Temporomandibular joint/muscle disorders (TMJD) represent a family of conditions that present with pain in the temporomandibular joint (TMJ) and muscles of mastication. Chronic TMJD occurs mainly in young women and is strongly associated with elevated levels of psychological stress. Chronic TMJD patients display minimal signs of tissue injury and benefit little from conventional anti-inflammatory drug therapies. The symptoms of chronic TMJD suggest a central neural dysfunction or problem of pain amplification. By contrast, most animal models of TMJ nociception rely on overt inflammation and do not account for known risk factors (i.e., estrogen status and stress). In this application we will use an established model of psychological stress, the repeated forced swim test (FST), known to induce persistent hyperalgesia and will determine its effects on TMJ nociceptive processing in female rats under high and low estrogen conditions. We will test the hypothesis that changes in estrogen status and psychological stress act through the periaqueductal gray-rostral ventromedial medulla (PAG-RVM), the main supraspinal pain modulatory system, to influence TMJ nociception. Since serotonergic (5HT) mechanisms mediate a significant portion of PAG- induced effects on spinal systems, we will test if specific 5HT receptors are involved in modulation of TMJ nociceptive processing at the dorsal horn level. We will stimulate TMJ afferent fibers by injection of the non-inflammatory agent, ATP, and record single neuron activity at the trigeminal subnucleus caudalis/upper cervical dorsal horn region (Vc/C1-2), the principal site of termination for TMJ nociceptors. Masseter muscle electromyographic (EMG) activity will allow us to assess treatment effects on a peripheral behavioral correlate of TMJ nociception.
Three Specific Aims are proposed.
Aim 1 will determine if estrogen status alters PAG-induced modulation of TMJ-evoked unit activity, masseter muscle EMG and c-fos immunoreactive neurons at the Vc/C1-2 region in sham and FST-conditioned rats.
Aim 2 will determine if local actions of 5HT receptors at the caudal brainstem level contribute to PAG-induced modulation of TMJ nociception.
Aim 3 will determine if local actions of 5HT receptors alone at the caudal brainstem level modify the responses to TMJ stimulation independent of overt PAG stimulation. 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.

Public Health Relevance

Pain in the jaw joint and muscles of mastication is the most common form of persistent facial pain. Female gender and co-occurrence with depressive illness and psychological stress are recognized risk factors in developing persistent jaw pain. Our understanding of the neurobiology of persistent jaw pain will be improved by the use of new animal models that consider these known risk factors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE012758-14
Application #
8291294
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Kusiak, John W
Project Start
1998-09-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
14
Fiscal Year
2012
Total Cost
$351,489
Indirect Cost
$118,715
Name
University of Minnesota Twin Cities
Department
Dentistry
Type
Schools of Dentistry
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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Okamoto, Keiichiro; Thompson, Randall; Katagiri, Ayano et al. (2013) Estrogen status and psychophysical stress modify temporomandibular joint input to medullary dorsal horn neurons in a lamina-specific manner in female rats. Pain 154:1057-64
Chang, Z; Okamoto, K; Bereiter, D A (2012) Differential ascending projections of temporomandibular joint-responsive brainstem neurons to periaqueductal gray and posterior thalamus of male and female rats. Neuroscience 203:230-43
Tashiro, A; Okamoto, K; Bereiter, D A (2012) Rapid estrogenic effects on TMJ-responsive brainstem neurons. J Dent Res 91:210-4
Okamoto, Keiichiro; Tashiro, Akimasa; Chang, Zheng et al. (2012) Temporomandibular joint-evoked responses by spinomedullary neurons and masseter muscle are enhanced after repeated psychophysical stress. Eur J Neurosci 36:2025-34
Bereiter, David A; Okamoto, Keiichiro (2011) Neurobiology of estrogen status in deep craniofacial pain. Int Rev Neurobiol 97:251-84
Duenes, Sara L; Thompson, Randy; Chang, Zheng et al. (2010) Psychophysical stress increases the expression of phospho-CREB, Fos protein and neurokinin-1 receptors in superficial laminae of trigeminal subnucleus caudalis in female rats. Neurosci Lett 486:207-10
Tashiro, A; Okamoto, K; Bereiter, D A (2009) Chronic inflammation and estradiol interact through MAPK activation to affect TMJ nociceptive processing by trigeminal caudalis neurons. Neuroscience 164:1813-20
Tashiro, A; Okamoto, K; Bereiter, D A (2009) NMDA receptor blockade reduces temporomandibular joint-evoked activity of trigeminal subnucleus caudalis neurons in an estrogen-dependent manner. Neuroscience 164:1805-12
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

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