Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, CT 06510, USA.
Exp Neurol. 2011 Dec;232(2):222-33. doi: 10.1016/j.expneurol.2011.08.028. Epub 2011 Sep 17.
Although prior studies have implicated maladaptive remodeling of dendritic spines on wide-dynamic range dorsal horn neurons as a contributor to pain after spinal cord injury, there have been no studies on dendritic spines after peripheral nerve injury. To determine whether dendritic spine remodeling contributes to neuronal hyperexcitability and neuropathic pain after peripheral nerve injury, we analyzed dendritic spine morphology and functional influence in lamina IV-V dorsal horn neurons after sham, chronic constriction injury (CCI) of the sciatic nerve, and CCI treatment with NSC23766, a selective inhibitor of Rac1, which has been implicated in dendritic spine development. 10 days after CCI, spine density increased with mature, mushroom-shaped spines preferentially distributed along dendritic branch regions closer to the cell body. Because spine morphology is strongly correlated with synaptic function and transmission, we recorded the response of single units to innocuous and noxious peripheral stimuli and performed behavioral assays for tactile allodynia and thermal hyperalgesia. Wide dynamic range dorsal horn neurons of CCI animals exhibited hyperexcitable responses to a range of stimuli. They also showed reduced nociceptive thresholds in the ipsilateral hind paw. 3-day treatment with NSC23766 significantly reduced post-CCI spine dimensions and densities, and attenuated injury-induced hyperexcitability. Drug treatment reduced behavioral measures of tactile allodynia, but not for thermal hyperalgesia. Together, our results demonstrate that peripheral nerve injury induces Rac1-regulated remodeling of dendritic spines on dorsal horn neurons, and suggest that this spine remodeling contributes to neuropathic pain.
尽管先前的研究表明，背角神经元上树突棘的适应性重塑是脊髓损伤后疼痛的原因之一，但尚未有关于周围神经损伤后树突棘的研究。为了确定树突棘重塑是否会导致周围神经损伤后的神经元过度兴奋和神经病理性疼痛，我们分析了假手术、坐骨神经慢性缩窄性损伤（CCI）以及 Rac1 选择性抑制剂 NSC23766 处理后的背角神经元的树突棘形态和功能影响，Rac1 被认为与树突棘发育有关。CCI 后 10 天，棘密度增加，成熟的蘑菇形棘优先分布在靠近胞体的树突分支区域。由于棘形态与突触功能和传递密切相关，我们记录了单个单位对无害和有害的外周刺激的反应，并进行了触觉过敏和热痛觉超敏的行为测定。CCI 动物的宽动态范围背角神经元对一系列刺激表现出过度兴奋的反应。它们还表现出同侧后爪的伤害感受阈值降低。3 天的 NSC23766 治疗显著降低了 CCI 后的棘尺寸和密度，并减弱了损伤引起的过度兴奋。药物治疗降低了触觉过敏的行为测量值，但对热痛觉超敏没有影响。综上所述，我们的研究结果表明，周围神经损伤会导致背角神经元上 Rac1 调节的树突棘重塑，并表明这种棘重塑与神经病理性疼痛有关。
