The mechanism of neuron pathic pain analyzed by DNA microarray.

神经性疼痛是脊髓损伤（SCI）后常见的并发症，不受控制的疼痛严重影响生活质量。与其他形式的慢性神经性疼痛一样，标准的药物治疗不能充分控制脊髓损伤后疼痛，需要一种新的基于机制的疼痛治疗。我们发现GABAA介导的强直抑制存在于脊髓中，而脊髓损伤可减弱这种强直抑制。这一发现使我们得出了我们的工作假设，即脊髓的强直抑制减弱介导了过度兴奋性和神经性疼痛的发展。最近在大脑中发现，在低环境浓度的GABA下，突触外区存在强直抑制受体，但关于脊髓中的强直抑制作用的信息很少。我们的建议是对脊髓的强直抑制进行全面的研究。我们从分子生物学研究开始，确定了在明胶质的二级感觉神经元中介导张力抑制的gaba能受体的亚基。接下来，我们使用一个特征良好的大鼠脊髓挫伤模型来研究强直抑制在脊髓损伤后神经性疼痛中的病理生理作用。最后，我们将探讨重组慢病毒介导的脊髓损伤后疼痛靶向强直抑制的“基因治疗”。该项目揭示了脊髓强直抑制在正常和损伤脊髓中的作用，并有助于开发基于机制的脊髓损伤后神经性疼痛治疗方法。

Neuropathic pain is a common complication after spinal cord injury (SCI) and uncontrolled pain severely compromises the quality of life. As in other forms of chronic neuropathic pain, standard pharmacotherapy fails to adequately control post-SCI pain and a new mechanism-based pain therapy is needed. We here discovered that tonic inhibition mediated by GABAA exist in the spinal cord and that SCI attenuates the tonic inhibition. This discovery led us to our working hypothesis that attenuated tonic inhibition in the spinal cord mediates hyperexcitability and the development of neuropathic pain. The presence of tonic inhibitory receptors always open in low ambient concentration of GABA at the extrasynaptic region was recently established in the brain, however, little information exists on the role of tonic inhibition in the spinal cord. Our proposal is a comprehensive study of the tonic inhibition in the spinal cord. We start with a molecular biological study identifying the subunits comprising the GABAergic receptors mediating tonic inhibition in the second order sensory neurons in substantia gelatinosa. Next we study the pathophysiological role of tonic inhibition in neuropathic pain after SCI using a well-characterized rat spinal contusion model. Finally a recombinant lentivirus mediated "gene-therapy" for post-SCI pain targeting tonic inhibition in the spinal cord will be examined. This project revealed the role of spinal tonic inhibition in normal and injured spinal cord and contribute towards the development of a mechanism-based therapy for post-SCI neuropathic pain.