Sex Differences in the Neuroimmune Modulation of Trigeminal Sensory Neurons

Abstract
Approximately a quarter of the population experiences oral and craniofacial pain, such as headache, migraine,
and pain associated with temporomandibular joint disorders. Inexplicably, these conditions are 3-4x more
prevalent in women. Women are more likely to experience severe pain associated with temporomandibular joint
disorders and are also more likely to experience pain comorbidities and widespread pain. While it is clear that
craniofacial pain is a major health issue for both men and women, women are not well represented in pain
research. In clinical and preclinical studies that include examining female subjects, it is evident that estrogen can
modulate craniofacial pain. However, the underlying craniofacial pain mechanisms at the trigeminal sensory
neurons by which estrogen acts on remain elusive. We have described a novel pain mechanism by which the
major estrogen 17-estradiol (E2), acting on nuclear estrogen receptor alpha (ER) localized to nociceptive
trigeminal sensory neurons, amplifies orofacial pain signaling. Specifically, E2 exacerbates the pronociceptive
effects of the monoamine neurotransmitter serotonin (5HT) at nociceptive trigeminal sensory neurons. While
5HT is well-known for its role in mood and antinociception in the central nervous system, its paradoxical role in
the periphery is to contribute to pain signaling by sensory neurons. We have reported that the pronociceptive
effects of 5HT at trigeminal sensory neurons is modulated by E2, however the relationship between 5HT and E2
in the environment of trigeminal sensory neurons has not been defined. 5HT is actively taken up via 5HT
transporter mechanisms and released by platelets, mast cells, damaged epithelial cells, and various immune
cells, such as macrophages. Increased 5HT levels have been associated with high E2 in both preclinical and
clinical studies and we have preliminary data indicating that E2 can alter the release of 5HT, and other
inflammatory mediators, from macrophages. Experiments outlined in this proposal will test the hypothesis that
estrogen enhances serotonergic neuroimmune modulation of trigeminal sensory neurons in a rat model of
temporomandibular joint disorder pain. Our studies are designed to determine the effects of 17β-estradiol (via
ERα, ERβ, and/or the G protein estrogen receptor GPER) on serotonergic neuroimmune communication
between trigeminal ganglia neurons and trigeminal ganglia macrophages. We will test our hypothesis using a
translational animal model of unilateral anterior crossbite (UAC) that we have preliminary data on characterizing
the development of pain behaviors. This project will also provide a challenging experimental framework for
training undergraduate and graduate students in orofacial neurosensory research.

Grant Number: 2R15DE025970-02
NIH Institute/Center: NIH
Principal Investigator: Dayna Averitt