Sensory Neuron-TRPV4 Modulates Temporomandibular Disorder Pain Via CGRP in Mice

Temporomandibular disorder (TMD) pain that involves inflammation and injury in the temporomandibular joint (TMJ) and/or masticatory muscle is the most common form of orofacial pain. We recently found that transient receptor potential vanilloid-4 (TRPV4) in trigeminal ganglion (TG) neurons is upregulated after TMJ inflammation, and TRPV4 coexpresses with calcitonin gene-related peptide (CGRP) in TMJ-innervating TG neurons. Here, we extended these findings to deter-mine the specific contribution of TRPV4 in TG neurons to TMD pain, and examine whether sensory neuron-TRPV4 modulates TMD pain via CGRP. In mouse models of TMJ inflammation or masseter mus-cle injury, sensory neuron-Trpv4 conditional knockout (cKO) mice displayed reduced pain. Coexpres-sion of TRPV4 and CGRP in TMJ-or masseter muscle-innervating TG neurons was increased after TMJ inflammation and masseter muscle injury, respectively. Activation of TRPV4-expressing TG neurons triggered secretion of CGRP, which was associated with increased levels of CGRP in peri-TMJ tissues, masseter muscle, spinal trigeminal nucleus, and plasma in both models. Local injection of CGRP into the TMJ or masseter muscle evoked acute pain in naieurove mice, while blockade of CGRP receptor attenu-ated pain in mouse models of TMD. These results suggest that TRPV4 in TG neurons contributes to TMD pain by potentiating CGRP secretion.Perspective: This study demonstrates that activation of TRPV4 in TG sensory neurons drives pain by potentiating the release of pain mediator CGRP in mouse models of TMJ inflammation and masse-ter muscle injury. Targeting TRPV4 and CGRP may be of clinical potential in alleviating TMD pain.(c) 2022 The Author(s). Published by Elsevier Inc. on behalf of United States Association for the Study of Pain, Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Automated summary

This study demonstrates that overactive TRPV4 neurons contribute to pain in temporomandibular disorder (TMD) by potentiating the release of CGRP. Targeting TRPV4 and CGRP may be of clinical potential in alleviating TMD pain.