中国药理学与毒理学杂志2025，Vol.39Issue(10)：721-730,10.DOI:10.3867/j.issn.1000-3002.2025.08466
孤啡肽受体激动剂调节腹侧被盖区CREB/BDNF抑制大鼠海洛因复吸
Nociceptin/orphanin FQ receptor agonist inhibits heroin relapse in rats via CREB/BDNF pathway in VTA
摘要
Abstract
OBJECTIVE To study the effects of Ro 64-6198,a selective nociceptin/orphanin FQ receptor(NOPR)agonist,on heroin self-administration and drug-seeking behavior in rats.METHODS Rats were trained to self-administer heroin intravenously at a dose of 0.05 mg·kg-1 under a fixed ratio 1(FR1)reinforcement schedule.Heroin motivation was assessed using a progressive ratio(PR)schedule.Firstly,a stable heroin self-administered rat model was established before the effects of Ro 64-6198 on heroin rewarding under the FR1 schedule were observed.After three days of self-administration recovery training,the effects of Ro 64-6198 on heroin reward motivation were observed under the PR3-4 schedule.Following extinction,the reinstatement of heroin seeking induced by either conditioned cues or heroin priming was evaluated in rats withdrawn from self-administration.The expressions of cAMP response element-binding protein(CREB)and brain-derived neurotrophic factor(BDNF)in the ventral tegmental area(VTA)were analyzed using Western blotting,while the expression of the NOPR in neurons in the VTA was examined through immunofluorescence staining.RESULTS Pretreatment with 3 mg·kg-1 Ro 64-6198 significantly reduced active responses and heroin infusions during FR1 testing,as well as decreased breakpoints,indicating reduced motivation under the PR schedule.At a dose of 1 mg·kg-1,Ro 64-6198 markedly attenuated the reinstatement of heroin-seeking behavior induced by conditioned cues or heroin priming.Furthermore,the administration of SB-612111,an NOPR antagonist,blocked the inhibitory effects of Ro 64-6198 on cue-induced heroin-seeking,although SB-612111 alone had no effect on heroin-seeking behavior.Ro 64-6198 treatment also suppressed the reduction of both phos-phorylated CREB(p-CREB)and BDNF levels in the VTA and the decreased expression of NOPR and p-CREB in dopaminergic neurons of the VTA.CONCLUSION These results demonstrate that Ro 64-6198 can mitigate heroin-seeking behavior through NOPR activation and CREB/BDNF pathway in the VTA.This study is expected to offer evidence for its potential as a clinical treatment for heroin addiction and relapse.关键词
孤啡肽受体/孤啡肽/阿片类药物/成瘾/复吸/脑源性神经营养因子Key words
nociceptin/orphanin FQ receptor/orphanin FQ/opioids/addiction/relapse/brain-derived neurotrophic factor分类
药学引用本文复制引用
陈杉珊,赖苗军,周漪颖,刘慧珍,王方敏,王雨婷,周文华..孤啡肽受体激动剂调节腹侧被盖区CREB/BDNF抑制大鼠海洛因复吸[J].中国药理学与毒理学杂志,2025,39(10):721-730,10.基金项目
国家自然科学基金(82471516) （82471516）
国家自然科学基金(82071499) （82071499）
宁波市医药卫生重点科研项目(2022030410) National Natural Science Foundation of China(82471516) （2022030410）
National Natural Science Foundation of China(82071499) （82071499）
and Ningbo Top Medical and Health Research Program(2022030410) （2022030410）
