The long-term goal of this program is to advance understanding of neural mechanisms of pelvic pain in females. The studies here focus on endometriosis, a disease in which endometrial growths occur abnormally outside the uterus and synthesize many substances such as cytokines and prostaglandins. Symptoms include reduced fertility and several pelvic pains, including dyspareunia (vaginal hyperagesia). A rat model of endometriosis, in which uterine tissue is autotransplanted into the abdomen and forms cysts, has been used to study reduced fertility. The autotransplants also induce vaginal hyperalgesia. Four studies in rats are proposed to test hypotheses concerning mechanisms underlying this hyperalgesia. Studies 1 and 2 will test the hypotheses that the hyperalgesia depends on estrogen and requires continued presence of the cysts. The studies will be done by determining how manipulating hormone levels or excising the cysts affects the hyperalgesia, which will be assessed using behavioral measures of vaginal nociception. Study 3 will test the hypothesis that the cysts contribute to vaginal hyperalgesia by sending nociceptive information to the central nervous system via their own induced nerve supply. The study will be done using selective markers for afferent and autonomic efferent nerve fibers to characterize the cysts' sensory and sympathetic innervation under different experimental conditions (time after surgery; estrous stage). Study 4 will test the hypothesis that cannabinoids contribute to the hyperalgesia by regulating, via CB1 receptors, the cysts' production of }ro- and anti-inflammatory cytokines and prostaglandins. The study will be done using enzyme-linked mmunosorbent assays to compare the cysts' production of cytokines and prostaglandins after treatments with cannabinoid agonist, antagonist, and control agents at different times after surgery and in different estrous stages. It is hoped that the results will contribute to our knowledge of the etiology of endometriosis and to improving treatment strategies for pelvic and other visceral pains in both women and men. ? ? ?
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