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