Transient receptor potential cation channel, subfamily A, member 1 (TRPA1) is expressed in muscle afferents and direct activation of these receptors induces acute mechanical
hypersensitivity. However, the functional role of TRPA1 under pathological
muscle pain conditions and mechanisms by which TRPA1 mediate
muscle pain and
hyperalgesia are not clearly understood. Two rodent behavioral models validated to assess craniofacial
muscle pain conditions were used to study
ATP- and
N-Methyl-D-aspartate (
NMDA)-induced acute mechanical
hypersensitivity and complete
Freund's adjuvant (CFA)-induced persistent mechanical
hypersensitivity. The rat grimace scale (RGS) was utilized to assess
inflammation-induced spontaneous
muscle pain. Behavioral pharmacology experiments were performed to assess the effects of AP18, a selective TRPA1 antagonist under these conditions. TRPA1 expression levels in trigeminal ganglia (TG) were examined before and after CFA treatment in the rat masseter muscle. Pre-treatment of the muscle with AP18 dose-dependently blocked the development of acute mechanical
hypersensitivity induced by
NMDA and α,β-methylene
adenosine triphosphate (αβmeATP), a specific agonist for
NMDA and
P2X3 receptor, respectively. CFA-induced mechanical
hypersensitivity and spontaneous
muscle pain responses were significantly reversed by post-treatment of the muscle with AP18 when CFA effects were most prominent. CFA-induced
myositis was accompanied by significant up-regulation of TRPA1 expression in TG. Our findings showed that TRPA1 in muscle afferents plays an important role in the development of acute mechanical
hypersensitivity and in the maintenance of persistent
muscle pain and
hypersensitivity. Our data suggested that TRPA1 may serve as a downstream target of pro-nociceptive
ion channels, such as P2X3 and
NMDA receptors in masseter afferents, and that increased TRPA1 expression under inflammatory conditions may contribute to the maintenance of persistent
muscle pain and
mechanical hyperalgesia. Mechanistic studies elucidating transcriptional or post-translational regulation of TRPA1 expression under pathological
pain conditions should provide important basic information to further advance the treatment of craniofacial
muscle pain conditions.