The analgesic paracetamol metabolite AM404 acts peripherally to directly inhibit sodium channels

• 成果类型: Article
• 署名作者: Maatuf, Yossef; Kushnir, Yishai; Nemirovski, Alina; Ghantous, Mariana; Iskimov, Ariel; Binshtok, Alexander M.; Priel, Avi
• 署名单位: Hebrew University of Jerusalem; Hebrew University of Jerusalem; Hebrew University of Jerusalem; Hebrew University of Jerusalem
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8471
• DOI: 10.1073/pnas.2413811122
• 发表日期: 2025-06-10
• 关键词: voltage-gated sodium; acid amide hydrolase; local-anesthetics; molecular determinants; inflammatory pain; dependent block; acetaminophen; receptors; mechanisms; anandamide

摘要

Paracetamol has been used for decades to relieve mild-to-moderate pain. Its analgesic effect is mainly attributed to its metabolite, AM404, acting on cannabinoid receptors or TRPV1 channels in central nervous system (CNS) neurons. Here, we show that AM404 is produced by primary sensory neurons. It inhibits sodium current in nociceptor neurons, blocking action potential (AP) generation and reducing nocifensive behavior in na & iuml;ve and inflamed rats. We demonstrated that this analgesic effect of AM404 is mediated by its direct inhibition of nociceptive voltage-gated sodium channels (NaV) 1.8 and 1.7 via the local anesthetic binding site. The NaV1.8 and 1.7 inhibition was specific for AM404 and not observed with other metabolites of paracetamol. Our findings suggest that the analgesic effect of paracetamol is mediated mainly by direct AM404-induced inhibition of nociceptive sodium channels at the peripheral nociceptor neurons. Our findings lay a foundation for the potential development of AM404 as a selective local analgesic.