Maatuf Yossef, Kushnir Yishai, Nemirovski Alina, Ghantous Mariana, Iskimov Ariel, Binshtok Alexander M, Priel Avi
The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel.
Department of Medical Neurobiology, Institute for Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112001, Israel.
Proc Natl Acad Sci U S A. 2025 Jun 10;122(23):e2413811122. doi: 10.1073/pnas.2413811122. Epub 2025 Jun 4.
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 naïve and inflamed rats. We demonstrated that this analgesic effect of AM404 is mediated by its direct inhibition of nociceptive voltage-gated sodium channels (Na) 1.8 and 1.7 via the local anesthetic binding site. The Na1.8 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.
几十年来，对乙酰氨基酚一直被用于缓解轻至中度疼痛。其镇痛作用主要归因于其代谢产物AM404作用于中枢神经系统（CNS）神经元中的大麻素受体或TRPV1通道。在此，我们表明AM404由初级感觉神经元产生。它抑制伤害性感受器神经元中的钠电流，阻断动作电位（AP）的产生，并减少未受伤和发炎大鼠的伤害防御行为。我们证明，AM404的这种镇痛作用是通过其经由局部麻醉药结合位点直接抑制伤害性电压门控钠通道（Na）1.8和1.7来介导的。Na1.8和1.7的抑制对AM404具有特异性，在对乙酰氨基酚的其他代谢产物中未观察到。我们的研究结果表明，对乙酰氨基酚的镇痛作用主要是由AM404在外周伤害性感受器神经元处直接诱导的对伤害性钠通道的抑制所介导的。我们的研究结果为AM404作为一种选择性局部镇痛药的潜在开发奠定了基础。
