Cannabinoid receptor 1 contributes to sprouted innervation in endometrial ectopic growth through mitogen-activated protein kinase activation.
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.
Department of Pathology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, 659 Zhizhaoju Road, Shanghai 200011, China.
Hongxiu
H
Han
Department of Pathology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, 659 Zhizhaoju Road, Shanghai 200011, China.
Xizi
X
Liang
Department of Physiology, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China.
Juan
J
Wang
Department of Pathology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, 659 Zhizhaoju Road, Shanghai 200011, China.
Qianqian
Q
Zhao
Department of Physiology, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China.
Mei
M
Yang
Department of Physiology, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China.
Weifang
W
Rong
Department of Physiology, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China. Electronic address: ghzhang2009@shsmu.edu.cn.
Guohua
G
Zhang
D000818:Animals; D002186:Cannabinoids / Q000494:pharmacology; D004717:Endometrium / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005727:Ganglia, Spinal / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016501:Neurites / Q000378:metabolism; D055495:Neurogenesis / Q000502:physiology; D000071446:Neuronal Outgrowth / Q000502:physiology; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism*; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D002186:Cannabinoids; C543264:Cnr1 protein, rat; D043884:Receptor, Cannabinoid, CB1; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases
Cannabinoid receptor 1; Endometriosis; Mitogen-activated protein kinase; Nerve growth