酒精使用障碍(alcohol use disorder,AUD)是一种复杂的慢性复发性脑部疾病,对个体健康和公共卫生构成重大影响。痛觉过敏是导致AUD治疗失败的关键因素。现有药物不能有效缓解AUD患者的疼痛,因而亟需研发新的干预措施。本文系统综述了AU...酒精使用障碍(alcohol use disorder,AUD)是一种复杂的慢性复发性脑部疾病,对个体健康和公共卫生构成重大影响。痛觉过敏是导致AUD治疗失败的关键因素。现有药物不能有效缓解AUD患者的疼痛,因而亟需研发新的干预措施。本文系统综述了AUD导致痛觉过敏的多系统神经生物学机制,从分子到环路,再从中枢到外周,揭示了神经递质失衡[如谷氨酸能兴奋增强/γ-氨基丁酸(γ-aminobutyric acid,GABA)能抑制]、神经胶质细胞介导的神经炎症等经典通路,并深入分析了表观遗传调控(DNA甲基化、组蛋白修饰和microRNA对关键基因的表达调控)和肠-脑轴(肠道菌群通过代谢物影响中枢神经系统)等新型机制,同时强调了性激素介导的性别差异性。基于这些见解,本文提出靶向神经环路、表观遗传修饰酶、肠道菌群等新型干预策略,为临床治疗AUD引起的痛觉过敏提供新视角,这对降低复饮率、改善患者预后具有重要意义。展开更多
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...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.展开更多
Addiction,a complex and chronic neurobiological disorder,is characterized by compulsive substance use despite harmful consequences,leading to persistent alterations in brain function,particularly within the reward,mot...Addiction,a complex and chronic neurobiological disorder,is characterized by compulsive substance use despite harmful consequences,leading to persistent alterations in brain function,particularly within the reward,motivation,and decision-making systems.Despite the availability of a range of treatment options,including pharmacotherapy and behavioral therapies,relapse remains a major challenge,with many individuals struggling to maintain long-term recovery.Current treatments often show limited efficacy,underscoring the need for novel therapeutic strategies that can address the underlying neurobiological disruptions in addiction.展开更多
基金supported by the National Natural Science Foundation of China(No.82271256 and 32200817)General Program from Nantong Commission of Health(No.MS2024049)Guided Research Program of Nantong Municipal Bureau of Science and Technology(No.JCZ2023023)。
文摘酒精使用障碍(alcohol use disorder,AUD)是一种复杂的慢性复发性脑部疾病,对个体健康和公共卫生构成重大影响。痛觉过敏是导致AUD治疗失败的关键因素。现有药物不能有效缓解AUD患者的疼痛,因而亟需研发新的干预措施。本文系统综述了AUD导致痛觉过敏的多系统神经生物学机制,从分子到环路,再从中枢到外周,揭示了神经递质失衡[如谷氨酸能兴奋增强/γ-氨基丁酸(γ-aminobutyric acid,GABA)能抑制]、神经胶质细胞介导的神经炎症等经典通路,并深入分析了表观遗传调控(DNA甲基化、组蛋白修饰和microRNA对关键基因的表达调控)和肠-脑轴(肠道菌群通过代谢物影响中枢神经系统)等新型机制,同时强调了性激素介导的性别差异性。基于这些见解,本文提出靶向神经环路、表观遗传修饰酶、肠道菌群等新型干预策略,为临床治疗AUD引起的痛觉过敏提供新视角,这对降低复饮率、改善患者预后具有重要意义。
基金supported by Ningbo Top Medical and Health Research Program(No.2022030410)National Key Research and Development Program of China(No.2022YFC3300905,2023YFC3304202).
文摘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.
基金supported by the National Natural Science Foundation of China(T2350008)the STI2030-Major Projects[2021ZD0203000(2021ZD0203003)]the Open Research Fund of the State Key Laboratory of Brain-Machine Intelligence,Zhejiang University(BMI2400014).
文摘Addiction,a complex and chronic neurobiological disorder,is characterized by compulsive substance use despite harmful consequences,leading to persistent alterations in brain function,particularly within the reward,motivation,and decision-making systems.Despite the availability of a range of treatment options,including pharmacotherapy and behavioral therapies,relapse remains a major challenge,with many individuals struggling to maintain long-term recovery.Current treatments often show limited efficacy,underscoring the need for novel therapeutic strategies that can address the underlying neurobiological disruptions in addiction.
