Sensory neuron-TRPV4 modulates temporomandibular disorder pain via CGRP in mice.


Temporomandibular disorder (TMD) pain that involves inflammation and injury in the temporomandibular joint (TMJ) and/or masticatory muscle is the most common form of orofacial pain. We recently found that transient receptor potential vanilloid-4 (TRPV4) in trigeminal ganglion (TG) neurons is upregulated after TMJ inflammation, and TRPV4 co-expresses with calcitonin gene-related peptide (CGRP) in TMJ-innervating TG neurons. Here, we extended these findings to determine the specific contribution of TRPV4 in TG neurons to TMD pain, and examine whether sensory neuron-TRPV4 modulates TMD pain via CGRP. In mouse models of TMJ inflammation or masseter muscle injury, sensory neuron-Trpv4 conditional knockout (cKO) mice displayed reduced pain. Co-expression of TRPV4 and CGRP in TMJ- or masseter muscle-innervating TG neurons was increased after TMJ inflammation and masseter muscle injury, respectively. Activation of TRPV4-expressing TG neurons triggered secretion of CGRP, which was associated with increased levels of CGRP in peri-TMJ tissues, masseter muscle, spinal trigeminal nucleus, and plasma in both models. Local injection of CGRP into the TMJ or masseter muscle evoked acute pain in naïve mice, while blockade of CGRP receptor attenuated pain in mouse models of TMD. These results suggest that TRPV4 in TG neurons contributes to TMD pain by potentiating CGRP secretion. Perspective: This study demonstrates that activation of TRPV4 in TG sensory neurons drives pain by potentiating the release of pain mediator CGRP in mouse models of TMJ inflammation and masseter muscle injury. Targeting TRPV4 and CGRP may be of clinical potential in alleviating TMD pain.





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Publication Info

Suttle, Abbie, Peng Wang, Fabiana C Dias, Qiaojuan Zhang, Yuhui Luo, Lauren Simmons, Andrey Bortsov, Inna E Tchivileva, et al. (2022). Sensory neuron-TRPV4 modulates temporomandibular disorder pain via CGRP in mice. The journal of pain. p. S1526-5900(22)00462-X. 10.1016/j.jpain.2022.12.001 Retrieved from

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Andrey V Bortsov

Assistant Professor in Anesthesiology

Dr. Andrey Bortsov is an Assistant Professor in the Department of Anesthesiology and holds a faculty position in the Center for Translational Pain Medicine (CTPM). He earned his Doctor of Medicine degree (1999) from Pavlov State Medical University, Saint Petersburg, Russia, and his PhD in Epidemiology (2010) from the University of South Carolina at Columbia.

In 2010, he joined the faculty at UNC Department of Anesthesiology as a Research Assistant Professor, where he studied genetics and non-genetic risk factors of chronic pain development after traumatic stressful events. Dr. Bortsov has published more than 30 peer-reviewed articles and presented his work at major and national and international conferences.

Dr. Bortsov joined the faulty at Duke University in 2016, where he continues his work on pain genomics. His major area of interest is application of novel computational and statistical methods to big genomic datasets to develop prediction models for disease risk and treatment outcomes. 


Andrea Gail Nackley

Associate Professor in Anesthesiology

Pain is a multidimensional sensory and emotional experience that is important for our survival, but once pain becomes chronic it is no longer beneficial and, instead, becomes a disorder in and of itself. Chronic pain remains one of our nation’s most significant healthcare problems due to a limited understanding of the underlying genetic and environmental factors. There are three main objectives of our lab’s research in this area: 

  1. To determine the factors that put some people, but not others, at risk for maladaptive chronic pain conditions. To achieve this objective, we study genetic, biological, and environmental factors associated with the initial onset of pain as well as its severity and duration. In addition, we are beginning to study factors associated with patient-centered outcomes, which may have the power to predict optimal management strategies for different individuals.
  2. To elucidate the mechanism(s) whereby genetic, biological, and environmental factors drive chronic pain. To achieve this objective, we integrate molecular genetics, animal models, and clinical epidemiologic measures in order to reveal pathogenic processes that are unique to as well as common across a particular condition or individual(s). This line of inquiry will provide novel targets for the development of individualized therapeutics for the management of chronic pain.
  3. To improve pharmacologic management of pain. To achieve this objective, we conduct pre-clinical studies to test the efficacy of new compounds and to optimize the efficacy of existing compounds in patient-relevant animal models.

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.

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