(268) - The influence of chronic WIN 55, 212-2 treatment on vaginal hyperalgesia, VEGF, and NGF in a rat model of endometriosis

Abstract

Endometriosis affects ~10% of women of reproductive age and is characterized by the growth of endometrial tissue outside the uterus. Approximately 50% of women with endometriosis suffer from debilitating chronic pelvic pain including dyspareunia (pain during sexual intercourse; vaginal hyperalgesia) and severe dysmenorrhea (menstrual pain). How the endometrial ectopic growths (cysts) contribute to painful symptoms is poorly understood. However, mounting evidence suggests the involvement of the endocannabinoid system in endometriosis and its associated pain. Cannabinoids and their receptors are known to be involved in uterine function and dysfunction, abnormal vascularization, neurite outgrowth, and neuronal guidance. Further, exogenous cannabinoids have been used for centuries to alleviate the endometriosis-associated painful symptom of dysmenorrhea. In a rat model of endometriosis (ENDO), uterus pieces are auto-transplanted onto abdominal arteries and form vascularized and innervated cysts similar to women. ENDO also produces painful symptoms similar to that of women with endometriosis, including vaginal hyperalgesia. Here, vaginal nociception was assessed behaviorally at baseline, for eight weeks after ENDO was induced (when vaginal hyperalgesia/cyst innervation stabilize), and then for eight weeks during chronic treatment with the CB1/CB2 agonist WIN 55, 212-2 (or in controls: DMSO or untreated). Cyst and uterus levels of vascular endothelial growth factor (VEGF) and nerve growth factor (NGF) were also assessed using protein array analysis. All data were analyzed in the proestrus stage. Our data demonstrate that treatment with WIN 55, 212-2 alleviates ENDO-induced vaginal hyperalgesia, significantly decreases VEGF expression in the cysts but not uterus, and does not significantly influence NGF expression in the cysts or uterus. Overall, these data suggest that cannabinoid receptor stimulation-mediated modulation of VEGF, potentially through VEGF's influence on vascularization and/or innervation, influences endometriosis-associated vaginal hyperalgesia. Further, these results also provide additional support for targeting the endocannabinoid system for endometriosis-associated pain.