Approximately 25% of patients who are prescribed opioids for chronic pain misuse them, and 5 to 10% develop an opioid use disorder. Although the neurobiological target of opioids is well known, the molecular mechanisms that are responsible for the development of addiction-like behaviors in some but not all individuals are poorly known. To address this issue, we used a unique outbred rat population (heterogeneous stock) that better models the behavioral and genetic diversity that is found in humans. We characterized individual differences in addiction-like behaviors using an addiction index that incorporates the key criteria of opioid use disorder: escalated intake, highly motivated responding, and hyperalgesia. Using in vitro electrophysiological recordings in the central nucleus of the amygdala (CeA), we found that rats with high addiction-like behaviors (HA) exhibited a significant increase in γ-aminobutyric acid (GABA) transmission compared with rats with low addiction-like behaviors (LA) and naive rats. The superfusion of CeA slices with nociceptin/orphanin FQ peptide (N/OFQ; 500 nM), an endogenous opioid-like peptide, normalized GABA transmission in HA rats. Intra-CeA levels of N/OFQ were lower in HA rats than in LA rats. Intra-CeA infusions of N/OFQ (1 μg per site) reversed the escalation of oxycodone self-administration in HA rats but not in LA rats. These results demonstrate that the downregulation of N/OFQ levels in the CeA may be responsible for hyper-GABAergic tone in the CeA that is observed in individuals who develop addiction-like behaviors. Based on these results, we hypothesize that small molecules that target the N/OFQ system might be useful for the treatment of opioid use disorder.

中文翻译：

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伤害感受肽通过使高度成瘾的大鼠中的 CeA-GABA 传输正常化来减弱羟考酮自我给药的增加。


大约 25% 因慢性疼痛而服用阿片类药物的患者会滥用药物，5% 至 10% 的患者会出现阿片类药物使用障碍。尽管阿片类药物的神经生物学靶标是众所周知的，但在某些但并非全部个体中导致成瘾样行为发展的分子机制却知之甚少。为了解决这个问题，我们使用了独特的近交大鼠群体（异质种群），可以更好地模拟人类的行为和遗传多样性。我们使用成瘾指数来描述成瘾样行为的个体差异，该指数包含阿片类药物使用障碍的关键标准：增加摄入量、高度积极的反应和痛觉过敏。利用杏仁核中央核（CeA）的体外电生理记录，我们发现与低成瘾样行为（HA）的大鼠相比，具有高成瘾样行为（HA）的大鼠表现出γ-氨基丁酸（GABA）传输显着增加行为（LA）和幼稚大鼠。 CeA 切片灌注伤害感受肽/孤啡肽 FQ 肽（N/OFQ；500 nM）（一种内源性阿片样肽），使 HA 大鼠中的 GABA 传输正常化。 HA 大鼠的 CeA 内 N/OFQ 水平低于 LA 大鼠。在 HA 大鼠中，CeA 内输注 N/OFQ（每个部位 1 μg）可逆转羟考酮自我给药的增加，但在 LA 大鼠中则不然。这些结果表明，CeA 中 N/OFQ 水平的下调可能是造成 CeA 中高 GABA 能张力的原因，这种张力在出现成瘾样行为的个体中观察到。基于这些结果，我们假设靶向 N/OFQ 系统的小分子可能有助于治疗阿片类药物使用障碍。