Blocking microglial pannexin-1 channels alleviates morphine withdrawal in rodents
Blocking microglial pannexin-1 channels alleviates morphine withdrawal in rodents
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DOI：
10.1038/nm.4281
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发表时间：
2017-03-01
期刊：
影响因子：
82.9
通讯作者：
Tuan Trang
中科院分区：
文献类型：
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作者：
Burma, Nicole E.;Bonin, Robert P.;Tuan Trang
阿片类药物对治疗疼痛至关重要，但阿片类药物治疗的终止可能会导致慢性使用者的衰弱性戒断综合征。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（1-4）。因此，戒断是依赖个体使用阿片类药物的一个关键决定因素，但其潜在机制知之甚少，缺乏有效的治疗方法。在这里，我们确定泛连接蛋白-1（Panx 1）通道作为阿片类药物戒断的治疗靶点。我们发现，吗啡戒断诱导长时程突触促进板层I和II神经元内的啮齿动物脊髓背角，阿片类镇痛的主要作用部位。在小胶质细胞中基因切除Panxl消除了脊髓突触易化，并改善了吗啡戒断的后遗症。Panx 1在其对大小高达1 kDa的分子的渗透性和ATP的释放方面是独特的（5，6）。我们发现，Panx 1激活驱动ATP释放小胶质细胞在吗啡戒断和内源性脊髓ATP通过管理腺苷三磷酸双磷酸酶产生减少戒断行为。相反，我们发现药物抑制ATP分解加剧了戒断。用Panx 1阻断肽（10）panx或临床上使用的广谱Panx 1阻断剂甲氟喹或丙磺舒治疗，抑制ATP释放并降低戒断严重程度。我们的研究结果表明，Panx 1介导的ATP释放从小胶质细胞所需的吗啡戒断在啮齿类动物和阻断Panx 1的戒断的严重程度，而不影响阿片类镇痛。
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(1-4). 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 Panxl 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(5,6). 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 ((10)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.