Journal of dental research
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Chronic pain, when not effectively treated, is a leading health and socioeconomic problem and has a harmful effect on all aspects of health-related quality of life. Therefore, understanding the molecular mechanism of how pain transitions from the acute to chronic phase is essential for developing effective novel analgesics. Accumulated evidence has shown that the transition from acute to chronic pain is determined by a cellular signaling switch called hyperalgesic priming, which occurs in primary nociceptive afferents. ⋯ Acid-sensing ion channel 3 (ASIC3) and transient receptor potential/vanilloid receptor subtype 1 (TRPV1) are 2 major acid sensors involved in the proton-induced hyperalgesic priming. The proton-induced hyperalgesic priming in muscle afferents can be prevented by a substance P-mediated signaling pathway. In this review, we summarize the factors that modulate hyperalgesic priming in both IB4-positive and IB4-negative nociceptors and discuss the role of acid signaling in inflammatory and noninflammatory pain as well as orofacial muscle pain.