Influence of endometriosis on visceromotor and cardiovascular responses induced by vaginal distention in the rat

Abstract

This study examined pseudoaffective responses elicited by vaginal distention in urethaneanesthetized rats, and tested hypotheses that responses would be increased by endometriosis (ENDO) and vary with the estrous cycle. Three groups were studied: ENDO, shamENDO, and Naïve. ENDO was induced by autotransplantating small pieces of uterine horn (or, for shamENDO, fat) on mesenteric arteries. Ten weeks later, rats in proestrus or metestrus were anesthetized with urethane. Distendable latex balloons were inserted into the vaginal canal. While an increasing series of vaginal distentions was delivered, changes in electromyographic activity of the external oblique musculature (visceromotor response, VMR) and mean arterial pressure (pressor) responses were simultaneously measured. Vaginal distention produced VMR and pressor responses in all groups. These responses were significantly greater in ENDO than in the other groups, and greater in proestrus than metestrus. Although the overall amount of cystic tissue was greater in proestrous than metestrous rats, there was no correlation between these amounts and VMR or pressor responses. Acute spinalization (T8-T9) and bilateral pelvic, but not hypogastric neurectomy attenuated both VMR and pressor responses, supporting the hypothesis that vaginal nociception involves suprathoracic spinal processing of information conveyed by the pelvic nerve. These effects on VMR and pressor responses to vaginal distention parallel behavioral escape responses to the same stimuli reported previously. The findings encourage continued use of VMR and pressor responses for further investigation of mechanisms underlying pain associated with ENDO and its potential treatment.

Endometriosis as a neurovascular condition: estrous variations in innervation, vascularization, and growth factor content of ectopic endometrial cysts in the rat

“…Our initial hypothesis was that proestrous-to-estrous changes in sensory innervation and cytokine content of the cysts, but not the uterine horn, contribute to proestrous-to-estrous differences in severity of ENDO-induced hyperalgesia (15,46). We did observe estrous changes in the cysts but not the uterine horn.…”

“…Like women with ENDO, rats with ENDO are subfertile (59). Once the cysts are fully developed, the rats also develop a vaginal hyperalgesia (15) that is accompanied by referred abdominal muscle hyperalgesia (46). In support of the clinical conclusion that ENDO is dependent on estrogens, the severity of both the vaginal and referred abdominal muscle hyperalgesia in rats varies with estrous stage in a manner that parallels estrous changes in circulating levels of estradiol.…”

Innervation of endometrium and myometrium in women with painful adenomyosis and uterine fibroids

“…Obviously, the presence of PGP9.5-immunoreactive small nerve fibers in the functional layer of the endometrium in women with adenomyosis, uterine fibroids, and endometriosis is dependent on a common symptom of pain but not a disease itself. Because adenomyosis and uterine fibroids are believed to be under the control of the same steroid hormones as endometriosis, and also cause pelvic pain (15,26,27), it is indicated that PGP9.5-immunoreactive small nerve fibers in the functional layer of the endometrium may be involved in the mechanisms of pain generation in women with uterine fibroids and adenomyosis, and regulated by estrogen (12,(18)(19)(20)(21)(22).…”

“…For example, when treated by combined OCs and progestogens, endometriotic lesions, pain symptoms, and nerve fiber density in ectopic and eutopic endometrium and myometrium are decreased and the levels of estrogen are reduced (8,17). It is suggested that the innervation of the endometrium and myometrium and pain symptoms in women with endometriosis are under the control of estrogen (18)(19)(20)(21)(22).…”

Prostaglandin levels, vaginal innervation, and cyst innervation as peripheral contributors to endometriosis-associated vaginal hyperalgesia in rodents

“…These uterine transplants over time produce innervated and vascularized cysts (Berkley et al, 2004; 2005) and symptoms similar to women including vaginal hyperalgesia (Berkley et al, 2007; McAllister et al, 2009, 2012) referred abdominal muscle hyperalgesia (Giamberardino et al, 2002; Nagabukuro and Berkley, 2007), and bladder hyperactivity (Morrison et al, 2006). Therefore, we examined the relationships between vaginal hyperalgesia, cyst sensory and sympathetic innervation density, and peritoneal fluid levels of PGE2 and PGF2α 4-6wks after surgery when individual differences in hyperalgesic severity are greatest (McAllister et al, 2012).…”