In order to understand dental pain we need better information (1) about the normal distribution, cytochemistry, ultrastructure and pulpal interactions of the different types of sensory nerves in teeth; and (2) about the mechanisms that drive their responses to injury in the peripheral tissue, in the trigeminal ganglion and in central pain pathways. Nociceptive fibers are now known to have a set of dynamic interactions with healthy tissue, and a very different set of functions after injury that cause pain and contribute to peripheral neuropathies, hyperexcitation of the dorsal horn, inflammation and wound healing. The proposed research is designed to learn more about the normal functions and injury reactions of dental pain fibers. We will use immunocytochemistry, quantitative morphometry biochemical assays, in situ hybridization, and electron microscopy to study three hypotheses related to normal dental innervation: (1) that normal booth function (chewing) of adult rat molars causes changes in neuropeptide immunoreactivity in dental nerves compared to a resting condition; (2) that preterminal regions of dental and periodontal nerves in rats have a focal concentration of glial fibrillary acidic protein, a newly discovered component of peripheral nerves; (3) that pulpal production of nerve growth factor (NGF) continues in old rat molars in regions near surviving dentinal innervation and primary odontoblasts. We will also study the effects of tooth injury on the expression of NGF receptors, neuropeptides, glial fibrillary acidic protein and Fos protein in injured rat molars, trigeminal ganglia and brainstem. We hypothesize that the duration and intensity of the ganglionic changes will depend on the severity of tooth injury, and that Fos protein in the CNS will continue as long as the ganglionic changes occur. We further hypothesize that pulpal inflammation and elevated NGF precede the ganglionic reactions, and that those reactions return to normal as pulpal tissue heals. Graded injuries will be made to produce specific types of pulpal and neural reactions, injury size and duration, and pulpal/dentinal healing. We will analyze the temporal relationships among reactions in teeth, trigeminal ganglia and brainstem at 1,3,7 and 14 days after injury in order to document the condition of the injured tissue when pathologic reactions are found in ganglion and CNS. The long range goal is to improve clinical treatment for pain by understanding the dynamic structure and cytochemistry of sensory nerve fibers in normal teeth and to determine the mechanisms that drive pathologic responses in nociceptive fibers, sensory ganglia and central pain pathways.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
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Oral Biology and Medicine Subcommittee 1 (OBM)
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University of Washington
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Byers, Margaret R; Westenbroek, Ruth E (2011) Odontoblasts in developing, mature and ageing rat teeth have multiple phenotypes that variably express all nine voltage-gated sodium channels. Arch Oral Biol 56:1199-220
Veerayutthwilai, O; Byers, M R; Pham, T-T T et al. (2007) Differential regulation of immune responses by odontoblasts. Oral Microbiol Immunol 22:5-13
Veerayutthwilai, Orapin; Luis, Nadyne A; Crumpton, Rosa M et al. (2006) Peripherin- and CGRP-immunoreactive nerve fibers in rat molars have different locations and developmental timing. Arch Oral Biol 51:748-60
Heyeraas, K J; Kim, S; Raab, W H et al. (1994) Effect of electrical tooth stimulation on blood flow, interstitial fluid pressure and substance P and CGRP-immunoreactive nerve fibers in the low compliant cat dental pulp. Microvasc Res 47:329-43
Sugaya, A; Chudler, E H; Byers, M R (1994) Uptake of exogenous fluorescent Di-I by intact junctional epithelium of adult rats allows retrograde labeling of trigeminal sensory neurons. Brain Res 653:330-4
Redd, P E; Byers, M R (1994) Regeneration of junctional epithelium and its innervation in adult rats: a study using immunocytochemistry for p75 nerve growth factor receptor and calcitonin gene-related peptide. J Periodontal Res 29:214-24
Nahin, R L; Byers, M R (1994) Adjuvant-induced inflammation of rat paw is associated with altered calcitonin gene-related peptide immunoreactivity within cell bodies and peripheral endings of primary afferent neurons. J Comp Neurol 349:475-85
Byers, M R (1994) Dynamic plasticity of dental sensory nerve structure and cytochemistry. Arch Oral Biol 39 Suppl:13S-21S
Byers, M R; Taylor, P E (1993) Effect of sensory denervation on the response of rat molar pulp to exposure injury. J Dent Res 72:613-8
Heyeraas, K J; Kvinnsland, I; Byers, M R et al. (1993) Nerve fibers immunoreactive to protein gene product 9.5, calcitonin gene-related peptide, substance P, and neuropeptide Y in the dental pulp, periodontal ligament, and gingiva in cats. Acta Odontol Scand 51:207-21

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