Opioid receptors and acetaminophen (paracetamol)

Raffa, Robert B.; Walker, Ellen A.; Sterious, Steven N.

doi:10.1016/j.ejphar.2004.08.055

Cited by 49Pain Mechanisms and TreatmentsNeuropeptides and Animal PhysiologyPain Management and Opioid Use

The DOI matches its Crossref record; 9 of the 9 references it cites were found in a registry or an index.

Opioid receptors and acetaminophen (paracetamol)

Raffa, Robert B., Walker, Ellen A., Sterious, Steven N.·2004·European Journal of Pharmacology

DOI 10.1016/j.ejphar.2004.08.055

Open this paper in CoChat — free account

Abstract

We report that the acetaminophen (paracetamol)-induced spinal (intrathecal, i.t.)/supraspinal (intracerebroventricular, i.c.v.) site/site antinociceptive 'self-synergy' in mice is attenuated by the opioid receptor subtype selective antagonists beta-funaltrexamine hydrochloride (beta-FNA; mu), naltrindole (delta), and nor-binaltorphine hydrochloride (nor-BNI; kappa). These findings further implicate endogenous opioids (viz., endorphins, enkephalins, and dynorphins) and their pathways as contributors to the central antinociceptive action of acetaminophen.

Integrity signals

Registry

Crossref · 10.1016/j.ejphar.2004.08.055

Cites

9 of 9 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

We couldn’t retrieve this paper’s full text, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

The analgesic mechanism of action of paracetamol is multidimensional and involves several pathways within the central nervous system, such as the endocannabinoid, serotonergic, and nitric oxide pathways.
“however, it is now evident that the analgesic MoA of paracetamol is multidimensional and involves several pathways within the central nervous system (CNS), such as the endocannabinoid, serotonergic, and nitric oxide pathways9–14 or for some authors opioid pathways.15”
From An Updated Review on the Metabolite (AM404)-Mediated Central Mechanism of Action of Paracetamol (Acetaminophen): Experimental Evidence and Potential Clinical Impact (2023) · cites this paper as [15]

THE ABDOMINAL CONSTRICTION RESPONSE AND ITS SUPPRESSION BY ANALGESIC DRUGS IN THE MOUSE
COLLIER, H. O. J., Dinneen, L. C., Johnson, C. A., & Schneider, C. (1968) · British Journal of Pharmacology and Chemotherapy · doi:10.1111/j.1476-5381.1968.tb00973.x · Cited by 1,228
Acetaminophen distribution in the rat central nervous system
Courade, J., Besse, D., Delchambre, C., Hanoun, N., Hamon, M., Eschalier, A., Caussade, F., & Cloarec, A. (2001) · Life Sciences · doi:10.1016/s0024-3205(01)01228-0 · Cited by 92
Central antinociceptive effects of non‐steroidal anti‐inflammatory drugs and paracetarmol
Björkman, R. (1995) · Acta Anaesthesiologica Scandinavica · doi:10.1111/j.1399-6576.1995.tb04249.x · Cited by 92
Discovery of “Self-Synergistic” Spinal/Supraspinal Antinociception Produced by Acetaminophen (Paracetamol)
Raffa, R. B., Stone, D. J., & Tallarida, R. J. (2000) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(24)38900-1 · Cited by 90
Self-citation
Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists, 1994: NSAID: AN UPDATE ON THEIR ANALGESIC EFFECTS
Walker, J. S. (1995) · Clinical and Experimental Pharmacology and Physiology · doi:10.1111/j.1440-1681.1995.tb01950.x · Cited by 68
Lack of binding of acetaminophen to 5-HT receptor or uptake sites (or eleven other binding/uptake assays)
Raffa, R. B., & Codd, E. E. (1996) · Life Sciences · doi:10.1016/0024-3205(96)00273-1 · Cited by 48
Self-citation
Cyclooxygenases 1, 2, and 3 and the Production of Prostaglandin I2: Investigating the Activities of Acetaminophen and Cyclooxygenase-2-Selective Inhibitors in Rat Tissues
Warner, T. D., Vojnovic, I., Giuliano, F., Jiménez, R., Bishop‐Bailey, D., & Mitchell, J. A. (2004) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.103.063875 · Cited by 48
Unexpected and pronounced antinociceptive synergy between spinal acetaminophen (paracetamol) and phentolamine
Raffa, R. B., Stone, D. J., & Tallarida, R. J. (2001) · European Journal of Pharmacology · doi:10.1016/s0014-2999(01)00722-1 · Cited by 22
Self-citation
Fifty years of muscle relaxants
Bevan, D. R. (1995) · Acta Anaesthesiologica Scandinavica · doi:10.1111/j.1399-6576.1995.tb04300.x · Cited by 13

