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

Yong Chen, Susan H. Williams, Amy L. McNulty, Ji Hee Hong, Suk Hee Lee, Nicole E. Rothfusz, Puja K. Parekh, Carlene Moore, Robert W. Gereau IV, Andrea B. Taylor, Fan Wang, Farshid Guilak, Wolfgang Liedtke

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68 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)1295-1304
Number of pages10
JournalPain
Volume154
Issue number8
DOIs
StatePublished - Aug 2013

Keywords

  • Bite force
  • ERK activation
  • Temporomandibular joint disorder
  • Trigeminal ganglion
  • Trpv4

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    Chen, Y., Williams, S. H., McNulty, A. L., Hong, J. H., Lee, S. H., Rothfusz, N. E., Parekh, P. K., Moore, C., Gereau IV, R. W., Taylor, A. B., Wang, F., Guilak, F., & Liedtke, W. (2013). Temporomandibular joint pain: A critical role for Trpv4 in the trigeminal ganglion. Pain, 154(8), 1295-1304. https://doi.org/10.1016/j.pain.2013.04.004