TMEM100, a regulator of TRPV1-TRPA1 interaction, contributes to temporomandibular disorder pain.

There is an unmet need to identify new therapeutic targets for temporomandibular disorder (TMD) pain because current treatments are limited and unsatisfactory. TMEM100, a two-transmembrane protein, was recently identified as a regulator to weaken the TRPA1-TRPV1 physical association, resulting in disinhibition of TRPA1 activity in sensory neurons. Recent studies have also shown that Tmem100, Trpa1, and Trpv1 mRNAs were upregulated in trigeminal ganglion (TG) after inflammation of the temporomandibular joint (TMJ) associated tissues. These findings raise a critical question regarding whether TMEM100 in TG neurons is involved in TMD pain via regulating the TRPA1-TRPV1 functional interaction. Here, using two mouse models of TMD pain induced by TMJ inflammation or masseter muscle injury, we found that global knockout or systemic inhibition of TRPA1 and TRPV1 attenuated pain. In line with their increased genes, mice exhibited significant upregulation of TMEM100, TRPA1, and TRPV1 at the protein levels in TG neurons after TMD pain. Importantly, TMEM100 co-expressed with TRPA1 and TRPV1 in TG neurons-innervating the TMJ and masseter muscle and their co-expression was increased after TMD pain. Moreover, the enhanced activity of TRPA1 in TG neurons evoked by TMJ inflammation or masseter muscle injury was suppressed by inhibition of TMEM100. Selective deletion of Tmem100 in TG neurons or local administration of TMEM100 inhibitor into the TMJ or masseter muscle attenuated TMD pain. Together, these results suggest that TMEM100 in TG neurons contributes to TMD pain by regulating TRPA1 activity within the TRPA1-TRPV1 complex. TMEM100 therefore represents a potential novel target-of-interest for TMD pain.

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 determine 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 muscle injury, sensory neuron-Trpv4 conditional knockout (cKO) mice displayed reduced pain. Coexpression 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 naïve mice, while blockade of CGRP receptor attenuated 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 masseter muscle injury. Targeting TRPV4 and CGRP may be of clinical potential in alleviating TMD pain.

Transient Receptor Potential (TRP) Ion Channels in Orofacial Pain.

Orofacial pain, including temporomandibular joint disorders pain, trigeminal neuralgia, dental pain, and debilitating headaches, affects millions of Americans each year with significant population health impact. Despite the existence of a large body of information on the subject, the molecular underpinnings of orofacial pain remain elusive. Two decades of research has identified that transient receptor potential (TRP) ion channels play a crucial role in pathological pain. A number of TRP ion channels are clearly expressed in the trigeminal sensory system and have critical functions in the transduction and pathogenesis of orofacial pain. Although there are many similarities, the orofacial sensory system shows some distinct peripheral and central pain processing and different sensitivities from the spinal sensory system. Relative to the extensive review on TRPs in spinally-mediated pain, the summary of TRPs in trigeminally-mediated pain has not been well-documented. This review focuses on the current experimental evidence involving TRP ion channels, particularly TRPV1, TRPA1, TRPV4, and TRPM8 in orofacial pain, and discusses their possible cellular and molecular mechanisms.