a Comparative Biology and Experimental Medicine , University of Calgary , Calgary, Alberta , Canada.
b Physiology and Pharmacology, Hotchkiss Brain Institute , University of Calgary , Calgary, Alberta , Canada.
Channels (Austin). 2017 Sep 3;11(5):487-494. doi: 10.1080/19336950.2017.1359361. Epub 2017 Jul 26.
Opioids are among the most powerful analgesics for managing pain, yet their repeated use can lead to the development of severe adverse effects. In a recent study, we identified the microglial pannexin-1 channel (Panx1) as a critical substrate for opioid withdrawal. Here, we investigated whether microglial Panx1 contributes to opioid-induced hyperalgesia (OIH) and opioid analgesic tolerance using mice with a tamoxifen-inducible deletion of microglial Panx1. We determined that escalating doses of morphine resulted in thermal pain hypersensitivity in both Panx1-expressing and microglial Panx1-deficient mice. In microglial Panx1-deficient mice, we also found that acute morphine antinociception remained intact, and repeated morphine treatment at a constant dose resulted in a progressive decline in morphine antinociception and a reduction in morphine potency. This reduction in morphine antinociceptive potency was indistinguishable from that observed in Panx1-expressing mice. Notably, morphine tolerant animals displayed increased spinal microglial reactivity, but no change of microglial Panx1 expression. Collectively, our findings indicate microglial Panx1 differentially contributes to opioid withdrawal, but not the development of opioid-induced hyperalgesia or tolerance.
阿片类药物是治疗疼痛最有效的镇痛药之一，但它们的重复使用会导致严重的不良反应。在最近的一项研究中，我们发现小胶质细胞 Panx1 通道（Panx1）是阿片类戒断的关键底物。在这里，我们使用可诱导型敲除小胶质细胞 Panx1 的小鼠，研究小胶质细胞 Panx1 是否与阿片类药物引起的痛觉过敏（OIH）和阿片类药物镇痛耐受有关。我们发现，递增剂量的吗啡会导致表达 Panx1 和缺乏小胶质细胞 Panx1 的小鼠出现热痛敏。在缺乏小胶质细胞 Panx1 的小鼠中，我们还发现急性吗啡镇痛作用仍然完整，而在恒定剂量下重复给予吗啡会导致吗啡镇痛作用逐渐下降和吗啡效力降低。这种吗啡镇痛效力的降低与在表达 Panx1 的小鼠中观察到的情况相同。值得注意的是，吗啡耐受动物的脊髓小胶质细胞反应性增加，但小胶质细胞 Panx1 表达没有变化。总的来说，我们的研究结果表明，小胶质细胞 Panx1 对阿片类药物戒断有差异贡献，但对阿片类药物引起的痛觉过敏或耐受的发展没有贡献。
