P2Y Signaling in Muscle Satellite Cells Contributes to Masseter Muscle Contraction-induced Pain.

The mechanism behind masseter muscle pain, a major symptom of temporomandibular disorder (TMD), has remained poorly understood. Previous report indicates that adenosine triphosphate (ATP) in involved in the masseter muscle pain development, but the role of its hydrolysis product, adenosine diphosphate (ADP), remains uncertain. Consequently, this study aimed to elucidate the ADP role derived from the sustained masseter muscle contraction in the masseter muscle pain development. The right masseter muscle was electrically stimulated daily by placing electrodes on the muscle fascia, inducing strong contraction and mechanical allodynia. This led to an increment of the ATP release from the masseter muscle and a consequent increase in ADP produced by the hydrolysis of ATP. The mechanical allodynia was suppressed by intramuscular P2Y receptor antagonism and tumor necrosis factor alpha (TNF-α) inhibition. Additionally, muscle satellite cells expressed P2Y receptors, and the increase in amount of TNF-α released from these cells due to sustained contraction of the masseter muscle was suppressed by intramuscular P2Y receptor antagonism. These findings suggest that sustained masseter muscle contraction increases ADP levels within the muscle; this ADP, produced by the hydrolysis of ATP via P2Y receptors, promotes the release of TNF-α. The TNF-α signaling is likely to enhance the excitability of primary neurons projecting to the masseter muscle, thereby inducing masseter muscle pain. Therefore, it is plausible that TNF-α-induced nociceptive neuronal hyperexcitability through enhanced ADP signaling via P2Y receptors in satellite cells could be a candidate for therapeutic intervention for masseter muscle pain, a major symptom of TMD. PERSPECTIVE: Sustained masseter muscle contraction in rats induced mechanical allodynia and increased the amount of ADP within the muscle. Muscle satellite cells expressed P2Y receptors, and ADP-P2Y signaling increased the TNF-α release from these cells. TNF-α signaling enhanced the primary neuronal excitability, inducing masseter muscle pain.