脊髓背角的中枢敏化是神经病理性疼痛发生的重要机制。由于对中枢敏化的内在机制缺乏了解，因此，神经病理性疼痛的疼痛治疗十分困难。周围神经节TRPM3是一种新型伤害性热感受器。我们发现脊髓背角的TRPM3可能在神经病理性疼痛的中枢敏化以及治疗上起着非常重要的作用。基于这一发现，我们假设TRPM3可能通过调控PSD-95和NR2B的相互作用，介导了脊髓背角的中枢敏化，进而通过ERK和CREB磷酸化途径改变细胞的分化和重塑。本课题拟在大鼠神经病理性疼痛模型上，运用遗传学手段条件性过表达、采用在体RNA干扰沉默TRPM3基因，并结合动物行为学测定，研究TRPM3在病理性疼痛中的作用以验证以上假说；并且运用研究蛋白质相互作用的手段，探讨TRPM3与NR2B/PSD-95相互作用的关系，以揭示TRPM3介导中枢敏化和神经病理性疼痛的发病机制。该研究对未来发现治疗神经病理性疼痛有效手段具有重要意义。

The spinal dorsal horn is the primary transfer station for accepting and modulating pain signal, and its central sensitization and hyper-excitability play a crucial role in neuropathic pain. Due to the lacking of the understanding of the mechanism of such sensitization, the treatment of neuropathic pain is still a clinical dilemma. Transient receptor potential melastatin 3 (TRPM3) is a new type of noceptive receptor related to heat and we recently discovered that TRPMs in the spinal dorsal horn might play critical role in neuropathic pain. TRPM3 is constitutively expressed in spinal neurons, and gene silencing of spinal TRPM3 not only attenuates behavioral hypersensitivity, but also inhibits interactions between NMDA receptor 2B subunit (NR2B) and post-synaptic density-95 (PSD-95), suggesting spinal TRPM3 may be involved in the development of neuropathic pain via modulating NR2B/PSD-95 interaction. The present proposal hypothesizes that spinal TRPM3 mediates the formation and transmission of nociceptive signal via modulating NR2B/PSD-95 interaction, activating ERK/CREB signaling pathway, affecting neuronal activity, differentiation, and synaptic remolding. We intend to characterize the expression profile in the spinal dorsal horn. Secondly, the role of spinal TRPM3 will be determined with gene silencing and pharmacological techniques. Thirdly, the possible mechanism(s) of spinal TRPM3 modulating persist pain will be explored by various methods, such as disrupting the interaction of spinal NR2B with PSD-95, and CREB antisense technique. The present proposal reveals scientific understanding of the role of TRPM3 in persist pain signal transduction using molecular techniques (RNAi and up-regulating) to explore NR2B/PSD-95 interaction both in vivo and in situ and correlate with behavioral changes in rat neuropathic pain models. The proposal is of great significance in revealing the spinal mechanisms underlying neuropathic pain to guide searching novel therapeutics.