ArticleScientific reports2017
Reactive metabolites of acetaminophen activate and sensitize the capsaicin receptor TRPV1.
Article in Scientific reports, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 36 citations in OpenAlex.
- Antipruritic Effect of Topical Acetaminophen Gel in Histaminergic and Non-histaminergic Itch Provocation: A Double-blind, Vehicle-controlled Pilot Study.Acta dermato-venereologica · 2022Trial
- Efficacy of N-acetylcysteine in enhancing paracetamol's analgesic effect and inhibiting hepatotoxicity: a preclinical mouse model.Pain reports · 2026Article
- TRP Channels from Sensory Coding to Physiology.Metabolites · 2025Review
- Paracetamol: the potential therapeutic pathways defining its clinical use.Inflammopharmacology · 2025Review
- Epidural injection of varying doses of capsaicin alleviates inflammatory pain in rats via the TLR4/AKT/NF-κB pathway.Inflammopharmacology · 2025Article
- 'Pain free if I ever will be': lived experience of workers seeking care for pain attributed to musculoskeletal disorders.BMC musculoskeletal disorders · 2024Article
- The interaction of TRPV1 and lipids: Insights into lipid metabolism.Frontiers in physiology · 2022Review
- Potential roles of gut microbiota and microbial metabolites in chronic inflammatory pain and the mechanisms of therapy drugs.Therapeutic advances in chronic disease · 2022Review
- N-acetylcysteine dose-dependently improves the analgesic effect of acetaminophen on the rat hot plate test.BMC pharmacology & toxicology · 2021Article
- Efficacy of broccoli and glucoraphanin in COVID-19: From hypothesis to proof-of-concept with three experimental clinical cases.The World Allergy Organization journal · 2021Review
- Potential Interplay between Nrf2, TRPA1, and TRPV1 in Nutrients for the Control of COVID-19.International archives of allergy and immunology · 2021Review
- Reactive dicarbonyl compounds cause Calcitonin Gene-Related Peptide release and synergize with inflammatory conditions in mouse skin and peritoneum.The Journal of biological chemistry · 2020Article
- Acetaminophen (Paracetamol) Metabolites Induce Vasodilation and Hypotension by Activating Kv7 Potassium Channels Directly and Indirectly.Arteriosclerosis, thrombosis, and vascular biology · 2020Article
- Oxidation of methionine residues activates the high-threshold heat-sensitive ion channel TRPV2.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Capsaicin: Physicochemical properties, cutaneous reactions and potential applications in painful and inflammatory conditions.Experimental and therapeutic medicine · 2019Review
- Is TRPA1International journal of molecular sciences · 2019Review
- Article
- New approaches and challenges to targeting the endocannabinoid system.Nature reviews. Drug discovery · 2018Review
- An insight into paracetamol and its metabolites using molecular docking and molecular dynamics simulation.Journal of molecular modeling · 2018Article
- Nanoparticles-Mediated Modulation of TRP Channels: Advances and Therapeutic Potential.Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnologyReview
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The irritant receptor TRPA1 was suggested to mediate analgesic, antipyretic but also pro-inflammatory effects of the non-opioid analgesic acetaminophen, presumably due to channel activation by the reactive metabolites parabenzoquinone (pBQ) and N-acetyl-parabenzoquinonimine (NAPQI). Here we explored the effects of these metabolites on the capsaicin receptor TRPV1, another redox-sensitive ion channel expressed in sensory neurons. Both pBQ and NAPQI, but not acetaminophen irreversibly activated and sensitized recombinant human and rodent TRPV1 channels expressed in HEK 293 cells. The reducing agents dithiothreitol and N-acetylcysteine abolished these effects when co-applied with the metabolites, and both pBQ and NAPQI failed to gate TRPV1 following substitution of the intracellular cysteines 158, 391 and 767. NAPQI evoked a TRPV1-dependent increase in intracellular calcium and a potentiation of heat-evoked currents in mouse spinal sensory neurons. Although TRPV1 is expressed in mouse hepatocytes, inhibition of TRPV1 did not alleviate acetaminophen-induced hepatotoxicity. Finally, intracutaneously applied NAPQI evoked burning pain and neurogenic inflammation in human volunteers. Our data demonstrate that pBQ and NAQPI activate and sensitize TRPV1 by interacting with intracellular cysteines. While TRPV1 does not seem to mediate acetaminophen-induced hepatotoxicity, our data identify TRPV1 as a target of acetaminophen with a potential relevance for acetaminophen-induced analgesia, antipyresia and inflammation.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.