Mouse incision study links peripheral CB1 activation to reduced pain via ASIC3

Peripherally restricted analgesics devoid of central side effects are urgently needed for postoperative pain management. The cannabinoid type-1 receptor (CB1R) expressed on primary sensory neurons represents an attractive peripheral target, yet its specific role and mechanism in postoperative pain remain poorly defined. Here, by constructing a mouse model of plantar incision and combining with nociceptor-selective Cnr1 knockout and site-specific pharmacology, we revealed that activation of CB1R in primary sensory neurons robustly alleviates postoperative mechanical allodynia. Peripheral CB1R co-localizes and physically associates with the proton-sensing ion channel ASIC3 in CGRP+ peptidergic nociceptors in the dorsal root ganglion (DRG). The activation of CB1R signaling suppresses ASIC3-mediated inward currents and subsequent calcium transients, thereby reducing neuronal excitability and ERK1/2 phosphorylation in nociceptors. Consequently, targeted activation of CB1R or blockade of ASIC3 signaling significantly alleviated postoperative pain hypersensitivity and promoted pain resolution. This study elucidated a novel peripheral mechanism by which CB1R-ASIC3 physical and functional coupling in peptidergic nociceptors drives the resolution of incisional pain and provided a theoretical basis for the development of peripherally acting, non-opioid analgesic strategies.