Cannabinoid CB1 Receptor in Nociceptors Mediates Postoperative Analgesia via ASIC3 Inhibition

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.