TRPM3通道参与IC/BPS慢性痛发生及机制的实验研究

IC/BPS发病机制不明。研究表明,感觉神经疼痛受体TRPV1、TRPA1激活导致的外周神经敏化是IC/BPS疼痛发生的重要机制。多种炎症介质、神经生长因子NGF及肥大细胞释放类胰蛋白酶可通过活化疼痛受体加强外周神经敏化。TRPM3是新发现的外周感觉神经表达的疼痛受体，被认为是优于TRPV1开发镇痛剂的新靶点。我们初步研究表明：TRPM3激活可导致膀胱疼痛及神经源性炎症，IC/BPS模型（CYP）大鼠膀胱外周感觉神经元TRPM3表达上调。我们推测：TRPM3激活是IC/BPS疼痛发生的中心环节，TRPM3激活在引起疼痛的同时，还通过引起膀胱神经源性炎症加强炎症介质、NGF释放增多及PAR2受体的激活，它们进一步活化TRPM3，形成TRPM3激活-炎症-TRPM3激活的恶性循环，导致外周神经敏化及疼痛。研究将通过组化、功能学、行为学、药理学等方法验证上述假设，为IC/BPS提供新的治疗靶点。

The underlying pathophysiological mechanism of interstitial cystitis/bladder pain syndrome (IC/BPS) is not clear yet. Peripheral sensitization has been considered the main underlying mechanism for IC/BPS. Studies indicate that activation of TRPV1 or TRPA1 expressed on bladder sensory nerves contribute to peripheral sensitization in IC/BPS conditions. Whereas, inflammation mediators, nerve growth factor (NGF) and tryptase released by activated mast cell in IC/BPS could enhance peripheral sensitization by activating TRPV1 or TRPA1. TRPM3 is a newly discovered pain channel expressed on peripheral nerve terminals (nociceptors). Our preliminary experiments revealed that activation of TRPM3 in bladder nerve terminals could induce pain and neurogenic inflammation which was evidenced by the dilation of blood vessels, infiltration of inflammation cells etc. In Cyclophosphamide-induced cystitis (CYP) rats, we found that the TRPM3 function was increased in bladder sensory neurons. Thus, we proposed that like TRPV1 or TRPA1, activation of TRPM3 channels expressed on bladder sensory nerves may be the key contributor for peripheral nerve sensitization and thus the generation of chronic pain, neurogenic inflammation induced by TRPM3 activation further enhanced peripheral nerve sensitization by increasing the release of inflammation mediators ( PGE2, bradykinin, histamine) and NGF, by the activation of mast cell-tryptase-PAR2 receptor, All these mediators and pathways could enhance TRPM3 activation. In our study, immunohistochemical, Ca2+ imaging, patch clamp, behavioral as well as pharmacological approach will be used to prove our hypothesis. Elucidation of TRPM3 involvement in IC/BPS will help us to understand the underlying pathophysiological mechanisms of IC/BPS and signify TRPM3 antagonist as a new analgesic for IC/BPS treatment.