The mechanism of neuron pathic pain analyzed by DNA microarray.

神经性疼痛是脊髓损伤后常见的并发症，无法控制的疼痛严重影响患者的生活质量。与其他形式的慢性神经性疼痛一样，标准药物治疗无法充分控制SCI后疼痛，需要一种新的基于机制的疼痛治疗。我们发现脊髓内存在GABAA介导的紧张性抑制，SCI可减弱这种抑制。这一发现使我们产生了我们的工作假设，即脊髓中的减弱的紧张性抑制介导了过度兴奋和神经性疼痛的发展。最近在大脑中建立了在突触外区域的低环境浓度的GABA中总是开放的强直抑制受体的存在，然而，关于脊髓中强直抑制的作用的信息很少。我们的建议是一个全面的研究紧张性抑制脊髓。我们从分子生物学研究开始，鉴定了在胶状质二级感觉神经元中介导紧张性抑制的GABA能受体亚基。接下来，我们研究了紧张性抑制在SCI后神经病理性疼痛的病理生理作用，使用一个良好的特点大鼠脊髓挫伤模型。最后，将研究一种重组慢病毒介导的“基因疗法”，用于脊髓损伤后疼痛靶向脊髓强直抑制。本研究揭示了脊髓紧张性抑制在正常和损伤脊髓中的作用，并有助于发展基于机制的SCI后神经病理性疼痛治疗。

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.