6B; p <0.001) na nke mbụ n’abalị ahụ ma e jiri ya tụnyere ụmụ nwoke ndị a na-emeso nnu nnu, nke a na-ahụghị n’oge mmemme na-esochi (oge nke naloxone- na ụmụ nwoke na-agwọ saline adịghị iche). Otu ihe a na-atụghị anya ya bụ na na nnwale a, ụmụ nwoke ndị a na-emeso nnu na-egosighi nkwado dị oke mkpa nke ugwu ma ọ bụ nkwụsị intromission (dị ka egosiri na nyocha niile akọwapụtara n'elu), na naanị ejaculation latency dị mkpụmkpụ n'ụbọchị nke ise ma e jiri ya tụnyere ụbọchị mbụ. (nnu: p = 0.001).

Nyocha 6. 

Endogenous opioids na VTA mediate ahụmahụ na-akwalite mmemme nke omume mmekọahụ na ogologo ya na-arụzi. Mmeghari mmekorita nke nwoke na nwanyi na - eme saline (Sal, n = 8) ma obu NLX (Ogwe ojii, n = 6) na ochichi nke intra-VTA. Ngosipụta gosiri bụ ụda ugwu (A), intromission (B), na ejaculation (C) na ụbọchị 1 na 5 nke ụbọchị ise nke oge mating. Tụkwasị na nke ahụ, a na-egosi data maka ụbọchị nyocha ikpeazụ nke ntanye, 7 nke na-esonụ ụbọchị 5 na enweghị nnu saline ma ọ bụ naloxone. Ngosipụta data pụtara ± SEM; + na-egosi nnukwu ọdịiche dị n'etiti ụbọchị 1 na 5 n'ime ọgwụgwọ; * na-egosi nnukwu ọdịiche dị n'etiti ule ụbọchị na ụbọchị 5 n'ime ọgwụgwọ; # gosiri na ọdịiche dị n'etiti naloxone na Sal ndị otu n'ime ụbọchị. Ihe odide sụgharịrị nke VTA ngalaba (H, -4.60; I, -5.00; J, -5.25 si bregma) na-egosi saịtị intruders intra-VTA maka ụmụ anụmanụ niile na Nlekọta 5 (saline, white; naloxone, black; Missed, gray), eji ederede eserese si Swanson Brain Maps (Swanson, 2004). Ndị a na-ahụ maka ịṅụ ọgwụ na-eme ka ndị mmadụ ghara ịkwado ya. fr, Fasciculus retroflexus; ML, Medial lemniscus; SN, substantia nigra.

Ngwọta naxolone intra-VTA gbochie nhazi nke omume mmekorita nwoke na nwanyị nwere mmekọahụ, dịka mmetụta nke naloxone dị n'usoro. N'ụzọ doro anya, na ule ikpeazụ nke ụmụ nwoke na-arịa ọrịa naloxone nwere ogologo oge ka ha ghara ịdị elu (Fig. 6A; p = 0.011), intromission (Fig. 6B; p = 0.010), na ejaculation (Fig. 6C; p = 0.015) ma e jiri ya tụnyere oge nke oge ha nke ise ma jiri ya tụnyere ụmụ nwoke na-emeso saline n'ụbọchị nyocha ikpeazụ (Fig. 6A, p = 0.006; B, p = 0.008). N'ụzọ dị iche, ụmụ anụmanụ anaghị agwọ ọrịa na-edozi saline adịghị iche n'ọgba aghara iji gbagoo na mpụga n'etiti ule ikpeazụ na ụbọchị 5 nke mating. Mmetụta ndị a bụ kpọmkwem maka nnyefe nke naloxone na VTA, dịka ụmụ nwoke nwere saịtị cannulation dị nso kama ọ bụghị icheta VTA (Fig. 6D; n = 3) gosipụtara nhazi oge ogologo nke omume mmekọahụ dị ka njikwa akara saline (ML, IL = 53 ± 6.245, EL = 389 ± 299.5 ma dị iche iche ma e jiri ya tụnyere anụmanụ naloxone intra-VTA na ụbọchị nyocha ikpeazụ (ML, IL: p = 0.029; EL: p = 0.0395).

