Patients who suffer from temporomandibular joint disorders often complain of debilitating pain that is associated with jaw movement. Nociceptors in the temporomandibular joint respond to mechanical stimulation by a process referred to as mechanoreception or mechanotranduction. However, the mechanisms that underlie mechanoreception by sensory neurons are unknown. Recent evidence indicates that functional linkages between the cytoskeleton and molecules of the extracellular matrix are vital to mechanoreception. Furthermore, evidence indicates that these important linkages are established via transmembrane receptors, termed integrins. Integrins are heterodimeric (i.e., alphabeta heterodimers) transmembrane proteins that bind specific extracellular matrix molecules or other cell surface receptors and connect with cytoplasmic proteins, including f-actin and signal transduction molecules. Thus, integrins establish linkages between the extracellular matrix and the cytoskeleton that are vital to mechanoreception. This project will test the central hypothesis that integrins are key regulators of mechanoreception by sensory neurons innervating the temporomandibularjoint.
In specific aim #1. we will determine the specific integrins that are expressed by sensory neurons innervating the temporomandibular joint and identify those integrins that mediate mechanoreception.
In specific aim #2, we will investigate potential mechanisms that may be involved in integrin-dependent mechanoreception in trigeminal ganglion neurons. Bradykinin, a algesic biochemical produced in symptomatic human temporomandibular joints, enhances mechanoreception through integrins in trigeminal ganglion neurons.
In specific aim #3, we will determine the mechanism by which bradykinin elicits this effect. Finally, in specific aim #4, we will determine the role of RGD-binding integrins as mediators of mechanoreception in the inflamed TMJ using an animal model. These studies should generate a fundamental understanding of mechanoreceptive mechanisms involved in TMJ pain and neurogenic inflammation, potentially leading to novel therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE015371-04
Application #
7065705
Study Section
Special Emphasis Panel (ZDE1-PZ (38))
Program Officer
Kusiak, John W
Project Start
2003-08-01
Project End
2008-05-31
Budget Start
2006-06-01
Budget End
2008-05-31
Support Year
4
Fiscal Year
2006
Total Cost
$356,423
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Dentistry
Type
Schools of Dentistry
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
Jeske, Nathaniel A; Patwardhan, Amol M; Henry, Michael A et al. (2009) Fibronectin stimulates TRPV1 translocation in primary sensory neurons. J Neurochem 108:591-600
Akopian, Armen N; Ruparel, Nikita B; Jeske, Nathaniel A et al. (2009) Role of ionotropic cannabinoid receptors in peripheral antinociception and antihyperalgesia. Trends Pharmacol Sci 30:79-84
Tashiro, A; Okamoto, K; Bereiter, D A (2008) Morphine modulation of temporomandibular joint-responsive units in superficial laminae at the spinomedullary junction in female rats depends on estrogen status. Eur J Neurosci 28:2065-74
Tashiro, A; Okamoto, K; Milam, S B et al. (2007) Differential effects of estradiol on encoding properties of TMJ units in laminae I and V at the spinomedullary junction in female rats. J Neurophysiol 98:3242-53
Berg, K A; Zardeneta, G; Hargreaves, K M et al. (2007) Integrins regulate opioid receptor signaling in trigeminal ganglion neurons. Neuroscience 144:889-97
Bereiter, David A; Cioffi, Jessica L; Bereiter, Dominique F et al. (2006) Local blockade of integrins in the temporomandibular joint region reduces Fos-positive neurons in trigeminal subnucleus caudalis of female rats produced by jaw movement. Pain 125:65-73