Nociceptin/orphanin FQ receptor agonist inhibits heroin relapse in rats via CREB/BDNF pathway in VTA
10.3867/j.issn.1000-3002.2025.08466
- VernacularTitle: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
- Author:
Shanshan CHEN
1
;
Miaojun LAI
1
;
Yiying ZHOU
1
;
Huizhen LIU
1
;
Fangmin WANG
1
;
Yuting WANG
1
;
Wenhua ZHOU
1
Author Information
1. 宁波大学附属康宁医院全省药物成瘾与脑健康重点实验室,浙江宁波 315201;宁波大学附属康宁医院精神科,浙江宁波 315201
- Publication Type:Journal Article
- Keywords:
nociceptin/orphanin FQ receptor;
orphanin FQ;
opioids;
addiction;
relapse;
brain-derived neurotrophic factor
- From:
Chinese Journal of Pharmacology and Toxicology
2025;39(10):721-730
- CountryChina
- Language:Chinese
-
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reinstatement of heroin seeking induced by either conditioned cues or heroin priming was evaluated in rats withdrawn from self-administration.The expressions of cAMP response element-binding protein(CREB)and brain-derived neurotrophic factor(BDNF)in the ventral tegmental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.