E choro ime ihe maka mmekorita nke mmekorita nke nwoke na nwanyi

Dabere na nchọpụta dị ugbu a, anyị na-eche na ọrụ EOP na VTA n'oge enwere ahụmahụ na mpempe akwụkwọ VTA na-eme ka mbelata mbido dị oke egwu maka nsụgharị nke mmetụ ume iji nweta ihe ndị na-akpata ụgwọ ọrụ na-akpata ụgwọ ọrụ ma n'ihi ya, nkwụsị nke mmezi nke omume mmekọahụ. Iji nyochaa echiche a, mmetụta nke igbochi ndị na-anabata opioid n'oge enwere ahụmahụ na nhụjuanya nke anụ ọkụkụ nke sitere na nkwupụta na-esote na njirimara na-ekwu banyere ụgwọ ọrụ mmekọahụ (ihe ọmụma gbasara ọnọdụ mmekọahụ). A na-ekpughekwa ụmụ anụmanụ ndị na-adịghị mma na-emetụta ihe ndị metụtara gburugburu ebe obibi, ma ndị a ejikọtaghị na ahụmahụ na-emetụta ahụmahụ na mbụ, n'ihi ya ha bụ ndị na-anọpụ iche. N'ikpeazụ, a chọpụtara ọkwa ndị dị na PALK na ndị na-ahụ maka ndị nwere mmekọahụ na ndị na-enweghị nchịkwa bụ ndị nọgidere na-elekọta ụlọ ma ghara ikpughe na nhọta ọ bụla (-No Cue). Ikwenye ma gbasaa nchọpụta gara aga (Balfour et al., 2004), ikpughe ihe ederede nke jikọtara ụgwọ ọrụ mmekorita nwoke na nwanyi gara aga mụbara ụba okwu na ụmụ nwoke nwere mmekọahụ na NAc (Fig. 7) na mPFC (Fig. 8A-C), ma emeghị ka ntinye aka na ntinye na BLA (Fig. 8D) ma ọ bụ CPu (data egosighi). E nwere mmetụta dị ukwuu nke igosipụta ngosi na NAc isi (F(1,12) = 12.1941, p = 0.004), ACA (F(1,12) = 5.541, p = 0.038), na PL (F(1,12) = 5.241, p = 0.041), na naloxone ọgwụgwọ na NAc isi (F(1,12) = 6.511, p = 0.025), ACA (F(1,12) = 15.242, p = 0.002), na PL (F(1,12) = 7.336, p = 0.019). Enwere mmekọrịta dị mkpa na NAc isi (F(1,12) = 10.107, p = 0.008), ACA (F(1,12) = 16.060, p = 0.002), PL (F(1,12) = 8.235, p = 0.014) na IL ((F(1,12) = 6.965, p = 0.022). Nke mbụ, mgbasa ozi Cue jikọrọ ọnụ na-arịwanye elu mụbaa na anụ ahụ a na-agwọ anụ ahụ (Exp Sal ​​+ Cue) ma e jiri ya tụnyere njikwa ndị na-adịghị ekpughere ọhụụ ọ bụla ma wepụ ha n'ụlọ ezinaụlọ (Exp Sal-No Cue) na NAc isi (Fig. 7A; p <0.001), na mPFC subregions ACA (Fig. 8A; p = 0.001), PL (Fig. 8B; p = 0.003), na IL (Fig. 8C; p = 0.029). N'ụzọ dị iche, na ụmụ anụmanụ na-azụ anụ saline, ndị na-emetụta ihe ọmụma dị iche iche, nke na-ejikọtaghị na ụgwọ ọrụ mmekọahụ, emeghị ka ọ bụrụ ihe ọ bụla n'ime akụkụ ụbụrụ (Naive Sal + Cue ma e jiri ya tụnyere naive Sal-No Cue; Mkpụrụ fig. 7, 8), na-egosi na ntinye nke PERK bụ kpọmkwem maka ikpughe nke njirimara metụtara mmekọahụ. Ọzọkwa, inwe mmekọahụ naanị ya agbanweghị akara ngosi ọ bụla na mpaghara ụbụrụ ọ bụla, ebe ọ bụ na enweghi ọdịiche dị n'etiti otu dị iche iche nke e wepụrụ site na ụlọ, ma ọ bụ na-enwe mmekọahụ ma ọ bụ ahụmahụ, ma mesoo ya saline ma ọ bụ naloxone.

Nyocha 7. 

