This NIH-supported research program has the long-term objective of elucidating the mechanisms and neuroplastic processes underlying acute and chronic dental and orofacial pain conditions and their control. Our recent data indicate that stimulation of the tooth pulp with an inflammatory irritant induces a NMDA receptor(NMDAR)-dependent 'central sensitization'of nociceptive neurons in the rat brainstem and thalamus and that the brainstem subnucleus caudalis ('medullary dorsal horn') is strategically involved in this process that has been implicated in the allodynia, hyperalgesia and spread and referral of pain that may occur after injury and inflammation. Purinergic receptor (P2XR) mechanisms have been recently identified as another modulatory process in spinal nociceptive transmission that may function through a powerful presynaptic regulation of glutamate release in the spinal dorsal horn. Recently, we have provided the first findings of a role for purinergic mechanisms in central nociceptive processing in the orofacial region. We propose to build upon these findings and use immunocytochemical and in vivo and in vitro electrophysiological techniques to test the hypotheses A) Afferent inputs to Vc from tooth pulp and dura include P2XR-expressing afferents that are sufficient to induce Vc central sensitization and associated sensorimotor behavior by central P2XR mechanisms;and B) Central P2XR produce a presynaptic facilitation of primary afferent transmission in Vc that is dependent on specific NMDAR subunits. Our experimental design will allow us to determine the afferents expressing P2XR, if these afferent inputs to brainstem are sufficient to induce central sensitization by central P2XR mechanisms, and if central P2XR presynaptically facilitate primary afferent transmission and act via NMDAR subunits. These studies will provide new information on a novel chemical mediator of nociceptive transmission, and new insights will be gained of the processing of sensory information from the tooth pulp and dura. These insights could be important in the development of improved therapeutic approaches for the prevention of pain associated with pulpal inflammation and for the relief of pain once it has been initiated.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE004786-31
Application #
7751281
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Kusiak, John W
Project Start
1978-01-01
Project End
2012-01-31
Budget Start
2010-02-01
Budget End
2011-01-31
Support Year
31
Fiscal Year
2010
Total Cost
$259,281
Indirect Cost
Name
University of Toronto
Department
Type
DUNS #
259999779
City
Toronto
State
ON
Country
Canada
Zip Code
M5 1-S8
Yao, Dongyuan; Yoshida, Mitsuhiro; Sessle, Barry J (2015) Dura-evoked neck muscle activity involves purinergic and N-methyl-D-aspartate receptor mechanisms. Neuroreport 26:1155-60
Wang, Hua; Cao, Ye; Chiang, Chen-Yu et al. (2014) The gap junction blocker carbenoxolone attenuates nociceptive behavior and medullary dorsal horn central sensitization induced by partial infraorbital nerve transection in rats. Pain 155:429-35
Cao, Ye; Wang, Hua; Chiang, Chen-Yu et al. (2013) Pregabalin suppresses nociceptive behavior and central sensitization in a rat trigeminal neuropathic pain model. J Pain 14:193-204
Wang, H; Xie, Y F; Chiang, C Y et al. (2013) Central ?-adrenoceptors contribute to mustard oil-induced central sensitization in the rat medullary dorsal horn. Neuroscience 236:244-52
Matsuura, Shingo; Shimizu, Kohei; Shinoda, Masamichi et al. (2013) Mechanisms underlying ectopic persistent tooth-pulp pain following pulpal inflammation. PLoS One 8:e52840
Cao, Ye; Li, Kai; Fu, Kai-Yuan et al. (2013) Central sensitization and MAPKs are involved in occlusal interference-induced facial pain in rats. J Pain 14:793-807
Kumar, Naresh; Cherkas, Pavel S; Varathan, Vidya et al. (2013) Systemic pregabalin attenuates facial hypersensitivity and noxious stimulus-evoked release of glutamate in medullary dorsal horn in a rodent model of trigeminal neuropathic pain. Neurochem Int 62:831-5
Kiyomoto, Masaaki; Shinoda, Masamichi; Okada-Ogawa, Akiko et al. (2013) Fractalkine signaling in microglia contributes to ectopic orofacial pain following trapezius muscle inflammation. J Neurosci 33:7667-80
Narita, N; Kumar, N; Cherkas, P S et al. (2012) Systemic pregabalin attenuates sensorimotor responses and medullary glutamate release in inflammatory tooth pain model. Neuroscience 218:359-66
Chiang, C-Y; Sessle, B J; Dostrovsky, J O (2012) Role of astrocytes in pain. Neurochem Res 37:2419-31

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