Estrogen exacerbates the nociceptive effects of peripheral serotonin on rat trigeminal sensory neurons

Orofacial pain disorders involving trigeminal sensory neurons disproportionately affect women and can be modulated by hormones, especially estrogen (E2). Proinflammatory mediators, like serotonin (5HT), can act on sensory neurons expressing the transient receptor potential vanilloid 1 (TRPV1) ion channel, resulting in peripheral sensitization. We previously reported peripheral 5HT evokes greater pain behaviors in the hindpaw of female rats during proestrus and estrus, stages when E2 fluctuates. It is unknown if this interaction is comparable in the trigeminal system. We hypothesized that E2 exacerbates 5HT-evoked nocifensive pain behaviors and pain signaling in female trigeminal sensory neurons. We report 5HT-evoked nocifensive behaviors are significantly higher during estrus and proestrus, which is attenuated by blocking the 5HT_2A receptor. The comparable dose of 5HT was not nociceptive in males unless capsaicin was also administered. When administered with capsaicin, a lower dose of 5HT evoked trigeminal pain behaviors in females during proestrus. Further, basal 5HT content in the vibrissal pad was higher in cycling females compared to males. Ex vivo, E2 enhanced 5HT-potentiated CGRP release from trigeminal neurons, which was not significantly reduced by blocking the 5HT_2A receptor. Our data indicates that estrogen fluctuation influences the pronociceptive effects of 5HT on trigeminal sensory neurons.