Abstract / Summary
ABSTRACT Peripherally restricted analgesics devoid of central side effects are urgently needed for postoperative pain management. The cannabinoid type‐1 receptor (CB 1 R) 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 CB 1 R in primary sensory neurons robustly alleviates postoperative mechanical allodynia. Peripheral CB 1 R 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 CB 1 R signaling suppresses ASIC3‐mediated inward currents and subsequent calcium transients, thereby reducing neuronal excitability and ERK 1/2 phosphorylation in nociceptors. Consequently, targeted activation of CB 1 R or blockade of ASIC3 signaling significantly alleviated postoperative pain hypersensitivity and promoted pain resolution. This study elucidated a novel peripheral mechanism by which CB 1 R‐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.