131: Cannabinoid CB1 receptor in nociceptors mediates postoperative analgesia via ASIC3 inhibition

Topic: Basic Science
Subtopic: Pain category (ICD-11), Acute postsurgical pain, , , , , , , , , , Pharmacological interventions, Electrophysiology, Behavioral studies

Background and Aims: Postoperative pain remains a common yet frequently inadequately managed clinical challenge. The cannabinoid type-1 receptor (CB1R) is considered a promising target for the pain treatment. However, the specific role and mechanism of peripheral CB1Rs in postoperative pain remain elusive.

Methods: Using a plantar incision mouse model, we investigated the contribution of CB1Rs in primary sensory neurons to postoperative pain through pharmacological interventions, conditional transgenic strategies, and behavioral phenotyping. The mechanistic underpinnings were elucidated using RNAscope in situ hybridization, immunofluorescence, RNA sequencing, co-immunoprecipitation, electrophysiology, and calcium imaging.

Results: We delineate a novel peripheral analgesic pathway wherein CB1R activation on sensory neurons alleviates postoperative pain via specific inhibition of acid-sensing ion channel 3 (ASIC3). Site-specific activation of peripheral CB1R robustly attenuated incision-induced mechanical hypersensitivity. Concordantly, nociceptor-specific CB1R knockout induced tactile allodynia. Incision provoked activation of ASIC3+ neurons and upregulated ASIC3 expression in dorsal root ganglia, which was functionally suppressed by CB1R activation. Mechanistically, CB1R co-localizes and physically interacts with ASIC3 in CGRP+ peptidergic nociceptors. CB1R signaling suppressed ASIC3-mediated currents and subsequent calcium influx, leading to reduced neuronal excitability and diminished phosphorylation of ERK1/2. Consequently,

Conclusions: Our findings establish a critical peripheral mechanism wherein CB1R activation produces analgesia in postsurgical pain by functionally inhibiting ASIC3 channels in nociceptors. This CB1R-ASIC3 interaction defines a previously unrecognized targetable pathway for improving postoperative pain management.

References: No

Presenting Author: Xu Kangtai
Submitting Author: Xu Kangtai

Senior Author: Wang zilong

IASP 2026 Global Year theme of Neuropathic Pain: Yes

• Wang Zilong: Professor - Southern University of Science and Technology