One of the hallmarks of injury or infection is inflammation, which is common in the oral cavity and associated tissues. For example, inflammation may arise in the dental pulp (pulpitis), connective tissues supporting the dentition (gingivitis and periodontitis), muscles involved in mastication (myositis), or temporomandibular joint (arthritis or temporomandibular disorder/TMD). Inflammation involving the aforementioned sites produces characteristic symptoms: swelling, redness, heat, and pain. To address inflammatory pain, which represents a major source of patient morbidity, it is critical to understand the underlying pathophysiological processes. Nociception is the process whereby noxious stimuli activate primary afferent sensory neurons (nociceptors) producing pain via signaling to the central nervous system (CNS) and contributing to inflammation by releasing inflammatory mediators at the site of injury. Nociceptors are a heterogeneous group;the differential expression of molecules (e.g., ion channels) serves to delineate nociceptor subgroups (e.g., TRPV1/heat, TRPM8/cold, and TRPA1/chemical irritants) (Basbaum, Bautista et al. 2009). The peripheral and central projection patterns of nociceptor fibers have been studied using retrograde labeling and immunohistochemistry (Gibbs, Melnyk et al. 2011;Kim, Chung et al. 2011). However, more powerful and sensitive methods using mouse reporter lines have not been employed to study the pathways initiated by nociceptor subtypes in the trigeminal network, which innervates oral cavity tissues. Furthermore, several lines of evidence suggest that the expression of the characteristic ion channels that delineate and initiate nociception and, consequently, the subpopulation profile of nociceptors in the inflamed tissue are altered by inflammation and the inflammatory milieu (Ji, Samad et al. 2002). In order to map of the expression profile and transduction pathway of nociceptor subtypes innervating the orofacial tissues we will employ a genetically modified, Cre-dependent, transsynaptically transported reporter strain of herpes simplex virus type 1, HSV129?TK-TT, in conjunction with available strains of reporter mice (TRPV1-Cre, TRPM8-Cre, TRPA1-Cre, peripherin-Cre, and Nav1.8-Cre). The virus/mouse reporter system will fluorescently label selectively targeted nociceptor sub-types and their synaptic partners. To explore whether inflammation induces any alterations in the expression profile and transduction pathway of nociceptor subtypes we will develop mouse models of pulpitis, periodontitis, myositis, and arthritis/TMD and again utilize the virus/mouse reporter system and fluorescent imaging to identify any alterations in nociceptor expression and synaptic partners. Similarly, we will determine if administration of non-steroidal anti-inflammatory (NSAIDs) agents attenuates inflammation-induced alterations, if observed. 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.

Public Health Relevance

Inflammation is present in a variety of diseases in the mouth and surrounding tissues and leads to significant pain and other negative consequences for patients;e.g., pulpal necrosis and root canal treatment, loss of teeth through periodontitis, myofascial pain, and temporomandibular disorder (TMD). This study aims to investigate the molecular and anatomical basis of pain signaling in the oral cavity and associated tissues, and determine if specific pain pathways to the brain and spinal cord are altered in a state of tissue inflammation. Our work will shed light on the causes of inflammatory pain and ultimately help to inform development of highly targeted pharmacological therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
1F30DE023476-01
Application #
8526099
Study Section
NIDCR Special Grants Review Committee (DSR)
Program Officer
Frieden, Leslie A
Project Start
2013-03-01
Project End
2017-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
1
Fiscal Year
2013
Total Cost
$39,466
Indirect Cost
Name
University of California San Francisco
Department
Dentistry
Type
Schools of Dentistry
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Emrick, J J; Gullard, A (2013) Integrating research into dental student training: a global necessity. J Dent Res 92:1053-5