Lentiviral-mediated targeted NF-κB blockade in dorsal spinal cord glia attenuates sciatic nerve injury-induced neuropathic pain in the rat
Lentiviral-mediated targeted NF-κB blockade in dorsal spinal cord glia attenuates sciatic nerve injury-induced neuropathic pain in the rat
复制标题
DOI：
10.1038/sj.mt.6300107
复制
发表时间：
2007-04-01
影响因子：
12.4
通讯作者：
Pohl, Michel
中科院分区：
文献类型：
--
作者：
Meunier, Alice;Latremoliere, Alban;Pohl, Michel
周围神经损伤后出现的神经病理性疼痛与脊髓中神经元和神经胶质细胞功能的改变有关。激活的神经胶质细胞会产生促过敏介质，加剧疼痛。在可能参与修饰的胶质功能的不同细胞内途径中，核因子-kappa B(NF-kappa B)系统尤其令人感兴趣，因为许多编码炎症和疼痛相关分子的基因都由这种转录因子控制。核因子-kappaB是一种多效性因子，也参与中枢神经系统的稳态。因此，为了研究其在慢性疼痛中的作用，有必要选择性地抑制激活的脊髓神经胶质细胞中的核因子-kappaB通路。在这里，我们发现，当限制在脊髓和针对胶质细胞，慢病毒载体介导的NF-kappa B超抑制物I kappa Bα导致抑制大鼠坐骨神经损伤(慢性压迫损伤，CCI)后脊髓中激活的NF-kappa B途径。同时，Ikappa Bα的过度产生阻止了与慢性缩窄性损伤相关的IL-6和诱导型一氧化氮合酶的表达增强，并导致了持久的止痛和止痛作用。这些数据表明，靶向阻断脊髓神经胶质细胞中的NF-kappa B活性可以有效地缓解CCL大鼠的疼痛行为，表明神经胶质细胞中的NF-kappa B通路积极参与了周围神经损伤后神经病理性疼痛的发生。
Neuropathic pain developing after peripheral nerve injury is associated with altered neuronal and glial cell functions in the spinal cord. Activated glia produces algogenic mediators, exacerbating pain. Among the different intracellular pathways possibly involved in the modified glial function, the nuclear factor kappa B (NF-kappa B) system is of particular interest, as numerous genes encoding inflammation- and pain-related molecules are controlled by this transcription factor. NF-kappa B is a pleiotropic factor also involved in central nervous system homeostasy. To study its role in chronic pain, it is thus essential to inhibit the NF-kappa B pathway selectively in activated spinal glial cells. Here, we show that when restricted to spinal cord and targeted to glial cells, lentiviral vector-mediated delivery of NF-kappa B superrepressor I kappa B alpha resulted in an inhibition of the NF-kappa B pathway activated in the rat spinal cord after sciatic nerve injury (chronic constriction injury, CCI). Concomitantly, I kappa B alpha overproduction prevented the enhanced expression of interleukin-6 and of inducible nitric oxide synthase associated with chronic constriction injury and resulted in prolonged antihyperalgesic and antiallodynic effects. These data show that targeted blockade of NF-kappa B activity in spinal glia efficiently alleviates pain behavior in CCl rats, demonstrating the active participation of the glial NF-kappa B pathway in the development of neuropathic pain after peripheral nerve injury.