Hains Bryan C, Waxman Stephen G
Department of Neurology, Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
J Neurosci. 2006 Apr 19;26(16):4308-17. doi: 10.1523/JNEUROSCI.0003-06.2006.
Traumatic spinal cord injury (SCI) results not only in motor impairment but also in chronic central pain, which can be refractory to conventional treatment approaches. It has been shown recently that in models of peripheral nerve injury, spinal cord microglia can become activated and contribute to development of pain. Considering their role in pain after peripheral injury, and because microglia are known to become activated after SCI, we tested the hypothesis that activated microglia contribute to chronic pain after SCI. In this study, adult male Sprague Dawley rats underwent T9 spinal cord contusion injury. Four weeks after injury, when lumbar dorsal horn multireceptive neurons became hyperresponsive and when behavioral nociceptive thresholds were decreased to both mechanical and thermal stimuli, intrathecal infusions of the microglial inhibitor minocycline were initiated. Electrophysiological experiments showed that minocycline rapidly attenuated hyperresponsiveness of lumbar dorsal horn neurons. Behavioral data showed that minocycline restored nociceptive thresholds, at which time spinal microglial cells assumed a quiescent morphological phenotype. Levels of phosphorylated-p38 were decreased in SCI animals receiving minocycline. Cessation of delivery of minocycline resulted in an immediate return of pain-related phenomena. These results suggest an important role for activated microglia in the maintenance of chronic central below-level pain after SCI and support the newly emerging role of non-neuronal immune cells as a contributing factor in post-SCI pain.
创伤性脊髓损伤（SCI）不仅会导致运动功能障碍，还会引发慢性中枢性疼痛，而这种疼痛对传统治疗方法可能难以奏效。最近的研究表明，在周围神经损伤模型中，脊髓小胶质细胞会被激活，并参与疼痛的发生发展。鉴于它们在周围神经损伤后疼痛中的作用，并且已知小胶质细胞在脊髓损伤后会被激活，我们检验了激活的小胶质细胞会导致脊髓损伤后慢性疼痛的假说。在本研究中，成年雄性Sprague Dawley大鼠接受了T9脊髓挫伤损伤。损伤后四周，当腰段背角多感受神经元变得反应过度，且行为学伤害性阈值对机械和热刺激均降低时，开始鞘内注射小胶质细胞抑制剂米诺环素。电生理实验表明，米诺环素能迅速减轻腰段背角神经元的反应过度。行为学数据显示，米诺环素恢复了伤害性阈值，此时脊髓小胶质细胞呈现静止的形态表型。接受米诺环素的脊髓损伤动物中，磷酸化p38的水平降低。停止米诺环素给药后，疼痛相关现象立即恢复。这些结果表明，激活的小胶质细胞在脊髓损伤后慢性中枢性低位疼痛的维持中起重要作用，并支持非神经元免疫细胞作为脊髓损伤后疼痛的一个促成因素这一新出现的作用。
