脊髓背角NMDA受体是痛觉调控的关键靶点。不同亚型的NMDA受体具有不同的生物学功能。神经损伤之后，GluN2B型NMDA受体（简称GluN2B）会快速、大量进入突触，显著增强痛觉的突触传递、诱发病理性疼痛；此时，选择性抑制GluN2B，会产生明显的镇痛作用。然而，申请者的预实验发现：随着病理性疼痛的进一步发展，GluN2A型NMDA受体（简称GluN2A）会逐渐进入突触、并替换GluN2B！这一慢性疼痛中的亚基转换，显著提高了GluN2A的痛觉传递功能，导致GluN2A在慢性疼痛的维持阶段发挥重要作用；而一种信号接头蛋白RIN1 (Ras/Rab Interactor 1)，可能是促进GluN2A替换突触GluN2B、持久维持病理性疼痛的关键分子。本项目的研究目标，就是深入探讨RIN1诱发NMDA受体亚基转换的分子机制；从RIN1的功能、结构特征入手，探索新的干预手段、逆转慢性痛敏状态。

NMDA receptor in spinal cord dorsal horn is a key target for pain modification. Different subtypes of NMDA receptors display distinct biological properties. Nerve injury can rapidly recruit GluN2B-subtype NMDA receptor (referred to as GluN2B) into synapses, which significantly boosts the nociceptive synaptic transmission and initiates pathological pain. Hence selective inhibition of GluN2B can generate effective analgesic action. Our preliminary experiments, however, revealed that, with the further development of pathological pain, GluN2A-subtype NMDA receptor (referred to as GluN2A) progressively entered into synapses and replaced GluN2B! This subunit switch during pathological pain noticeably enhanced the nociceptive transmission mediated by GluN2A and conferred to GluN2A an important role in the maintenance of chronic pain. The applicants found that the GluN2B-to-GluN2A switch and long-lasting maintenance of pathological pain might depend on a key adaptor protein RIN1 (Ras/Rab Interactor 1). This project aims to systematically investigate the molecular mechanisms for RIN1 to switch the subunit composition of synaptic NMDA receptor. By analyzing the functional and structural characters of RIN1, the applicants hope to discover new methods to reverse the enduring pain hypersensitivity.