Flagged first, then by citations

Sorted by citations

The modern pharmacology of paracetamol: therapeutic actions, mechanism of action, metabolism, toxicity and recent pharmacological findings
Graham, G. G., Davies, M. J., Day, R. O., Mohamudally, A., & Scott, K. F. (2013) · Inflammopharmacology · doi:10.1007/s10787-013-0172-x · Cited by 671
Analgesic Effect of Acetaminophen: A Review of Known and Novel Mechanisms of Action
Ohashi, N., & Kohno, T. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.580289 · Cited by 223
Synergism between paracetamol and nonsteroidal anti-inflammatory drugs in experimental acute pain
Miranda, H. F., Puig, M. M., Prieto, J. C., & Pinardi, G. (2006) · Pain · doi:10.1016/j.pain.2005.11.012 · Cited by 184
Acetaminophen Reinforces Descending Inhibitory Pain Pathways
Pickering, G., Estève, V, Loriot, M.-A., Eschalier, A., & Dubray, C. (2008) · Clinical Pharmacology & Therapeutics · doi:10.1038/sj.clpt.6100403 · Cited by 168
What do we (not) know about how paracetamol (acetaminophen) works?: Paracetamol’s analgesic mechanism?
Toussaint, K., Yang, X. C., Zielinski, M. A., Reigle, K. L., Sacavage, S. D., Nagar, S., & Raffa, R. B. (2010) · Journal of Clinical Pharmacy and Therapeutics · doi:10.1111/j.1365-2710.2009.01143.x · Cited by 135
Self-citation
Randomized study of tramadol/acetaminophen versus placebo in painful diabetic peripheral neuropathy
Freeman, R. L., Raskin, P., Hewitt, D., Vorsanger, G., Jordan, D. M., Xiang, J. X., Rosenthal, N. R., & for the CAPSS-237 Study Group (2006) · Current Medical Research and Opinion · doi:10.1185/030079906x162674 · Cited by 111
Endogenous opiates and behavior: 2004
Bodnar, R. J., & Klein, G. E. (2005) · Peptides · doi:10.1016/j.peptides.2005.06.010 · Cited by 86
An Updated Review on the Metabolite (AM404)-Mediated Central Mechanism of Action of Paracetamol (Acetaminophen): Experimental Evidence and Potential Clinical Impact
Mallet, C., Desmeules, J., Pegahi, R., & Eschalier, A. (2023) · Journal of Pain Research · doi:10.2147/jpr.s393809 · Cited by 83
“Historically, it was believed that the paracetamol-mediated analgesia stems solely from its cyclooxygenase (COX)dependent inhibitory effect on prostaglandin (PG) synthesis(8); however, it is now evident that the analgesic MoA of paracetamol is multidimensional and involves several pathways within the central nervous s…”
Background
The effects of preoperative intravenous acetaminophen in patients undergoing abdominal hysterectomy
Moon, Y. E., Lee, Y., Lee, J., & Moon, D. E. (2011) · Archives of Gynecology and Obstetrics · doi:10.1007/s00404-011-1860-7 · Cited by 73
Different mechanisms underlie the analgesic actions of paracetamol and dipyrone in a rat model of inflammatory pain
Rezende, R. M., França, D. S., Menezes, G. B., dos Reis, W. G. P., Bakhle, Y. S., & Francischi, J. N. (2007) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0707630 · Cited by 72
Ibuprofen: Pharmacology, Therapeutics and Side Effects
Rainsford, K. D. (2012) · Springer eBooks · doi:10.1007/978-3-0348-0496-7 · Cited by 63
Paracetamol in critical illness: a review
Jefferies, S., Saxena, M. K., & Young, P. J. (2012) · Critical Care and Resuscitation · doi:10.1016/s1441-2772(23)01817-3 · Cited by 41
Developmental exposure to paracetamol causes biochemical alterations in medulla oblongata
Blecharz‐Klin, K., Joniec‐Maciejak, I., Jawna, K., Pyrzanowska, J., Piechal, A., Wawer, A., & Widy‐Tyszkiewicz, E. (2015) · Environmental Toxicology and Pharmacology · doi:10.1016/j.etap.2015.07.001 · Cited by 37
Analgesic action of acetaminophen in symptomatic osteoarthritis of the knee
Shen, H., Sprott, H., Aeschlimann, A. G., Gay, R. E., Michel, B. A., Gay, S., & Sprott, H. (2006) · Lara D. Veeken · doi:10.1093/rheumatology/kei253 · Cited by 35
The analgesic effect of decursinol
Seo, Y., Kwon, M., Park, S.-H., Sim, Y., Choi, S., Huh, G.-H., Lee, J.-K., & Suh, H. (2009) · Archives of Pharmacal Research · doi:10.1007/s12272-009-1617-z · Cited by 31
Paracetamol—The outcome on neurotransmission and spatial learning in rats
