Peripheral glutamate receptor and transient receptor potential channel mechanisms of craniofacial muscle pain.

Abstract

Temporomandibular joint disorder is a common chronic craniofacial pain condition, often involving persistent, widespread craniofacial muscle pain. Although the etiology of chronic muscle pain is not well known, sufficient clinical and preclinical information supports a contribution of trigeminal nociceptors to craniofacial muscle pain processing under various experimental and pathological conditions. Here, we review cellular and molecular mechanisms underlying sensitization of muscle nociceptive afferents. In particular, we summarize findings on pronociceptive roles of peripheral glutamate in humans, and we discuss mechanistic contributions of glutamate receptors, including N-methyl-D-aspartate receptors and metabotropic glutamate receptors, which have considerably increased our understanding of peripheral mechanisms of craniofacial muscle pain. Several members of the transient receptor potential (TRP) family, such as transient receptor potential vanilloid 1 (TRPV1) and transient receptor potential ankyrin 1, also play essential roles in the development of spontaneous pain and mechanical hypersensitivity in craniofacial muscles. Furthermore, glutamate receptors and TRP channels functionally and bi-directionally interact to modulate trigeminal nociceptors. Activation of glutamate receptors invokes protein kinase C, which leads to the phosphorylation of TRPV1. Sensitization of TRPV1 by inflammatory mediators and glutamate receptors in combination with endogenous ligands contributes to masseter hyperalgesia. The distinct intracellular signaling pathways through which both receptor systems engage and specific molecular regions of TRPV1 are offered as novel targets for the development of mechanism-based treatment strategies for myogenous craniofacial pain conditions.