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, and “therapy-refractoriness” of its pain, and its largely elusive pathogenesis. Against this background we sought to investigate 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 pro-nociceptive 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 WT mice. Similar effects were seen with systemic application of a specific TRPV4 inhibitor. TMJ-inflammation and mandibular bony changes were apparent after CFA injections, but remarkably independent of Trpv4 genotype. Intriguingly, as a result of TMJ-inflammation, WT mice exhibited significant up-regulation of TRPV4 and phosphorylated ERK in TMJ-innervating trigeminal sensory neurons, absent in Trpv4−/− mice. Mice with genetically-impaired MEK/ERK phosphorylation in neurons showed a similar resistance to reduction of bite-force as Trpv4−/− mice. Thus, TRPV4 is necessary for masticatory sensitization in TMJ-inflammation, and likely functions up-stream of MEK/ERK phosphorylation in trigeminal ganglion sensory neurons in-vivo. TRPV4 therefore represents a novel pro-nociceptive target in TMJ inflammation, and should be considered a target-of-interest in human TMJD.

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“…4E). Moreover, when a selective TRPV4 blocker, GSK205 (43,58,59), was used, WT 1°MK showed responses similar to those of Trpv4 −/− 1°MK (Fig. 4F).…”

“…S1D). Interestingly, whereas sensitization could be verified in control mice, it was absent in tam-treated iKO mice, as documented by labeling for phosphorylated ERK (pERK), a known marker of sensory neuron activation in response to inflammation and irritation (43,55) (Fig. 1E).…”

“…For pathological pain, it is relevant for inflammation-and nerve-damage-induced pain sensitization (41)(42)(43). Of note, Trpv4 −/− mice exhibit impaired skin-…”

Synergy between Piezo1 and Piezo2 channels confers high-strain mechanosensitivity to articular cartilage

“…For cartilage, knee and hip cartilage (n = 3 samples; each sample contained pooled tissues from three to four mice) was harvested and stored in RNA-later (Life Technologies) until RNA extraction. Total RNA was extracted for subsequent RT-qPCR, as described previously (73)(74)(75). Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was used as a housekeeping gene for normalization, and expression in lung was defined as "1."…”

TRPV channel-mediated calcium transients in nociceptor neurons are dispensable for avoidance behaviour

“…Of note, both subfamilies have been linked to pain signalling and are known to conduct Ca 2+ (refs 5, 15, 24, 25). Most of these channels show an increased selectivity for Ca 2+ over Na + (refs 1, 16, 26, 27, 28), presumably as a function of the selectivity filter.…”