Blecharz‐Klin, K., Piechal, A., Pyrzanowska, J., Joniec‐Maciejak, I., Kiliszek, P., & Widy‐Tyszkiewicz, E. (2013) · Behavioural Brain Research · doi:10.1016/j.bbr.2013.07.008 · Cited by 31
Paracetamol impairs the profile of amino acids in the rat brain
Blecharz‐Klin, K., Joniec‐Maciejak, I., Piechal, A., Pyrzanowska, J., Wawer, A., & Widy‐Tyszkiewicz, E. (2013) · Environmental Toxicology and Pharmacology · doi:10.1016/j.etap.2013.11.004 · Cited by 29
Effect of prenatal and early life paracetamol exposure on the level of neurotransmitters in rats—Focus on the spinal cord
Blecharz‐Klin, K., Joniec‐Maciejak, I., Jawna, K., Pyrzanowska, J., Piechal, A., Wawer, A., & Widy‐Tyszkiewicz, E. (2015) · International Journal of Developmental Neuroscience · doi:10.1016/j.ijdevneu.2015.09.002 · Cited by 29
Continuous Multimechanistic Postoperative Analgesia: A Rationale for Transitioning from Intravenous Acetaminophen and Opioids to Oral Formulations
Pergolizzi, J. V., Raffa, R. B., Tallarida, R. J., Taylor, R., & Labhsetwar, S. A. (2011) · Pain Practice · doi:10.1111/j.1533-2500.2011.00476.x · Cited by 28
Self-citation
Contributions of peripheral, spinal, and supraspinal actions to analgesia
Sawynok, J., & Liu, J. (2014) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2014.04.006 · Cited by 26
Involvement of 5-HT1A/1B receptors in the antinociceptive effect of paracetamol in the rat formalin test
Roca-Vinardell, A., Berrocoso, E., Llorca-Torralba, M., Garcia-Partida, J. A., Gibert‐Rahola, J., & Micó, J. A. (2018) · Neurobiology of Pain · doi:10.1016/j.ynpai.2018.01.004 · Cited by 20
Effect of drugs modulating serotonergic system on the analgesic action of paracetamol in mice
Karandikar, Y., Belsare, P., & Panditrao, A. (2016) · Indian Journal of Pharmacology · doi:10.4103/0253-7613.182874 · Cited by 18
Preventive Analgesia, Hemodynamic Stability, and Pain in Vitreoretinal Surgery
Stasiowski, M. J., Pluta, A., Lyssek-Boroń, A., Kawka, M., Krawczyk, L., Niewiadomska, E., Dobrowolski, D., Ręjdak, R., Król, S., Żak, J., et al. (2021) · Medicina · doi:10.3390/medicina57030262 · Cited by 15
Paracetamol: the potential therapeutic pathways defining its clinical use
Al-Kuraishy, H. M., Al-Gareeb, A. I., Albuhadily, A. K., Abdelmaksoud, E. M., Shokr, M. M., Alexiou, A. T., Papadakis, M., & Batiha, G. E. (2025) · Inflammopharmacology · doi:10.1007/s10787-025-01779-x · Cited by 16
Paracetamol and opioid pathways: a pilot randomized clinical trial
Pickering, G. P., Moustafa, F., Desbrandes, S., Cardot, J.-M., Roux, D., & Dubray, C. (2011) · Fundamental and Clinical Pharmacology · doi:10.1111/j.1472-8206.2011.01010.x · Cited by 14
The differential effects of acetaminophen on lipopolysaccharide induced hyperalgesia in various mouse pain models
SEO, Y., Kwon, M., CHOI, H., Choi, S. M., NAM, J., Lee, J., JUNG, J., PARK, S., & Suh, H. W. (2008) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2008.06.020 · Cited by 11
Patient-controlled Analgesia With Propacetamol-Fentanyl Mixture for Prevention of Postoperative Nausea and Vomiting in High-risk Patients Undergoing Spine Surgery: A Randomized Controlled Trial
Kim, E. J., Shim, J., Soh, S., Song, J. W., Lee, S. R., & Kwak, Y. L. (2015) · Journal of Neurosurgical Anesthesiology · doi:10.1097/ana.0000000000000252 · Cited by 11
Voluntary intake of paracetamol-enriched drinking water and its influence on the success of embryo transfer in mice
Fleischmann, T., Arras, M., Sauer, M., Saleh, L., Rülicke, T., & Jirkof, P. (2016) · Research in Veterinary Science · doi:10.1016/j.rvsc.2016.12.005 · Cited by 12
The investigation of possible roles of central 5-HT7 receptors in antipyretic effect mechanism of paracetamol in LPS-induced hyperthermia model of mice
Köse, D., Çadırcı, E., Halıcı, Z., Sirin, B., & Dinçer, B. (2019) · Inflammopharmacology · doi:10.1007/s10787-019-00617-1 · Cited by 10
Effects of naloxone and flumazenil on antinociceptive action of acetaminophen in rats
Madenoğlu, H., Kaçmaz, M., Aksu, R., Biçer, C., Yaba, G., Yıldız, K., Doğru, K., & Boyacı, A. (2010) · Current Therapeutic Research · doi:10.1016/j.curtheres.2010.03.001 · Cited by 7
