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

Chen, Yonga; Williams, Susan H.b,1; McNulty, Amy L.c,1; Hong, Ji Heea,d; Lee, Suk Heea; Rothfusz, Nicole E.c; Parekh, Puja K.a; Moore, Carlenea; Gereau, Robert W. IVh; Taylor, Andrea B.e,f; Wang, Fang; Guilak, Farshidc; Liedtke, Wolfganga,d,i,*

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doi: 10.1016/j.pain.2013.04.004
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Trpv4 is critical for sensitization of trigeminal ganglion sensory neurons that innervate the inflamed temporomandibular joint, as shown by using bite-force measurements in the laboratory mouse to measure nocifensive behavior.

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.

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

aDepartment of Medicine, Duke University, Durham, NC, USA

bHeritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA

cDepartment of Orthopaedic Surgery, Duke University, Durham, NC, USA

dDuke Clinics for Pain and Palliative Care, Durham, NC, USA

eDepartment of Community and Family Medicine, Duke University, Durham, NC, USA

fDepartment of Evolutionary Anthropology, Duke University, Durham, NC, USA

gDepartment of Cell Biology, Duke University, Durham, NC, USA

hDepartment of Anesthesiology, Washington University, St. Louis, MO, USA

iDuke Center for Neuroengineering, Durham, NC, USA

*Corresponding author. Address: Duke University Medical Center, Department of Medicine/Division of Neurology; Duke Clinics for Pain and Palliative Care, Durham, NC 27710, USA. Tel.: +1 919 6840058.

1These authors contributed equally to this article.

E-mail address: wolfgang@neuro.duke.edu

Submitted December 19, 2012; revised March 7, 2013; accepted April 1, 2013.

© 2013 Lippincott Williams & Wilkins, Inc.
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