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Papers of the Week

Papers: 5 Feb 2022 - 11 Feb 2022

2022 Feb 02


Estrogen modulation of the pronociceptive effects of serotonin on female rat trigeminal sensory neurons is timing- and dosage-dependent and requires estrogen receptor alpha.


The role of the major estrogen estradiol (E2) on orofacial pain conditions remains controversial with studies reporting both a pronociceptive and antinociceptive role of E2. E2 modulation of peripheral serotonergic activity may be one mechanism underlying the female prevalence of orofacial pain disorders. We recently reported that female rats in proestrus and estrus exhibit greater serotonin (5HT)-evoked orofacial nocifensive behaviors compared to diestrus and males. Further coexpression of 5HT2A receptor mRNA in nociceptive trigeminal sensory neurons that express transient receptor potential vanilloid 1 ion channels (TRPV1) contribute to pain sensitization. E2 may exacerbate orofacial pain via 5HT-sensitive trigeminal nociceptors, but whether low or high E2 contributes to orofacial pain and by what mechanism remains unclear. We hypothesized that steady-state exposure to a proestrus level of E2 exacerbates 5HT-evoked orofacial nocifensive behaviors in female rats, we explored the transcriptome of E2-treated females, and we determined which E2 receptor contributes to sensitization of female trigeminal sensory neurons. We report that a diestrus level of E2 is protective against 5HT-evoked orofacial pain behaviors, which increase with increasing E2 concentrations, and E2 differentially alters several pain genes in the trigeminal ganglia. Further, E2 receptors co-expressed with 5HT2A and TRPV1 and enhanced capsaicin-evoked signaling in the trigeminal ganglia via ERα. Overall our data indicate that low, but not high, physiological levels of E2 protect against orofacial pain, and we provide evidence that ERα receptor activation, but not others, contribute to sensitization of nociceptive signaling in trigeminal sensory neurons.