Racz Ildiko, Nadal Xavier, Alferink Judith, Baños Josep E, Rehnelt Jennifer, Martín Miquel, Pintado Belén, Gutierrez-Adan Alfonso, Sanguino Elena, Manzanares Jorge, Zimmer Andreas, Maldonado Rafael
Institute of Molecular Psychiatry, University of Bonn, 53105 Bonn, Germany.
J Neurosci. 2008 Nov 12;28(46):12125-35. doi: 10.1523/JNEUROSCI.3400-08.2008.
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 CB(2) cannabinoid receptors in the regulation of the central immune responses leading to the development of neuropathic pain. CB(2) 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 CB(2) receptors. These results demonstrate the crucial role of CB(2) 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 CB(2) knock-outs, thus demonstrating the implication of the CB(2) receptor expressed in hematopoietic cells in the development of neuropathic pain at the spinal cord.
神经性疼痛是一种神经损伤的临床表现，即使使用强效镇痛化合物也难以治疗。在此，我们使用不同品系的基因改造小鼠来阐明CB(2)大麻素受体在调节导致神经性疼痛发展的中枢免疫反应中所起的作用。将CB(2)基因敲除小鼠和野生型同窝小鼠暴露于坐骨神经损伤，两种基因型在同侧爪均出现相似的痛觉过敏和异常性疼痛。最引人注目的是，基因敲除小鼠还出现了对侧镜像疼痛，伴有对侧脊髓角中微胶质细胞和星形胶质细胞表达增强。同样，在过表达CB(2)受体的转基因小鼠中，坐骨神经损伤诱导的痛觉过敏、异常性疼痛以及微胶质细胞和星形胶质细胞激活均减弱。这些结果证明了CB(2)大麻素受体在调节对神经损伤的胶质细胞激活中的关键作用。在用CB(2)基因敲除小鼠的骨髓细胞重建的辐照野生型小鼠中，复制了神经性疼痛的增强表现，从而证明了造血细胞中表达的CB(2)受体在脊髓神经性疼痛发展中的作用。
