Department of Comparative Biology and Experimental Medicine, University of Calgary, Calgary, Alberta, Canada.
Department of Physiology and Pharmacology, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
Nat Med. 2017 Mar;23(3):355-360. doi: 10.1038/nm.4281. Epub 2017 Jan 30.
Opiates are essential for treating pain, but termination of opiate therapy can cause a debilitating withdrawal syndrome in chronic users. To alleviate or avoid the aversive symptoms of withdrawal, many of these individuals continue to use opiates. Withdrawal is therefore a key determinant of opiate use in dependent individuals, yet its underlying mechanisms are poorly understood and effective therapies are lacking. Here, we identify the pannexin-1 (Panx1) channel as a therapeutic target in opiate withdrawal. We show that withdrawal from morphine induces long-term synaptic facilitation in lamina I and II neurons within the rodent spinal dorsal horn, a principal site of action for opiate analgesia. Genetic ablation of Panx1 in microglia abolished the spinal synaptic facilitation and ameliorated the sequelae of morphine withdrawal. Panx1 is unique in its permeability to molecules up to 1 kDa in size and its release of ATP. We show that Panx1 activation drives ATP release from microglia during morphine withdrawal and that degrading endogenous spinal ATP by administering apyrase produces a reduction in withdrawal behaviors. Conversely, we found that pharmacological inhibition of ATP breakdown exacerbates withdrawal. Treatment with a Panx1-blocking peptide (panx) or the clinically used broad-spectrum Panx1 blockers, mefloquine or probenecid, suppressed ATP release and reduced withdrawal severity. Our results demonstrate that Panx1-mediated ATP release from microglia is required for morphine withdrawal in rodents and that blocking Panx1 alleviates the severity of withdrawal without affecting opiate analgesia.
阿片类药物对于治疗疼痛至关重要，但阿片类药物治疗的终止可能会导致慢性使用者出现衰弱性戒断综合征。为了减轻或避免戒断的不良症状，许多人继续使用阿片类药物。因此，戒断是依赖个体使用阿片类药物的关键决定因素，但它的潜在机制尚未得到很好的理解，也缺乏有效的治疗方法。在这里，我们确定了 Panx1 通道（pannexin-1）是阿片类药物戒断的治疗靶点。我们发现，从吗啡戒断中诱导了啮齿动物脊髓背角 I 层和 II 层神经元中的长期突触易化，这是阿片类药物镇痛的主要作用部位。小胶质细胞中 Panx1 的基因缺失消除了脊髓突触易化，并改善了吗啡戒断的后遗症。Panx1 对大小可达 1 kDa 的分子具有独特的通透性，并且能够释放 ATP。我们发现，在吗啡戒断期间，Panx1 的激活导致小胶质细胞中 ATP 的释放，而通过施用 apyrase 降解内源性脊髓 ATP 会减少戒断行为。相反，我们发现抑制 ATP 分解会加剧戒断。用 Panx1 阻断肽（panx）或临床使用的广谱 Panx1 阻断剂，甲氟喹或丙磺舒治疗，抑制了 ATP 的释放并减轻了戒断的严重程度。我们的研究结果表明，Panx1 介导的小胶质细胞中 ATP 的释放是啮齿动物吗啡戒断所必需的，并且阻断 Panx1 可以减轻戒断的严重程度而不影响阿片类药物的镇痛作用。
