Women report greater temporomandibular joint (TMJ) pain when the concentration of estrogen is diminishing. Consistent with these results, estrogen reduces TMJ hypersensitivity in proestrus rats, when estrogen concentrations are highest. In our lab, a large gene array study (>10,000 genes) indicated that gene expression in the rat trigeminal ganglia (TG) was significantly affected by increased estrogen. High proestrus versus low diestrus levels of 17-estradiol resulted in a 16 to 34 fold increase in the GABAA receptor subunit ?6 (Gabr?6), the glycine receptor subunit ?2 (Glr?2) and the beta-adrenergic receptor subunit 1 (Adr1). This significant increase occurred in the TG of nave rats and in rats with ligature of the masseter tendon, a model of chronic (>6 months) myogenic TMJ hypersensitivity. Since GABA, glycine and sympathomimetic amines can inhibit hypersensitivity the knock-down of Gabr?6, Glr?2 and Adr1 expression would be expected to increase hypersensitivity. In preliminary studies siRNA knock-down of Gabr?6 expression in the TG increased hypersensitivity, increased the level of phosphorylated-ERK (p-ERK) in TG neurons and increased neuronal electrical activity. A homology search for estrogen receptor ? and (ER ? and ER) binding sites 10kb of the transcriptional start site for these three genes showed that at least one potential binding site was present but the mechanism regulating the estrogen response of these genes is unknown. Based on this information we hypothesize that 17 -estradiol decreased TMJ hypersensitivity at proestrus by increasing Gabr?6, Glr?2 and Adr1 expression in the TG and that this estrogen effect was due to interaction with the estrogen receptor and sequence proximal of the transcriptional start site. To address this hypothesis we propose two specific aims, in Aim #1 we will determine in the TG the role of Gabr?6, Glr?2 and Adr1 in modulating TMJ hypersensitivity/cellular activity in both males and females. To complete aim #1 a ligature will be placed on the masseter tendon and TG expression of Gabr?6, Glr?2, and Adr1 will be reduced through antagonists or siRNA. Hypersensitivity/cellular activity will be assessed at an acute stage (7 days post-ligature) and at a chronic stage (6 months post-ligature) using von Frey filaments, meal duration, electrophysiological recordings and by quantitating p-ERK levels. The goal of Aim #2 will be to characterize the role of ER? and ER in controlling Gabr?6, Glr?2, and Adr1 expression using chromatin immunoprecipitation, electrophoretic mobility shift assays and luciferase reporter constructs. We expect to show that an altered expression of these three genes can affect the TMJ nociceptive response and that these genes are responsible, in part, for the decrease in hypersensitivity observed in proestrus rats. We also expect to determine the mechanism by which estrogen modulates expression of these genes in TG cells.

Public Health Relevance

Novel genes by which 17-estradiol effects TMJ hypersensitivity will be identified, providing a greater understanding of why females suffer greater TMJ pain and allowing for targeted control of expression to reduce orofacial pain.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
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Somatosensory and Chemosensory Systems Study Section (SCS)
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Vallejo-Estrada, Yolanda
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Texas A&M University
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Schools of Dentistry/Oral Hygn
College Station
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Kramer, Phillip; Rao, Mahesh; Stinson, Crystal et al. (2018) Aromatase Derived Estradiol Within the Thalamus Modulates Pain Induced by Varicella Zoster Virus. Front Integr Neurosci 12:46
Strand, Jennifer; Stinson, Crystal; Bellinger, Larry L et al. (2018) Gi protein functions in thalamic neurons to decrease orofacial nociceptive response. Brain Res 1694:63-72
Umorin, Mikhail; Kramer, Phillip R; Bellinger, Larry L (2017) Distance-based permutation of inter-meal differences as a sensitive test of temporomandibular joint nociception in rats. J Appl Biobehav Res 22:
Kramer, Phillip R; Stinson, Crystal; Umorin, Mikhail et al. (2017) Lateral thalamic control of nociceptive response after whisker pad injection of varicella zoster virus. Neuroscience 356:207-216
Kramer, Phillip R; Strand, Jennifer; Stinson, Crystal et al. (2017) Role for the Ventral Posterior Medial/Posterior Lateral Thalamus and Anterior Cingulate Cortex in Affective/Motivation Pain Induced by Varicella Zoster Virus. Front Integr Neurosci 11:27
Umorin, Mikhail; Stinson, Crystal; Bellinger, Larry L et al. (2016) Genes in the GABA Pathway Increase in the Lateral Thalamus of Sprague-Dawley Rats During the Proestrus/Estrus Phase. J Cell Physiol 231:1057-64
Kramer, Phillip R; Umorin, Mikhail; Bellinger, Larry L (2015) Attenuation of myogenic orofacial nociception and mechanical hypersensitivity by viral mediated enkephalin overproduction in male and female rats. BMC Neurol 15:34
Kramer, P R; Bellinger, L L (2014) Infusion of Gabr?6 siRNA into the trigeminal ganglia increased the myogenic orofacial nociceptive response of ovariectomized rats treated with 17?-estradiol. Neuroscience 278:144-53
Kramer, Phillip R; Bellinger, Larry L (2014) Meal duration as a measure of orofacial nociceptive responses in rodents. J Vis Exp :e50745
Kramer, P R; Bellinger, L L (2013) Modulation of temporomandibular joint nociception and inflammation in male rats after administering a physiological concentration of 17?-oestradiol. Eur J Pain 17:174-84

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