Endogenous opioid achoro achoro maka mmeghari ihe ndi na-acho na NAc site n'inwe mmekọahụ. Ọnụ ọgụgụ nke mkpụrụ ndụ PERK-IR maka mm2 na nucleus accumbens isi (A) na shei (B) na ụmụ nwanyị na-acha ọcha (ndị ọcha) na ndị nwere ahụmahụ (Exp, black) na-eme ka ndị NLX ma ọ bụ Saline (sal) na-arụ ọrụ n'oge a na-emekọ ihe ọnụ (Ndị nwoke na-ahụ maka nwoke) ma ọ bụ na-ejikọta ụmụ nwoke. A na-egosiputa otu dị iche iche na ihe ndị dị na Cue (Cue), bụ ndị na-ejikọta ọnụ na ndị nwoke na ndị na-anọghị na ntanetị na anụmanụ Naiva, ma ọ bụ wepụ ha n'ụlọ nkwụ (No Cue; A na-enye data dịka ihe dịka ± SEM; * na-egosi oke dị iche ma e jiri ya tụnyere saline-pretreated ma ọ bụrụ na ọ bụghị njikwa a na-egosipụta (Naive Sal-No Cue and Exp Sal-No Cue); # gosiri ntụgharị dị ịrịba ama ma e jiri ya tụnyere ndị na-ekpughere Gọọmenti (Exp Sal ​​+ Cue). Ihe ngosi ndi nnochite nke mkpụrụ ndụ PERK-IR kwa mm2 na NAc nke ụmụ nwoke nwere mmekọahụ na Sal (C, D) ma ọ bụ NLX (E, F) nke a na - ewepụ site n'ụlọ nkwụ (No Cue, C, E), ma ọ bụ kpughere ihe odide okwu gbasara ihe gbasara ntụrụndụ (Cue; D, F). N = 4 nke ọ bụla ma e wezụga Naive NLX (No Cue), n = 3. ac, Akara mma. Ogwe mmanya, 100 μm.

Nyocha 8. 

Mmetụta nke naloxone na ngwunye na-ejupụta na ngwongwo na-emepụta okwu na mpaghara VTA ndị ọzọ. Ọnụ ọgụgụ nke mkpụrụ ndụ PERK-IR maka mm2 na ụmụ nwanyị na-acha ọcha (na-acha ọcha) na anụ ahụ (Exp, black) na-eme ka NLX ma ọ bụ saline (sal) na-arụ ọrụ n'oge a na-emekọ ihe ma gosipụta ya na CA) ma ọ bụ ụlọ ezigara (ACQ)A), PL (B), IL (C), na BLA (D). Data na-anọchite anya ± SEM; * na-egosi oke dị iche ma e jiri ya tụnyere saline-pretreated ma ọ bụrụ na ọ bụghị njikwa a na-egosipụta (Naive Sal-No Cue and Exp Sal-No Cue); # egosiputa ihe dị oke iche ma e jiri ya tụnyere ndị na-eme ka a ghara ịkwa iko (Naive Sal + Cue).

Na nkwado nke nkwenye anyị, ọgwụgwọ naloxone n'oge enwere mmekọahụ nwere ike ime ka ọ dịkwuo ike imepụta site na njirimara ndị nwere mmekọahụ. KWUKWU okwu ndị a na-egosi na ụmụ nwoke nwere ahụmahụ (Exp NLX + Cue) abụghị ihe dị iche na okwu ọhụụ nke ọ bụla n'ime ndị na-amaghị nwoke ma ọ bụ ndị isi na-ahụ maka ihe ndị dị na ya (Naive Sal-No Cue or Naive NLX- Enweghi Ntu). Ọzọkwa, kọwaa okwu n'ime ụmụ nwoke nwere ahụmahụ na-ahụ maka ndị naloxone (Exp NLX + Cue) bụ nke dị ntakịrị karị ma e jiri ya tụnyere anụ ahụ nwere ahụmahụ (salut) salula (Exp Sal ​​+ Cue) na NAc isi (Fig. 7A; p = 0.002) na subregions mPFC (Fig. 8A, ACA: p <0.001; B, PL: p = 0.002; C, IL: p = 0.015).

