Crucial Role of CB2 Cannabinoid Receptor in the Regulation of Central Immune Responses during Neuropathic Pain
Crucial Role of CB2 Cannabinoid Receptor in the Regulation of Central Immune Responses during Neuropathic Pain
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DOI：
10.1523/jneurosci.3400-08.2008
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发表时间：
2008-11-12
影响因子：
5.3
通讯作者：
Maldonado, Rafael
中科院分区：
文献类型：
--
作者：
Racz, Ildiko;Nadal, Xavier;Maldonado, Rafael
神经性疼痛是神经损伤的一种临床表现，即使使用强效镇痛药物也难以治疗。在这里，我们使用不同的转基因小鼠系来阐明CB2大麻素受体在调节中枢免疫反应中所起的作用，从而导致神经性疼痛的发生。CB2敲除小鼠和野生型幼崽暴露于坐骨神经损伤，两种基因型在同侧足部出现类似的痛觉过敏和异位性疼痛。最引人注目的是，基因敲除还会产生对侧镜像疼痛，这与对侧脊髓角的小胶质细胞和星形细胞表达增强有关。与此一致的是，在过表达CB2受体的转基因小鼠中，坐骨神经损伤引起的痛觉过敏、异常痛觉以及小胶质细胞和星形胶质细胞的激活被减弱。这些结果表明CB2大麻素受体在神经损伤反应中调节神经胶质激活的关键作用。在用CB2敲除的骨髓细胞重建的辐照野生型小鼠中，可以复制神经性疼痛的增强表现，从而证明造血细胞中表达的CB2受体在脊髓神经性疼痛的发展中具有重要意义。
Neuropathic pain is a clinical manifestation of nerve injury difficult to treat even with potent analgesic compounds. Here, we used different lines of genetically modified mice to clarify the role played by CB2 cannabinoid receptors in the regulation of the central immune responses leading to the development of neuropathic pain. CB2 knock-out mice and wild-type littermates were exposed to sciatic nerve injury, and both genotypes developed a similar hyperalgesia and allodynia in the ipsilateral paw. Most strikingly, knock-outs also developed a contralateral mirror image pain, associated with an enhanced microglial and astrocytic expression in the contralateral spinal horn. In agreement, hyperalgesia, allodynia, and microglial and astrocytic activation induced by sciatic nerve injury were attenuated in transgenic mice overexpressing CB2 receptors. These results demonstrate the crucial role of CB2 cannabinoid receptor in modulating glial activation in response to nerve injury. The enhanced manifestations of neuropathic pain were replicated in irradiated wild-type mice reconstituted with bone marrow cells from CB2 knock-outs, thus demonstrating the implication of the CB2 receptor expressed in hematopoietic cells in the development of neuropathic pain at the spinal cord.