Acetaminophen: Ancient drug with a novel analgesic mechanism of action
Irinmwinuwa, E. O., Unekwe, P. C., Egba, E. U., Metu, E. C., & Cherech, N. C. (2022) · World Journal of Advanced Research and Reviews · doi:10.30574/wjarr.2022.16.1.1046 · Cited by 7
Synergistic Interaction Between Fentanyl and a Tramadol:Paracetamol Combination on the Inhibition of Nociception in Mice
Fernández‐Dueñas, V., Poveda, R., Sánchez, S., & Ciruela, F. (2012) · Journal of Pharmacological Sciences · doi:10.1254/jphs.11161sc · Cited by 7
Postoperative pain management using an intravenous combination of ibuprofen and acetaminophen compared with acetaminophen alone after thyroidectomy: A prospective randomized controlled trial
Park, J., Lee, D. K., Kim, J. E., Bae, J. S., Kim, J., & Moon, Y. E. (2024) · Head & Neck · doi:10.1002/hed.27701 · Cited by 6
Adverse Events Following Vitreoretinal Surgeries Under Adequacy of Anesthesia with Combined Paracetamol/Metamizole—Additional Report
Marczak, K., Stasiowski, M. J., Lyssek-Boroń, A., & Zmarzły, N. (2025) · Journal of Clinical Medicine · doi:10.3390/jcm14176261 · Cited by 5
Evaluating the Efficacy of Pre-Emptive Peribulbar Blocks with Different Local Anesthetics or Paracetamol Using the Adequacy of Anesthesia Guidance for Vitreoretinal Surgeries: A Preliminary Report
Stasiowski, M. J., Lyssek-Boroń, A., Krysik, K., Majer, D., Zmarzły, N., & Grabarek, B. O. (2024) · Biomedicines · doi:10.3390/biomedicines12102303 · Cited by 4
Adequacy of Anesthesia Guidance Combined with Peribulbar Blocks Shows Potential Benefit in High-Risk PONV Patients Undergoing Vitreoretinal Surgeries
Majer, D., Stasiowski, M. J., Lyssek-Boroń, A., Krysik, K., & Zmarzły, N. (2025) · Journal of Clinical Medicine · doi:10.3390/jcm14228081 · Cited by 2
Drug Derivatives and Formulations
Rainsford, K. D. (2012) · Springer eBooks · doi:10.1007/978-3-0348-0496-7_5 · Cited by 2
Preventive Effect of Intrathecal Paracetamol on Spinal Cord Injury in Rats
Şahin, M., Sayar, İ., Peker, K., Güllü, H., & Yıldız, H. (2014) · Iranian Red Crescent Medical Journal · doi:10.5812/ircmj.22151 · Cited by 2
ACETAMINOPHEN
Smith, H. S., & Royal, M. A. (2009) · Elsevier eBooks · doi:10.1016/b978-1-4160-4836-7.00058-4 · Cited by 2
Risk Factors for Intolerable Postoperative Pain After Vitreoretinal Surgery Under AoA-Guided General Anesthesia with Intravenous COX-3 Inhibitors: A Post Hoc Analysis
Stasiowski, M. J., Marczak, K., Lyssek-Boroń, A., & Zmarzły, N. (2025) · Pharmaceuticals · doi:10.3390/ph18121826 · Cited by 1
Paroxetine Augments while Naloxone Abolishes the Analgesic Effect of Paracetamol in Acute Nociceptive Pain in Mice
Abdalla, M. R., Malki, W. A., & Ahmed, M. (2013) · Pharmacology & Pharmacy · doi:10.4236/pp.2013.44057 · Cited by 1
The efficacy and safety of Acetaminophen for pain reliefPreprint
Al-Kuraishy, H. M., Al-Gareeb, A. I., Albuhadily, A. K., Abdelmaksoud, E. M., Alexiou, A. T., Papadakis, M., & Batiha, G. E. (2024) · doi:10.22541/au.171361353.33776062/v1 · Cited by 1
Synergistic interaction between acetaminophen and carbamazepine in mice.
Chiţac, L. C., Chiriac, S. I. B., Neamţu, M., Bulea, D., & Bild, V. (2014) · DOAJ (DOAJ: Directory of Open Access Journals)
Analgesia for acute pain
van Rensburg, R. (2016) · South African Family Practice · doi:10.4102/safp.v58i1.4435
INTERACCION ANALGESICA DE PARACETAMOL Y NIMESULIDA EN DOLOR EXPERIMENTAL TERMICO AGUDO
Odontología, F. D. (2006)
Effect of Interacting Nonsteroidal Anti-Inflammatory Agents (NSAIDs) and Opioids on Mood
Manchia, M., Pinna, M., & Denovan‐Wright, E. M. (2016) · Elsevier eBooks · doi:10.1016/b978-0-12-800634-4.00011-1
Kronik bel ve boyun ağrılı hastada temel analjezikler
Eroğlu, M., & Eyigör, S. (2017) · Türk Ortopedi ve Travmatoloji Birliği Derneği · doi:10.14292/totbid.dergisi.2017.20
Journal of Experimental and Clinical Medicine Deneysel ve Klinik Tip Dergisi
Türkyılmaz, A., & Dali, G. C. A. (2012)
TOXICIDADE IN VITRO E IN VIVO DO ORTOBENZAMOL, ANÁLOGO DO PARACETAMOL.
Melo, L. T. M., & de Queiroz, D. (2014)

