The Impact of Sex Differences on Abdominal Pain

Abstract

Background: Irritable bowel syndrome (IBS) is a chronic abdominal pain disorder that affects women twice as often as men. While luminal mediators of both host and bacterial origin modulate abdominal pain in IBS patients, gonadal hormones also influence pain signaling. This PhD thesis aimed to identify the impact of fluctuating gonadal hormones on nociceptive signaling and compare the effects of fecal supernatants (FS) from male and female IBS patients on abdominal pain pathways. I hypothesized that the sensory neuronal excitability changes during the female reproductive cycle, with the proestrus/estrus stage increasing sensitivity to mechanical stimuli and luminal mediators, thus contributing to the female predominance of IBS. Methods: Extracellular afferent nerve recordings were performed to assess action potential frequency changes during spontaneous firing and in response to colonic distension in vitro, and visceromotor responses (VMR) measured the response to colorectal distension in vivo. Current clamp recording techniques were utilised to measure rheobase in dorsal root ganglia (DRG) neurons. Finally, tail flick latency tests evaluated somatic pain in vivo. FS from male and female IBS patients were used. The estrous cycle was monitored through vaginal swabbing. The production of gonadal hormones was stopped using ovariectomy (OVX) and orchidectomy (ORCD) models. Results: The findings demonstrated that FS from female IBS patients reporting high abdominal pain increased overall colonic nerve activity, but FS from male IBS patients with high abdominal pain had no effect on nerve activity. Colonic afferent nerves exhibited increased activity only when exposed to FS from IBS patients reporting high abdominal pain, compared to FS from IBS patients reporting moderate or low pain. When separating female mice based on the estrous cycle, proestrus/estrus mice exhibit increased neuronal excitability compared to metestrus/diestrus and male mice. OVX decreased spontaneous firing and afferent nerve response to distension in the presence of FS from female IBS patients. ORCD increased DRG neuronal excitability and decreased tail withdrawal thresholds compared to controls but only altered basal colonic nerve firing in the presence of IBS FS. Conclusion: This work suggests that the production of gonadal hormones impact abdominal pain signaling, potentially contributing to the female predominance of IBS.