Na akwara NAc, nchọpụta ANOVA abụọ ụzọ adịghị emepụta mmetụta dị ịrịba ama nke ihe ndị na-egosi ikpughe na ọgwụgwọ naloxone. Nte ededi, uwụtn̄kpọ uwụtn̄kpọ ke uwụtn̄kpọ emi ẹkewụtde ke uwụtn̄kpọ emi ama anam mbon emi ẹkedọhọde ke utom emi ẹkedọhọde ke saline (Exp SAL + Cue) ke ini ẹkotde mbon ukpeme emi mîkemeke ndiwụt ke Saline (Fig. 7B; Naive SAL-No Cue: p = 0.0163).

Nkwurịta

Nnyocha a na-amụ ugbu a na-egosi na EOP na-eme ihe na VTA n'oge omume mmekọahụ, omume ọma nke ụgwọ ọrụ, mere ka mbelata nke oke VTA dopamine na-ebuwanye ibu. Ebeghi oke mbemiso na VTA nonu dopamine neurons, ma obu dopamine neurons di nso noo nigra, na-ekwu na mgbanwe a bu ihe di mkpa maka sel Vamine dopamine. Nke a VEM dopamine plasticity na-egosi yiri nke a na-agbazi site na ikpochapu nke opiate (Sklair-Tavron et al., 1996; Russo et al., 2007; Mazei-Robison et al., 2011) ma mee ka enweghi ndidi na ugwo olu nke opiate (morphine). Anyị gosipụtara na VTA dopamine plasticity dị oké egwu maka ogologo oge (mmezi) ma ọ bụghị oge dị mkpirikpi (mmepe), ịkwalite omume mmekọahụ na ụgwọ ọrụ na-arụ ọrụ na-arụ ọrụ (PERK) na VTA lekwasịrị anya mpaghara: NAc na MPFC. Nchọpụta ndị a na-egosi ọrụ maka VTA dopamine plasticity na okwu ogologo oge nke mmetụ na-akpali akpali nke nsụgharị ụgwọ ọrụ ma ọ bụ ụgwọ ọrụ ụgwọ ọrụ.

Edewo ya nke ọma na ahụmahụ mmekọahụ na-ebute mmezi nke omume mmekọahụ na-esote, gụnyere ngwa ngwa ịmalite ịmalite ịlụ di ma ọ bụ nwunye na ịrụ ọrụ dị elu (Balfour et al., 2004; Pitchers et al., 2010a,b, 2012). Mmekọrịta a ma ọ bụ mmesi ike nke omume mmekọahụ na-echere ma ọ dịkarịa ala 28 d mgbe mating (Pitchers et al., 2012). Ọzọkwa, e gosipụtarala na omume mmekọahụ na nkwupụta ụbụrụ na-ebu amụma banyere ụgwọ ọrụ mmekọahụ na-eme ka MOR internalization na VTA ma mee ka ọkpụkpụ na-arụ ọrụ n'ime usoro mesolimbic, gụnyere na VTA (dopamine na nondopamine neurons), NAc, PFC, na BLA (na-Balfour et al., 2004, 2006). Ọ bụ nke ọma guzobere VTA dopamine neurons na-arụ ọrụ dị oké mkpa n'ịmụta na nsụgharị nke mmetụ ncheta nke ụgwọ ọrụ-metụtara stimuli (Berridge na Robinson, 1998; Berridge et al., 2009; Flagel et al., 2011) ma dị oké egwu maka amụma ọdịnihu (Schultz, 2010). Ihe nchọpụta dị ugbu a na-agbasawanye na ihe ọmụma anyị ugbu a site na ịmepụta VTA neuroplasticity nke na-akwụghachi ụgwọ ọrụ dị oké egwu maka ọrụ ndị a, ọ dabere na nkwado MOR site na EOP na VTA. A maghị EOP ugbu a na EOP bụ MOR ligand nke na-eme na VTA n'oge omume nwoke na nwanyị. Ọ bụ ezie na endorphin β abụọ na enkephalin anọwo na-akpali akpali maka mkpali maka nri (Hayward et al., 2002), nke a ka ga-eguzobe maka omume nwoke na nwanyị. Ayi egosila na uzo enweghi β-endorphin adighi-arụ ọrụ na oge aging, ma enweghi uba na MRNA POMC; ya mere, na-atụ aro na endorphin β nwere ike ọ gaghị abụ oké egwu EOP na-arụ ọrụ na VTA n'oge enwere (Davis et al., 2007). VTA dopamine plasticity dị mkpa maka ọrụ ntanetị na mPFC, NAc, na VTA na-esote mgbasa ozi mmekọahụ-ịkọ ọdịdị gburugburu ebe obibi. Ọzọkwa, VTA dopamine plasticity dị oké egwu maka okwu ogologo oge nke ịmalite ịmalite na omume nke omume mmekọahụ. N'ụzọ dị iche, enweghi ihe nkwụsị nke VTA mere site na ahụmahụ mmekọahụ iji nweta nzaghachi na-eme ka ọ bụrụ ụgwọ ọrụ nwoke (mkpebi CPP kpebisiri ike) na mkpirikpi oge ịkwalite mkpali na omume (n'oge enwe mmekọahụ ma ọ bụ 1 mgbe emesịrị) nọgidere na-emebi emebi n'agbanyeghị MOR na -Mehrara na Baum, 1990). Kama nke ahụ, data ahụ na-egosi na VTA dopamine neuroplasticity na-akwado oge dị ogologo (7 d mgbe enwere mmekọahụ; Pitchers et al., 2012) okwu nke "choro" nke ugwo olu nwanyi ma mee ka ndi mmadu meghachi omume n'olu di na nwunye (Miller na Baum, 1987; Berridge na Robinson, 1998).

