Linalyl acetate alleviates inflammatory pain via OLFR482 activation in the mouse anterior cingulate cortex

Introduction: Chronic pain severely impairs quality of life and causes heavy socioeconomic burdens worldwide. Linalyl acetate (LA), a major volatile terpenoid ester from essential oils, possesses potential analgesic effects. Methods: A CFA-induced chronic inflammatory pain mouse model was established. Behavioral tests, immunofluorescence, whole-cell patch-clamp recording, RNA-seq, molecular docking, molecular dynamics simulation and AAV-mediated gene knockdown were applied to explore the analgesic mechanism of LA. Results: Systemic LA administration significantly alleviated inflammatory pain and suppressed neuronal hyperexcitability in the anterior cingulate cortex (ACC). Transcriptome analysis revealed marked upregulation of Olfr482 in the ACC of CFA-treated mice, and molecular docking confirmed the interaction between LA and OLFR482. Olfr482 knockdown largely abolished the analgesic effect of LA. Discussion: LA relieves chronic inflammatory pain via an olfactory-independent mechanism by activating OLFR482 and reducing neuronal hyperexcitability in the ACC. LA is a promising candidate for developing novel analgesic drugs.