Role of Spinal Cord PSD-93/Chapsyn-110 in Chronic Pain

描述(由申请人提供)：了解与慢性或持续性疼痛相关的机制在制定治疗策略方面很重要。PSD-93/chaopn-110是一种含有PDZ结构域的神经元蛋白，它与突触上的NMDA受体结合并聚集在一起，并在NMDA受体周围组装一组特定的信号蛋白。这项建议集中在PSD-93/chaopn-110 PDZ结构域与NMDA受体在慢性或持续性疼痛的中枢机制中的相互作用。我们有了新的发现：1)PSD-93/chaopn-110主要在脊髓背角浅层表达，在那里它与NMDA受体共定位并相互作用；2)靶向阻断PSD-93/chaopn-110基因显著减弱NMDA受体介导的脊髓背角神经元兴奋性突触后电流，并降低由NMDA受体激活引发的痛敏反应。这项建议旨在进一步确定PSD-93/CHAPECN-110在慢性或持续性疼痛中的作用，并探索在慢性疼痛状态下PSD-93/CHAPECN-110缺失导致的抗伤害感受的细胞和分子机制。我们将确定在完全弗氏佐剂诱导的炎症性疼痛和神经损伤诱导的神经病理性疼痛模型中，PSD-93/chaopn-110的敲除和敲除是否会影响热痛和机械性疼痛的超敏反应。我们将在慢性疼痛状态下，确定PSD-93/chaopn-110缺失对NMDA受体介导的兴奋性感觉突触电位的影响，以及对NMDA受体介导的外周伤害性刺激和电刺激诱导的脊髓背角神经元收缩反应的影响。在野生型和PSD-93/chaopn-110基因敲除小鼠中，我们将比较NMDA受体在脊髓神经元中的表面表达和突触定位。这些研究将为慢性疼痛的发病机制提供新的见解，并为慢性疼痛的预防和治疗提供一个新的潜在的生化靶点。

DESCRIPTION (provided by applicant): Understanding mechanisms associated with chronic or persistent pain is important in developing therapeutic strategies. PSD-93/chapsyn-110 is a neuronal PDZ domain-containing protein that binds to and clusters NMDA receptors at synapses, and assembles a specific set of signaling proteins around the NMDA receptors. This proposal is focused on the interaction between the PSD-93/chapsyn-110 PDZ domain and NMDA receptors in central mechanisms of chronic or persistent pain. We have made the novel discoveries that 1) PSD-93/chapsyn-110 is expressed mainly in the superficial dorsal horn of spinal cord, where it co-localizes and interacts with NMDA receptors, and 2) targeted disruption of the PSD-93/chapsyn-110 gene significantly attenuates NMDA receptor-mediated excitatory postsynaptic currents in spinal dorsal horn neurons and reduces pain hypersensitivity triggered via NMDA receptor activation. This proposal seeks to further determine the role of PSD-93/chapsyn-110 in chronic or persistent pain, and explores cellular and molecular mechanisms of antinociception resulting from the deletion ofPSD-93/chapsyn-110 in chronic pain states. We will define whether knockout and knockdown of the PSD-93/chapsyn-110 affect thermal and mechanical pain hypersensitivity in complete Freund's adjuvant-induced inflammatory and nerve injury-induced neuropathic pain models. We will determine, in chronic pain states, the effect of PSD-93/chapsyn-110 deletion on NMDA receptor mediated excitatory sensory synaptic potentials, and on NMDA receptor-mediated response to peripheral noxious stimulation and to electrical stimulation-induced wind-up in spinal dorsal horn neurons. In wild type and PSD- 93/chapsyn-110 knockout mice, we will compare surface expression and synaptic localization of NMDA receptors in spinal cord neurons. These studies will provide a novel insight to the mechanisms of chronic pain and a new and potential biochemical target for the prevention and therapy of chronic pain.