Estrogen and TMJ Pain


Principal Investigator: Phillip R Kramer
Abstract: DESCRIPTION (provided by applicant): 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[unreadable]-estradiol resulted in a 16 to 34 fold increase in the GABAA receptor subunit [unreadable]6 (Gabr[unreadable]6), the glycine receptor subunit [unreadable]2 (Glr[unreadable]2) and the beta-adrenergic receptor subunit [unreadable]1 (Adr[unreadable]1). This significant increase occurred in the TG of na[unreadable]ve 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[unreadable]6, Glr[unreadable]2 and Adr[unreadable]1 expression would be expected to increase hypersensitivity. In preliminary studies siRNA knock-down of Gabr[unreadable]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 [unreadable] and [unreadable] (ER [unreadable] and ER[unreadable]) 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 [unreadable]-estradiol decreased TMJ hypersensitivity at proestrus by increasing Gabr[unreadable]6, Glr[unreadable]2 and Adr[unreadable]1 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[unreadable]6, Glr[unreadable]2 and Adr[unreadable]1 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[unreadable]6, Glr[unreadable]2, and Adr[unreadable]1 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[unreadable] and ER[unreadable] in controlling Gabr[unreadable]6, Glr[unreadable]2, and Adr[unreadable]1 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.
Funding Period: 2012-08-15 - 2016-07-31
more information: NIH RePORT

Top Publications

  1. pmc Reduced GABAA receptor α6 expression in the trigeminal ganglion enhanced myofascial nociceptive response
    P R Kramer
    Department of Biomedical Sciences, Texas A and M Health Science Center Baylor College of Dentistry, 3302 Gaston Avenue, Dallas, TX 75246, United States
    Neuroscience 245:1-11. 2013

Detail Information


  1. pmc Reduced GABAA receptor α6 expression in the trigeminal ganglion enhanced myofascial nociceptive response
    P R Kramer
    Department of Biomedical Sciences, Texas A and M Health Science Center Baylor College of Dentistry, 3302 Gaston Avenue, Dallas, TX 75246, United States
    Neuroscience 245:1-11. 2013
    ..From these results we conclude GABAA receptors consisting of the Gabrα6 subunit inhibit TG nociceptive sensory afferents in the trigeminal pathway and have an important role in the regulation of myofascial nociception...

Research Grants30

  1. Control of Nociception in the Spinal Cord
    Sukhbir S Mokha; Fiscal Year: 2013
    ..Further, antinociception produced by activation of KOR and ORL1 is not linked to addictive side- effects characteristic of other opioid receptor subpopulations. ..
  2. Mapping Orofacial Nociceptive Pathways and Alterations Due to Inflammation
    JOSHUA EMRICK; Fiscal Year: 2013
    ..Our work will be critical for a better understanding nociceptor pathways and processes underlying hypersensitivity pain and may ultimately lead to novel targets for its treatment. ..
  3. Vascular Interactions of Estrogen Receptor GPR30 and the Renin-Angiotensin System
    Sarah Hoffmann Lindsey; Fiscal Year: 2013
    ..These studies will establish the regulation of'Vascular GPR30 expression and assess its acute and chronic interaction with the renin-angiotensin system. ..
  4. Transplant Tolerance in Non-Human Primates
    ..This goal will be accomplished via four interrelated projects and two supporting cores. ..
  5. Central actions of estrogens: Effects of GnRH neurons
    Suzanne M Moenter; Fiscal Year: 2013
    ..Integration of the data resulting from the study of an excitatory and an inhibitory afferet network into existing knowledge will increase our understanding of the central neuronal control of ovulation by estradiol. ..
  6. Mechanisms/Treatments of Lower Urinary Tract Dysfunction After Spinal Cord Injury
    ANTHONY JOHN KANAI; Fiscal Year: 2013
    ..We are confident that our experience and unique approaches will lead to a very interactive and fruitful program. ..
  7. SERT KO rats are a model of sex specific visceral pain
    James J Galligan; Fiscal Year: 2013
    ..The data would indicate that the SERT KO rat is a model for studying changes in the sensory nerve supply of the gut that leads to visceral hypersensitivity. ..
  8. Central mechanisms of maintenance of orofacial pain after injury
    Asaf Keller; Fiscal Year: 2013
    ..Our findings will lead to a transformative shift in the search for unique treatment approaches for persistent pain. ..
  9. Group III mGLURs: Mechanisms of Analgesia
    Susan M Carlton; Fiscal Year: 2013
  10. Cellular/Molecular Pathophysiology of Intellectual and Developmental Disabilities
    Stuart A Lipton; Fiscal Year: 2013
    ..The CORE supports administration, statistics, tissue culture, and crystallography/modeling of NMDAR subunits and functional sites, all critical to the proposed Projects. ..
  11. Immune-Based Interventions Against Infectious Diseases
    Alan L Rothman; Fiscal Year: 2013
    ..3. Recruit promising junior investigators and provide mentoring by established NIH-funded researchers. 4. Support a multidisciplinary research program led by junior investigators in translational infectious diseases immunology. ..
  12. Pacific NorthWest Regional Center of Excellence (PNWRCE)
    Jay A Nelson; Fiscal Year: 2013
    ..pseudomallei host pathogen response during both the septicemic as well as the intracellular phases of the disease. ..
    Salvatore DiMauro; Fiscal Year: 2013
  14. Center for Reproductive Science and Medicine
    Pamela L Mellon; Fiscal Year: 2013
    ..The SCCPIR Human Ovary Tissue Bank provides tissue to NIH-funded investigators nation-wide. ..
  15. Trigeminal-autonomic relations in ocular homeostasis
    David A Bereiter; Fiscal Year: 2013
    ..Disruption of trigeminal-PaNS relations may contribute to symptoms in diverse conditions as dry eye disease, glaucoma and ocular hypertension that can lead to loss of visual acuity and cause discomfort. ..
  16. Endothelin mechanisms in metastic prostate cancer pain
    Gary R Strichartz; Fiscal Year: 2013
  17. Synaptic Function: Effects of the Nerve Injury, Repair, and Altered Activity
    Timothy C Cope; Fiscal Year: 2013
    ..The Resume and Summary of Discussion above summarizes the final outcome of the group discussion. OVERALL PROGRAM EVALUATION ..
  18. Estrogen and Psychological Stress in TMJD Pain
    David A Bereiter; Fiscal Year: 2013
    ..These studies will provide new information on the influence of estrogen status and psychological stress on the neurobiology of brainstem systems thought to be critical for TMJD pain. ..
    Robert S Sandler; Fiscal Year: 2013
    ..Through all of its activities, the Center improves communication, promotes collaboration, develops careers and generally enriches the intellectual climate for digestive disease research. ..