癌性疼痛的发生发展机制尚不明确，临床治疗效果有限，是极具挑战的理论和临床问题。临床上胆囊癌伴癌痛常见，主因可能是肿瘤细胞浸润神经，但具体机制不明。我们前期发现：与癌旁组织相比，胆囊癌组织IL-33与SP显著高表达，并相互促进表达；SP能够促进胆囊癌浸润神经；IL-33能够上调并激活背根神经元中TAK1，抑制TAK1可取消IL-33对SP的促进作用及其诱发的疼痛。据此，我们推测IL-33激活TAK1，上调SP，并形成正反馈，共同调控胆囊癌浸润神经，促进中枢敏化，参与癌性疼痛发生发展。本项目拟收集临床标本，应用胆囊癌/原代背根神经元共培养体系及癌痛模型，通过考察痛行为、神经元兴奋性、相关蛋白及钠离子通道电流的变化情况，阐明并验证TAK1在IL-33促进SP表达中的作用以及IL-33/SP在胆囊癌浸润神经纤维诱发维持癌性疼痛中的作用与相关机理，为肿瘤浸润神经导致癌性疼痛的防治提供新的策略和靶点。

The underlying mechanisms of cancer pain remain elusive and methods of treating are very limited. Treating cancer pain is a major challenge for pain scientists and clinicians in the field. Gallbladder carcinoma patients are usually suffered severe pain, mainly induced by perineural invasion, however, the mechanism is unknown. Our previous studies indicated that, the expression of IL-33 and substance P (SP) in gallbladder carcinoma were significantly increased compared with the adjacent tissues. Moreover, a mutual promotion phenomenon was generated between IL-33 and SP. Our further experiments showed that SP promoted the cell proliferation, migration and invasion. IL-33 could increase and activate TAK1 in DRG. And TAK1 inhibitor reversed the effects of SP, as well as the allodynia caused by IL-33. Based on the above analysis, we hypothesis IL-33 and SP regulate the perineural invasion of gallbladder cancer cells in a positive feedback process, promote central sensitization, then participate in the induction and maintenance phase of cancer pain. Furthermore, the biological function of SP induced by IL-33 is mediated by TAK1. This study will use human samples, cells, and rodents to explore the interaction between IL-33 and SP, and their roles in the pathogenesis of cancer pain in gallbladder carcinoma, as well as the molecular mechanism. This study will provide new evidence that demonstrate, the critical roles of IL-33/SP in the development of cancer pain, thus open a newavenue of understanding mechanisms of cancer pain. Further, this study will find molecules that could effectively treat cancer pain in laboratory animals with potential in future-patients.