Journal
PAIN
Volume 163, Issue 8, Pages E899-E916Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/j.pain.0000000000002604
Keywords
Estrogen; GPER; ER alpha; ER beta; Serotonin; Pain; 5HT(2A) receptor; Trigeminal sensory neurons
Categories
Funding
- National Institutes of Health NIDCR [DE025970]
- Texas Enhancement Program grant from TWU
- Center for Student Research grants from TWU
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This study investigated the role of major estrogen estradiol (E2) in orofacial pain and found that low levels of E2 can protect against pain while high levels can exacerbate it. The study also identified that estrogen receptor alpha is involved in the sensitization of pain signaling in trigeminal sensory neurons.
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 with diestrus and male rats. Further coexpression of 5HT(2A) receptor mRNA in nociceptive trigeminal sensory neurons that express transient receptor potential vanilloid 1 ion channels contributes to pain sensitization. E2 may exacerbate orofacial pain through 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, explored the transcriptome of E2-treated female rats, and 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 that E2 differentially alters several pain genes in the trigeminal ganglia. Furthermore, E2 receptors coexpressed with 5HT(2A) and transient receptor potential vanilloid 1 and enhanced capsaicin-evoked signaling in the trigeminal ganglia through estrogen receptor alpha. Overall, our data indicate that low, but not high, physiological levels of E2 protect against orofacial pain, and we provide evidence that estrogen receptor alpha receptor activation, but not others, contributes to sensitization of nociceptive signaling in trigeminal sensory neurons.
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