Ụmụ anụmanụ ndị nwere mmekọahụ na-egosipụta nnyefe obe na ụgwọ ọrụ morphine, dịka mmetụta nke ụkwụ na-agbagharị na ụmụ oke, omume ọzọ na-akwụghachi ụgwọ, ihe na-egbochi ya na ọgwụgwọ naloxone (Lett et al., 2001, 2002) ma kpebisie ike ịdabere na VTA dopamine cell plasticity (nchọpụta ugbu a). Yiri n 'ugwo ugwo, ugwo nke ndi ozo na morphine ma obu heroin utara na mbelata nke VTA dopamine amalite (Sklair-Tavron et al., 1996; Spiga et al., 2003; Russo et al., 2007; Mazei-Robison et al., 2011). Ọzọkwa, ikpochapụ opiate na oge mkpụmkpụ dị mkpụmkpụ na-eweta nkwụsị ụgwọ nkwụsị, dị ka a na-achọ ka usoro ọgwụgwọ dị elu dị elu na-achọ ka a na -Shippenberg et al., 1987; Russo et al., 2007), ma na-eme ka ụmụ anụmanụ na-ahụ maka onwe ha ka ha ghara ịṅụ ọgwụ ọjọọ (Ahmed et al., 2000; Walker et al., 2003). N'ihi ya, EOP na opiates na-eme ihe dị iche iche na-eme ka ha nwee ike ịnagide ntachibido mgbe ha na-ewepụ onwe ha, nke nwere ike igosi usoro mgbochi iji nweta nsogbu site na nkwupụta ugboro ugboro (Koob na Le Moal, 2005). N'ụzọ dị iche, n'oge ọgwụ ọjọọ opiate na-adịte aka, nnwere onwe na-emegharị ka ọ bụrụ na ọ na-echebara ihe ndị na-akwụ ụgwọ ụgwọ ọgwụ ọjọọ (Harris na Aston-Jones, 2003; Aston-Jones na Harris, 2004; Harris na Gewirtz, 2004). N'ụzọ na-adọrọ mmasị, a chọpụtawo mmekorita mmekọahụ nke oge 7-28 d na-enwe mmekọahụ na-akpata ntụgharị uche maka ụgwọ ọrụ psychostimulant (Pitchers et al., 2010a), nke dabere na ngosipụta deltaFosB na mating na ngwangwa na 1 ntinye nghazi dopamine na NAc (Pitchers et al., 2013). N'ihi ya, ụgwọ ọrụ mmekọahụ na-akpata utọ ụgwọ ọrụ opia dị iche iche na nlebara anya psychostimulant, ọ bụ ezie na ogologo oge abstinence na morphine ụgwọ ọrụ ndidi ka na-anwale. Anyị na-ekwu na mmetụta ndị a na-ezighị ezi banyere ọgwụgwọ ọgwụ nwere ike ịgbasa site n'ụdị dị iche iche nke plasticity dị na akụkụ dị iche iche nke usoro mesolimbic: VTA EOP ihe na dopamine plasticity na-akwado ụgwọ ọrụ ụgwọ ọrụ (nke a na-amụ ugbu a), ebe NAC deltaFosB okwu akara psychostimulant sensitization (Pitchers et al., 2013). Ihe abuo abuo a nwere ike inye aka n'ekpochapu nke ogwu (Ahmed na Koob, 1998, 1999; Ahmed et al., 2000, 2002, 2003; Walker et al., 2003).

