Han Hongxiu, Liang Xizi, Wang Juan, Zhao Qianqian, Yang Mei, Rong Weifang, Zhang Guohua
Department of Pathology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, 659 Zhizhaoju Road, Shanghai 200011, China.
Department of Physiology, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China.
Brain Res. 2017 May 15;1663:132-140. doi: 10.1016/j.brainres.2017.03.016. Epub 2017 Mar 18.
The endocannabinoid system regulates neurite outgrowth and neurogenesis during development of the central nervous system. Cannabinoid receptor 1 (CB1R) is expressed in neurons, including the somata and fibers, that innervate the endometrial ectopic cyst in rats. Here, we investigated the contribution of CB1R and its downstream signaling to the innervation of endometrial ectopic growth. We found that intrathecal injection of a CB1R agonist enhanced both the density of protein gene product (PGP) 9.5-immunoreactive sprouted nerve fibers and the protein level of PGP 9.5 of the ectopic cyst, and the CB1R antagonist induced opposite effects. The CB1R agonist increased the expression of phosphorylated extracellular signal-regulated kinase (pERK) and c-Jun N-terminal kinase (pJNK), but not pp38, in dorsal root ganglion (DRG), whereas the CB1R antagonist only decreased the expression of pERK. In cultured DRG neurons, CB1R agonists dose-dependently increased neurite elongation. The mitogen-activated protein kinase (MAPK)/ERK kinase (MEK) and JNK inhibitors, but not the p38 inhibitor, attenuated CB1R agonist-induced neurite elongation. The inhibitions of CB1R and its downstream ERK and JNK signaling pathways may alleviate the sprouted innervation that has been involved in ENDO-associated pain. This finding may provide a new therapeutic target for patients with endometriosis.
内源性大麻素系统在中枢神经系统发育过程中调节神经突生长和神经发生。大麻素受体1（CB1R）在支配大鼠子宫内膜异位囊肿的神经元中表达，包括胞体和纤维。在此，我们研究了CB1R及其下游信号传导对子宫内膜异位生长神经支配的作用。我们发现鞘内注射CB1R激动剂可增强异位囊肿中蛋白基因产物（PGP）9.5免疫反应性发芽神经纤维的密度以及PGP 9.5的蛋白水平，而CB1R拮抗剂则产生相反的效果。CB1R激动剂可增加背根神经节（DRG）中磷酸化细胞外信号调节激酶（pERK）和c-Jun氨基末端激酶（pJNK）的表达，但不增加pp38的表达，而CB1R拮抗剂仅降低pERK的表达。在培养的DRG神经元中，CB1R激动剂剂量依赖性地增加神经突伸长。丝裂原活化蛋白激酶（MAPK）/细胞外信号调节激酶（MEK）和JNK抑制剂而非p38抑制剂可减弱CB1R激动剂诱导的神经突伸长。抑制CB1R及其下游ERK和JNK信号通路可能减轻与子宫内膜异位症相关疼痛中涉及的发芽神经支配。这一发现可能为子宫内膜异位症患者提供新的治疗靶点。
