Sex differences in the inflammatory mediator-induced sensitization of dural afferents

Abstract

Scheff NN, Gold MS. Sex differences in the inflammatory mediatorinduced sensitization of dural afferents. J Neurophysiol 106: 1662-1668, 2011. First published July 13, 2011 doi:10.1152 doi:10. /jn.00196.2011 of the adult population suffers from migraine. This debilitating pain disorder is three times more prevalent in women than in men. To begin to evaluate the underlying mechanisms that may contribute to this sex difference, we tested the hypothesis that there is a sex difference in the inflammatory mediator (IM)-induced sensitization of dural afferents. Acutely dissociated retrogradely labeled dural afferents from adult Sprague-Dawley rats were examined with whole cell patchclamp recordings. Baseline passive and active electrophysiological properties of dural afferents from both sexes were comparable. However, while IM-induced increases in the excitability of dural afferents from male and female rats were also comparable, the proportion of dural afferents from female rats sensitized by IM (ϳ100%) was significantly greater than that of dural afferents from male rats (ϳ50%). This appeared to be due to differences downstream of IM receptors, as tetrodotoxinresistant sodium current was increased by IM in a majority of male dural afferents (13/14). These data indicate that there are both quantitative and qualitative differences in the IM-induced sensitization of dural afferents that may contribute to the sex difference in the manifestation of migraine.trigeminal ganglion neuron; current clamp; primary afferent; chloride current; pain CONSERVATIVE ESTIMATES INDICATE that over 20% of the adult population suffers from migraine. Interestingly, this debilitating pain disorder is far more common in women than in men, with a prevalence roughly three times higher in women than in men [18% vs. 6% (Stewart et al. 1992)] and an incidence more than two times higher [43% vs. 18% (Stewart et al. 2008)]. The underlying mechanisms of this sex difference have yet to be identified.While there is still debate over the mechanisms underlying the initiation of a migraine attack, compelling evidence indicates that activation of primary afferents innervating the dural vasculature mediates migraine pain. Electrical stimulation of the dura and associated vasculature is associated with mi-

Ion Channels and Migraine

“…Reasons for gender difference in migraine prevalence are not clear. Excitability and sensitization were compared between male and female dural afferents in rats, and there was no difference between male and female dural afferents with respect to baseline excitability . However, a significantly higher proportion of dural afferent from female rats (100%) than from male rats (50%) were sensitized, which could contribute to higher susceptibility to migraine in women.…”

“…Excitability and sensitization were compared between male and female dural afferents in rats, and there was no difference between male and female dural afferents with respect to baseline excitability . However, a significantly higher proportion of dural afferent from female rats (100%) than from male rats (50%) were sensitized, which could contribute to higher susceptibility to migraine in women. The mechanisms for these differences are not yet clear, but future studies should examine expression levels of IL‐6 activated pathways, Nav1.7, and the IM‐sensitive Cl − current.…”

Sex-Specific Pharmacotherapy for Migraine: A Narrative Review

“…Females show an increased sensitivity to IS application compared with males (Stucky et al, 2011). Elevated estrogen levels increase the response of dural afferent fibers and brainstem trigeminal sensory neurons (Bolay et al, 2011;Scheff and Gold, 2011;Finocchi and Strada, 2014;Pavlovic et al, 2017). Both estrogen receptors (ERs), ER α and ER β , are widely expressed by trigeminal ganglion neurons (Wang et al, 2012;Pavlovic et al, 2017).…”

Female sex and obesity increase photophobic behavior in mice

“…This has been demonstrated with respect to susceptibility to cortical spreading depression (Brennan et al, 2007), activation of dural afferents by inflammatory mediators (Scheff and Gold, 2011), and migraine-like behavior in response to chronic dural application of inflammatory mediators (Stucky et al, 2011). Sex differences also exist in the expression levels of signaling molecules thought to be involved in migraine pathophysiology, including calcitonin gene-related peptide and its receptor components (Stucky et al, 2011) and serotonin-synthesizing enzymes (Asghari et al, 2011).…”