Sex differences in spinal processing of transient and inflammatory colorectal stimuli in the rat

Abstract

Sex differences in the spinal processing of somatic and visceral stimuli contribute to greater female sensitivity in many pain disorders. The present study examined spinal mechanisms that contribute to sex differences in visceral sensitivity. The visceromotor response to colorectal distention (CRD) was more robust in normal female rats and following intracolonic mustard oil compared to males. No sex difference was observed in the CRD-evoked response of lumbosacral (LS) and thoracolumbar (TL) colonic afferents in normal and mustard oil-treated rats, but there was a sex difference in spontaneous activity that was exacerbated by intracolonic mustard oil. The response of visceroceptive dorsal horn neurons to CRD was greater in normal females in the LS and TL spinal segments. The effect of intracolonic mustard oil on the CRD-evoked response of different phenotypes of visceroceptive dorsal horn neurons was dependent on sex and segment. The NMDA receptor antagonist APV dose-dependently attenuated the visceromotor response in normal rats with greater effect in males. Correspondingly, there was greater cell membrane expression of the GluN1 subunit in dorsal horn extracts in females. Following intracolonic mustard oil there was no longer a sex difference in the effect of APV nor GluN1 expression in LS segments but greater female expression in TL segments. These data document a sex difference in spinal processing of nociceptive visceral stimuli from the normal and inflamed colon. Differences in dorsal horn neuronal activity and NMDA receptor expression contribute to the sex differences in the visceral sensitivity observed in awake rats.

Mechanisms of Stress-induced Visceral Pain

“…For example, sex differences in pain responsiveness and differences in regional brain activity resembling that observed in IBS have been seen in male and female animals. [89][90][91][92][93][94] In rodents experimental methodology that includes CRD to assess visceral sensitivity or a mechanical stimulus applied to the hindpaw or tail to assess somatic sensitivity, have uncovered sex differences in nociceptive behaviors following ELS, with responses in females being greater than males. 92,95 Studies performed in adult rodent models have demonstrated that estrogen and progesterone modulate pain reporting, and that variations in the response to colonic distension occurred during the estrus cycle.…”

Sex differences and hormonal modulation of deep tissue pain

“…We and others have reported sex differences in the visceromotor response to colorectal distention (Figure 1) with the majority of studies indicating females have greater sensitivity (greater magnitude visceromotor response) than males in both rats and mice (Holdcroft et al, 2000; Ji et al, 2006; Ji et al, 2012b; Kamp et al, 2003). Similar results were reported using alternate responses (hindquarter elevation) to colorectal distention (Bourdu et al, 2005).…”

“…Spinal administration of the NDMA receptor antagonist APV dose-dependently attenuated the visceromotor response to colorectal distention with greater effect in males. This corresponded with greater cell membrane expression of the GluN1 subunit of the NMDA receptor in the dorsal horn in females, suggesting females had more functional NMDA receptors (Ji et al, 2012b). This was likely due to E2 modulation of NMDA receptor activity.…”

Anatomical and Physiological Factors Contributing to Chronic Muscle Pain

“…Thus different models may show different mechanisms underlying sexual dimorphism. Greater excitability of dorsal horn neurons in female rats may contribute to such sex differences (Ji et al 2012). Further, sexual dimorphism in the autonomic system may also contribute, as females differ substantially in their response to vagotomy and medullectomy in both bradykinin- and epinephrine-evoked muscle pain (Khasar et al 2003c).…”