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激活孤啡肽受体减弱大鼠甲基苯丙胺动机与复吸：涉及伏隔核磷酸化CREB和Akt机制(英文)

蔡雨佳^1,2, 王方敏^1,3, 赖苗军^1,3, 周漪颖¹, 庄丁丁¹, 吴曼青¹, 刘慧珍¹, 沈雯雯¹, 周文华^1,*

¹浙江省全省药物成瘾与脑健康重点实验室，宁波大学附属康宁医院，宁波 315201；²四川省精神卫生中心，绵阳市第三人民医院，绵阳 621000；³宁波大学附属康宁医院精神科，宁波 315201

摘要

越来越多的证据表明，内源性伤害感受肽/孤啡肽(nociceptin/orphanin FQ peptide, N/OFQ)及其受体(nociceptin opioidreceptor, NOP)在酒精和可卡因奖赏中发挥作用；然而，NOP激动剂在甲基苯丙胺(methamphetamine, MAP)强化、动机和复吸中的作用尚不明确。本研究评估了选择性NOP激动剂Ro 64-6198 对大鼠MAP相关行为的影响。通过固定比率1 (fixedratio1, FR1)程序训练大鼠建立稳定的MAP 静脉自我给药模型(0.05 mg/kg/次)，持续12 天后，采用渐进比率(progressive-ratio, PR)程序量化觅药动机，并通过戒断后线索诱导和MAP激发测试评估复吸行为。蛋白质印迹分析显示，药物可使伏隔核(nucleus accumbens, NAc)内磷酸化CREB、ERK和Akt 表达水平发生变化。急性给予Ro 64-6198 (1 mg/kg)可显著降低PR测试中的MAP动机行为(与对照组相比P < 0.05)；两种剂量Ro 64-6198 (0.3 和1 mg/kg)均能抑制戒断或线索诱导的觅药行为(P < 0.05)，而仅高剂量Ro 64-6198 (1 mg/kg)可减弱MAP激发的觅药行为(P < 0.05)。这些行为学改变与NAc内CREB和Akt磷酸化水平上调相关。本研究为NOP激活可干预多种成瘾相关行为提供了临床前证据，提示Ro 64-6198 或可作为治疗MAP使用障碍的潜在候选药物。

关键词： 物质使用障碍; 伤害感受肽/孤啡肽; 伤害感受肽类阿片受体; 阿片受体; 甲基苯丙胺

Activation of nociceptin receptor attenuates methamphetamine motivation and relapse in rats: Involvement of phosphorylated CREB and Akt in the nucleus accumbens

CAI Yu-Jia^1,2, WANG Fang-Min^1,3, LAI Miao-Jun^1,3, ZHOU Yi-Ying¹, ZHUANG Ding-Ding¹, WU Man-Qing¹, LIU Hui-Zhen¹, SHEN Wen-Wen¹, ZHOU Wen-Hua^1,*

¹Zhejiang Key Laboratory of Drug Addiction & Brain Health, The Affiliated Kangning Hospital of Ningbo University, Ningbo 315201, China；²Sichuan Mental Health Center, The Third Hospital of Mianyang, Mianyang 621000, China；³Department of Psychiatry, The Affiliated Kangning Hospital of Ningbo University, Ningbo 315201, China

Abstract

Accumulating evidence has highlighted the functional role of the endogenous nociceptin/orphanin FQ peptide (N/OFQ) and its nociceptin opioid receptor (NOP) in alcohol and cocaine reward. However, the effects of NOP agonists on methamphetamine (MAP) reinforcement, motivation, and relapse remain uncertain. In this study, we evaluated the effects of Ro 64-6198, a selective NOP agonist, on MAP reinforcement, motivation, and relapse in rats. Rats underwent a fixed-ratio 1 (FR1) training to establish stable MAP intravenous self-administration (0.05 mg/kg/infusion) for 12 days, and the motivation for MAP was quantified using a progressive-ratio (PR) schedule, while the relapse was assessed through cue- and MAP-primed reinstatement after abstinence. Western blot analysis was employed to measure the relative expression of phosphorylated CREB, ERK, and Akt in the nucleus accumbens (NAc) following drug priming. Acute treatment of Ro 64-6198 (1 mg/kg) significantly reduced the motivated behavior for MAP under PR testing (P < 0.05 vs. vehicle). Ro 64-6198 at doses of 0.3 and 1 mg/kg could suppress the drug-seeking behavior induced by extinction or cues, respectively (P < 0.05), whereas only the higher dose (1 mg/kg) could attenuate MAP primed drug-seeking (P < 0.05). These behavioral effects were related to the upregulated phosphorylation of CREB and Akt in the NAc. Our results provide preclinical evidence that NOP activation disrupts multiple addiction-relevant behaviors, positioning Ro 64-6198 as a potential therapeutic candidate for treating MAP use disorders.

Key words: substance use disorders; nociceptin/orphanin FQ; nociceptin opioid receptor; opioid receptor; methamphetamine

收稿日期：　　录用日期：

通讯作者：周文华　　E-mail:

DOI: 10.13294/j.aps.2026.0027

引用本文：

蔡雨佳, 王方敏, 赖苗军, 周漪颖, 庄丁丁, 吴曼青, 刘慧珍, 沈雯雯, 周文华. 激活孤啡肽受体减弱大鼠甲基苯丙胺动机与复吸：涉及伏隔核磷酸化CREB和Akt机制(英文)[J]. 生理学报 2026; 78 (2): 413-424.

CAI Yu-Jia, WANG Fang-Min, LAI Miao-Jun, ZHOU Yi-Ying, ZHUANG Ding-Ding, WU Man-Qing, LIU Hui-Zhen, SHEN Wen-Wen, ZHOU Wen-Hua. Activation of nociceptin receptor attenuates methamphetamine motivation and relapse in rats: Involvement of phosphorylated CREB and Akt in the nucleus accumbens. Acta Physiol Sin 2026; 78 (2): 413-424