Temporomandibular joint pain: a critical role for Trpv4 in the trigeminal ganglion.


Temporomandibular joint disorder (TMJD) is known for its mastication-associated pain. TMJD is medically relevant because of its prevalence, severity, chronicity, the therapy-refractoriness of its pain, and its largely elusive pathogenesis. Against this background, we sought to investigate the pathogenetic contributions of the calcium-permeable TRPV4 ion channel, robustly expressed in the trigeminal ganglion sensory neurons, to TMJ inflammation and pain behavior. We demonstrate here that TRPV4 is critical for TMJ-inflammation-evoked pain behavior in mice and that trigeminal ganglion pronociceptive changes are TRPV4-dependent. As a quantitative metric, bite force was recorded as evidence of masticatory sensitization, in keeping with human translational studies. In Trpv4(-/-) mice with TMJ inflammation, attenuation of bite force was significantly less than in wildtype (WT) mice. Similar effects were seen with systemic application of a specific TRPV4 inhibitor. TMJ inflammation and mandibular bony changes were apparent after injections of complete Freund adjuvant but were remarkably independent of the Trpv4 genotype. It was intriguing that, as a result of TMJ inflammation, WT mice exhibited significant upregulation of TRPV4 and phosphorylated extracellular-signal-regulated kinase (ERK) in TMJ-innervating trigeminal sensory neurons, which were absent in Trpv4(-/-) mice. Mice with genetically-impaired MEK/ERK phosphorylation in neurons showed resistance to reduction of bite force similar to that of Trpv4(-/-) mice. Thus, TRPV4 is necessary for masticatory sensitization in TMJ inflammation and probably functions upstream of MEK/ERK phosphorylation in trigeminal ganglion sensory neurons in vivo. TRPV4 therefore represents a novel pronociceptive target in TMJ inflammation and should be considered a target of interest in human TMJD.


Journal article





Animals, Bite Force, Cell Size, Disease Models, Animal, Female, Freund's Adjuvant, Gene Expression Regulation, Glycoproteins, Green Fluorescent Proteins, Inflammation, MAP Kinase Kinase Kinases, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Nerve Tissue Proteins, Sensory Receptor Cells, Sex Factors, TRPV Cation Channels, Temporomandibular Joint Dysfunction Syndrome, Time Factors, Tomography, X-Ray Computed, Trigeminal Ganglion


Published Version (Please cite this version)


Publication Info

Chen, Yong, Susan H Williams, Amy L McNulty, Ji Hee Hong, Suk Hee Lee, Nicole E Rothfusz, Puja K Parekh, Carlene Moore, et al. (2013). Temporomandibular joint pain: a critical role for Trpv4 in the trigeminal ganglion. Pain, 154(8). pp. 1295–1304. 10.1016/j.pain.2013.04.004 Retrieved from https://hdl.handle.net/10161/12973.

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Yong Chen

Associate Professor in Neurology

Dr. Yong Chen is an Associate Professor of Neurology at the Duke University School of Medicine.  He is also affiliated with Duke Anesthesiology-Center for Translational Pain Medicine (CTPM) and Duke-Pathology.

The Chen lab mainly studies sensory neurobiology of pain and itch, with a focus on TRP ion channels and neural circuits. The main objective of our lab is to identify molecular and cellular mechanisms underlying chronic pain and chronic-disease associated itch, using a combination of animal behavioral, genetic, molecular and cellular, advanced imaging, viral, and optogenetic approaches.  There are three major research areas in the lab: craniofacial pain, arthritis pain and joint function, and systemic-disease associated itch.


Amy Lynn McNulty

Associate Professor in Orthopaedic Surgery

The McNulty Lab is working to develop strategies to prevent osteoarthritis and to promote tissue repair and regeneration following joint injury. In order to accomplish this, we are working in three main areas.  1) We are working to understand the pathways that are activated by normal and injurious mechanical loading of cartilage and meniscus and how these mechanotransduction pathways are altered during aging, injury, and tissue degeneration. A greater understanding of alterations in mechanosensitive signaling mechanisms with aging and injury will likely reveal potential targets to promote tissue repair and prevent tissue degeneration and osteoarthritis development. 2) We are developing meniscus tissue engineered constructs that will be utilized to repair and replace meniscus tissue lost due to injury and surgical resection.  3)  We are focusing on the biological and biomechanical changes that occur in the joint following meniscus injury and how these may contribute to osteoarthritis development.   


Carlene D Moore

Assistant Professor in Neurology

Andrea Beth Taylor

Adjunct Professor in the Department of Orthopaedic Surgery

Feeding behavior and diet are two of the most important factors influencing the evolution of behavior and morphology in humans and nonhuman primates. Variation in such parameters as body size, life history, metabolic rate, and brain size, can all be linked to some extent to the ability of animals to acquire, process, and consume resources. Shifts in feeding behavior and diet also provide the evolutionary context for a variety of morphological changes in the jaws, face, and teeth. This is my area of research - the evolution of craniofacial form in humans and other primates as it relates to feeding behavior and the biomechanical demands of diet. I rely on a variety of primate models and methodological approaches to investigate the mechanisms that influence musculoskeletal form and function, and to link masticatory form and function with performance in living and extinct species. I collaborate extensively with other functional morphologists, experimental biologists, and primatologists and provide research and training opportunities for graduate and undergraduate students and postdoctoral researchers. In collaboration with Dr. Christopher Vinyard (NEOMED), we have been investigating the functional correlates of gape and muscle force production in primates (funded by the National Science Foundation BCS 0452160, BCS 0833394, BCS 0635649 and the National Skeletal Muscle Research Center R24-HD 050837-01). This work is informing our understanding of how jaw muscles are structured to meet the mechanical demands of diverse diets, how their bony and muscular systems function together, and how mechanical trade-offs are met. With Dr. Callum Ross (University of Chicago), we are currently investigating the scaling of primate feeding systems, integrating kinematic, morphological, and experimental approaches to test biomechanical models of the scaling of chew cycle during in primates (funded by the National Science Foundation BCS 0962677). In a related area of research, I am collaborating with colleagues in the DPT Program and in Pediatrics to investigate the effects of exercise on muscle fiber architecture and performance in a Pompe mouse model (Funded by the National Skeletal Muscle Research Center R24-HD050837).


Fan Wang

Adjunct Professor in the Department of Neurobiology

My lab studies neural circuit basis of sensory perception. 
Specifically we are interested in determining neural circuits underlying (1) active touch sensation including tactile processing stream and motor control of touch sensors on the face; (2) pain sensation including both sensory-discriminative and affective aspects of pain; and (3) general anesthesia including the active pain-suppression process. We use a combination of genetic, viral, electrophysiology, and in vivo imaging (in free-moving animals) techniques to study these questions.


Wolfgang Bernhard Liedtke

Adjunct Professor in the Department of Neurology

Research Interests in the Liedtke-Lab:

  • Pain/ nociception
  • Sensory transduction and -transmission
  • TRP ion channels
  • Water and salt equilibrium regulated by the central nervous system

Visit the lab's website, download papers and read Dr. Liedtke's CV here.

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