Discovery of “Self-Synergistic” Spinal/Supraspinal Antinociception Produced by Acetaminophen (Paracetamol)
Raffa, R. B., Stone, D. J., & Tallarida, R. J. (2000) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(24)38900-1 · Cited by 90
Self-citation
EFFECT OF NONSELECTIVE AND SELECTIVE OPIOID RECEPTORS ANTAGONISTS ON ANTINOCICEPTIVE ACTION OF ACETAMINOPHEN [PART III]
Pharmacol, P. J., & Bujalska, M. (2013)
5-HT receptor subtypes involved in the spinal antinociceptive effect of acetaminophen in rats
Courade, J., Chassaing, C., Bardin, L., Alloui, A., & Eschalier, A. (2001) · European Journal of Pharmacology · doi:10.1016/s0014-2999(01)01464-9 · Cited by 65
Involvement of mu- and delta-opioid receptors in the antinociceptive effects induced by AMPA receptor antagonist in the spinal cord of rats
Kong, L.-L., & Yu, L. (2006) · Neuroscience Letters · doi:10.1016/j.neulet.2006.03.071 · Cited by 13
Possible antinociceptive mechanisms of opioid receptor antagonists in the mouse formalin test
Choi, S.-S., Han, K.-J., Lee, H., Han, E., & Suh, H. (2003) · Pharmacology Biochemistry and Behavior · doi:10.1016/s0091-3057(03)00144-8 · Cited by 20

