title: Temporomandibular joint pain: a critical role for Trpv4 in the trigeminal ganglion.
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.
authors.affiliation: Department of Medicine, Duke University, Durham, NC, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Chen
authors.forename: Susan H
authors.initials: SH
authors.lastname: Williams
authors.forename: Amy L
authors.initials: AL
authors.lastname: McNulty
authors.forename: Ji Hee
authors.initials: JH
authors.lastname: Hong
authors.forename: Suk Hee
authors.initials: SH
authors.lastname: Lee
authors.forename: Nicole E
authors.initials: NE
authors.lastname: Rothfusz
authors.forename: Puja K
authors.initials: PK
authors.lastname: Parekh
authors.forename: Carlene
authors.initials: C
authors.lastname: Moore
authors.forename: Robert W
authors.initials: RW
authors.lastname: Gereau
authors.forename: Andrea B
authors.initials: AB
authors.lastname: Taylor
authors.forename: Fan
authors.initials: F
authors.lastname: Wang
authors.forename: Farshid
authors.initials: F
authors.lastname: Guilak
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Liedtke
mesh_terms: D000818:Animals; D001732:Bite Force; D048429:Cell Size / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D005620:Freund's Adjuvant / Q000633:toxicity; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006023:Glycoproteins / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D020930:MAP Kinase Kinase Kinases / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000378:metabolism; D012737:Sex Factors; D050916:TRPV Cation Channels / Q000172:deficiency / Q000378:metabolism*; D013706:Temporomandibular Joint Dysfunction Syndrome / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology; D013997:Time Factors; D014057:Tomography, X-Ray Computed; D012668:Trigeminal Ganglion / Q000378:metabolism* / Q000473:pathology
chemical_list: D006023:Glycoproteins; D009419:Nerve Tissue Proteins; D050916:TRPV Cation Channels; C486576:Trpv4 protein, mouse; C473590:isolectin B4-binding glycoprotein, mouse; D049452:Green Fluorescent Proteins; D005620:Freund's Adjuvant; D020930:MAP Kinase Kinase Kinases