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对于制定治疗策略非常重要。PSD-93/chapsyn-110是一种含有神经元PDZ结构域的蛋白，其结合并聚集在突触处的NMDA受体，并在NMDA受体周围组装一组特定的信号蛋白。本研究的重点是探讨PSD-93/chapsyn-110 PDZ结构域与NMDA受体在慢性或持续性疼痛中枢机制中的相互作用。我们已经取得了新的发现，1）PSD-93/chapsyn-110主要在脊髓的浅层背角中表达，在那里它与NMDA受体共定位并相互作用，以及2）PSD-93/chapsyn-110基因的靶向破坏显著减弱脊髓背角神经元中NMDA受体介导的兴奋性突触后电流，并降低通过NMDA受体激活触发的疼痛超敏性。本研究旨在进一步确定PSD-93/chapsyn-110在慢性或持续性疼痛中的作用，并探讨PSD-93/chapsyn-110缺失导致慢性疼痛状态下抗伤害感受的细胞和分子机制。我们将确定PSD-93/chapsyn-110的敲除和敲低是否影响完全弗氏佐剂诱导的炎症和神经损伤诱导的神经性疼痛模型中的热和机械疼痛超敏性。我们将确定，在慢性疼痛状态下，PSD-93/chapsyn-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受体介导的对外周伤害性刺激和电刺激诱导的脊髓背角神经元缠绕的反应的影响。在野生型和PSD- 93/chapsyn-110基因敲除小鼠中，我们将比较脊髓神经元中NMDA受体的表面表达和突触定位。这些研究将为慢性疼痛的机制提供新的见解，并为慢性疼痛的预防和治疗提供新的和潜在的生化靶点。

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.