Authors: Raffa, R. B., Walker, E. A., & Sterious, S. N.
Affiliations: Temple University (US)
Corresponding author: Raffa, Robert B.
ORCID: Raffa, Robert B.
Walker, Ellen A.
Venue: European Journal of Pharmacology
Publisher: Elsevier BV
Published: 2004-10
Volume: 503
Issue: 1-3
Pages: 209-210
ISSN: 0014-2999 (ISSN-L)
DOI: 10.1016/j.ejphar.2004.08.055
OpenAlex: W2060585851
Cited by: 49
References: 9
Citations by year: 2025: 4 · 2024: 3 · 2023: 1 · 2022: 1 · 2021: 1 · 2020: 1 · 2019: 1 · 2018: 1 · 2017: 1 · 2016: 4 · 2015: 3 · 2014: 4 · 2013: 4 · 2012: 5
FWCI: 1.44
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
Locations: European Journal of Pharmacology (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Physiology (medical) › Pain Mechanisms and Treatments
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
Health Sciences › Medicine › Anesthesiology and Pain Medicine › Pain Management and Opioid Use
Keywords: paracetamol, opioid receptors, antinociception, beta-funaltrexamine, naltrindole, mu-opioid receptor, delta opioid receptor, kappa opioid receptor, endogenous opioids, endorphins, enkephalin, dynorphin, intrathecal administration, intracerebroventricular administration
MeSH terms: Acetaminophen, Animals, Dynorphins, Endorphins, Enkephalins, Injections, Intraventricular, Injections, Spinal, Male, Mice, Inbred ICR, Naltrexone, Narcotic Antagonists, Receptors, Opioid, Receptors, Opioid, mu, Receptors, Opioid, delta, Receptors, Opioid, kappa, Analgesics, Non-Narcotic, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

Opioid receptors and acetaminophen (paracetamol)

Abstract

Overview

Integrity signals

Verification

Claims the paper makes

Claims other papers make about this one

Citations

Cites

Cited by

Related

Metadata

Record

About these checks