An interaction between estrogen and serotonin in sensory neurons as a key regulator of nociception

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Orofacial pain conditions, such as migraine, are at least two times more common in women and have a complex etiology. Orofacial pain, relayed by trigeminal sensory neurons, is linked to gonadal hormone (estrogen; progesterone) fluctuations. The neurotransmitter serotonin (5HT) is a proinflammatory and pronociceptive mediator in the periphery and has been implicated in several female prevalent pain disorders. 5HT can directly activate trigeminal sensory neurons or can sensitize the transient receptor potential vanilloid 1 ion channel (TRPV1), a cation channel activated by capsaicin and heat. TRPV1 activation results in calcium influx and calcitonin gene-related peptide (CGRP) release, leading to peripheral sensitization that heightens pain sensitivity. Previous studies in male rats have shown that 5HT receptors colocalize with and sensitize TRPV1. Furthermore, serotonergic potentiation of CGRP release occurs from the dental pulp of women during the luteal phase of the menstrual cycle (when gonadal hormones are fluctuating). It is unknown whether estradiol (E2; primary estrogen) enhances or attenuates this serotonergic pain mechanism. As >90% of pain research has been conducted in males, and a small subset examines the trigeminal system, gonadal hormone modulation of female trigeminal sensory neurons is grossly understudied and warrants investigation. Our overarching hypothesis is that hormone status alters serotonergic neuromodulation of the TRPV1-expressing subpopulation of trigeminal sensory neurons. Thus, we examined whether (1) naturally fluctuating gonadal hormones can alter 5HT-evoked pain behaviors, (2) varying E2 concentration and exposure time can alter trigeminal pain signaling and transcriptome, and (3) E2 and estrogen receptors (ERs) can modulate the pronociceptive effects of 5HT on TRPV1 function. We report that exogenous 5HT evokes significant pain behaviors in females during proestrus and estrus. 5HT2A receptor antagonism or a steady-state diestrus level E2 attenuates 5HT-evoked pain behaviors. We also report that ERα, ERβ, and G protein coupled ER (GPER) localize to sensory neurons expressing 5HT2A and TRPV1 mRNA. Lastly, E2 modulates specific trigeminal pain genes and enhances ERα-dependent serotonergic potentiation of CGRP release. Together, the data presented in this dissertation provides behavioral, neuroanatomical, and cellular evidence of a mechanism present in female trigeminal sensory neurons that may exacerbate trigeminal pain disorders in women.

Estrogen, Serotonin, Trigeminal pain, Sex differences, TRPV1