Usoro ihe omumu nke EOP na - emetụta VTA dopamine neurons n'oge ugwo olu ugwo. Ụzọ ọnụọgụ IRS2-Akt-mTORC2 bụ onye na-agbakarị nkwụsị nke ụda olu nke VTA mere site ugboro ugboro morphine (Jaworski et al., 2005; Russo et al., 2007; Mazei-Robison et al., 2011). A na-egbochi usoro nchịkwa morphine nke gbanwere ngbanwe nke mpempe dopamine na VTA site na intra-VTA infusions nke ụbụrụ na-enweta ihe ndị na-akpata nyocha (BDNF; Sklair-Tavron na Nestler, 1995). BDNF na - eme ka ụzọ a site na njirimara TrkB (Russo et al., 2007), onye na-anabata nkwonkwo kinase dị elu maka BDNF na akụkụ nke ụzọ ụzọ IRS2-Akt (Seroogy na Gall, 1993; Numan na Seroogy, 1999), ma kwuo na dopamine na GABA neurons na VTA. Mgbanwe nke akụkụ dị iche iche nke okporo ụzọ IRS2-Akt na-eji ngwa ụzụ ndị na-enyefe ihe ndị na-emepụta viral na-emetụta mmetụta nke ikpochapụ opia na-adịghị ala ala. Ọzọkwa, enwere ike ịnapụta ihe ndị na - apụta ìhè site na iweghachi ụzọ a na -Russo et al., 2007) na ikwu okwu nke mTORC2 na-egbochi morphine-induced VTA dopamine amalite mbelata (Mazei-Robison et al., 2011). Ya mere, ọrụ ndị gara aga na-enyocha mmetụta nke ndị opiates na-adịghị ala ala na VTA dopamine amalitela na-egosi na ọnụọgụ nke morphine nke usoro ụzọ IRS2-Akt-mTOR bụ zuru ezu ma dị mkpa maka mmetụta a (Mazei-Robison na Nestler, 2012). Ya mere, ọ bụ ihe na-anwa anwa ịkọwapụta na mmetụta nke ahụmahụ mmekọahụ na VTA dopamine neuroplasticity yiri BDNF na usoro IRS2-Akt-mTORC2.

N'ikpeazụ, nchọpụta dị ugbu a gosipụtara na ọ bụ ahụmahụ na-enye ụgwọ ọrụ na-akpata VTA neuroplasticity, karịsịa site na omume nwoke na nwanyị na-enwe mmekọahụ. Kpọmkwem, EOP mere na VTA iji belata nhazi dopamine, nke a na-ekwu na ọ ga - ejikọta ya na ọnụọgụ nke na - emeghị ihe na - eme ka ọ bụrụ usoro hypodopaminergic, ma na - agbanwe usoro mesolimbic na - arụ ọrụ na nzaghachi na - Ozokwa, nyocha nke VTA bụ ihe dị mkpa maka mkpali na-akpali akpali ma na-akwụ ụgwọ ọrụ, ma ọ bụghị n'ihi mmetụta dị egwu nke omume mmekọahụ. N'ikpeazụ, ọkpụkpụ VTA na-akpata site na nkwụghachi ụgwọ nke anụ ahụ na-esote oge nkwụghachi ụgwọ nke ụgwọ ọrụ abstinence na-emetụta ụgwọ ọrụ opiate ma nwee ike imetụta ọhụụ nke mmebi ahụ.

Ihe odide ala

  • Enwetara January 12, 2014.
  • Ntughari natara May 17, 2014.
  • Nara May 20, 2014.

  • A na - akwado nkwado a site na Nlekọta Ụlọ Ọrụ Na-ahụ Maka Ahụ Ike Kanada na LMC na Nkà Na - ahụ Maka Nkà na Nkà na Injinia na KKP.

  • Ndị na-ede akwụkwọ ekwupụtaghị ihe gbasara ego.

  • Ekwesịrị ịkwado akwụkwọ ozi na Dr Lique M. Coolen, Mahadum nke Mississippi Medical Center, Ngalaba Na-ahụ Maka Ahụike na Biophysics, 2500 North State Street, Jackson, MS 39216-4505. [email protected]

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