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      Paracetamol: New Vistas of an Old Drug

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          ABSTRACT

          Paracetamol (acetaminophen) is one of the most popular and widely used drugs for the treatment of pain and fever. It occupies a unique position among analgesic drugs. Unlike NSAIDs it is almost unanimously considered to have no antiinflammatory activity and does not produce gastrointestinal damage or untoward cardiorenal effects. Unlike opiates it is almost ineffective in intense pain and has no depressant effect on respiration. Although paracetamol has been used clinically for more than a century, its mode of action has been a mystery until about one year ago, when two independent groups (Zygmunt and colleagues and Bertolini and colleagues) produced experimental data unequivocally demonstrating that the analgesic effect of paracetamol is due to the indirect activation of cannabinoid CB 1 receptors. In brain and spinal cord, paracetamol, following deacetylation to its primary amine (p‐aminophenol), is conjugated with arachidonic acid to form N‐arachidonoylphenolamine, a compound already known (AM404) as an endogenous cannabinoid. The involved enzyme is fatty acid amide hydrolase. N‐arachidonoylphenolamine is an agonist at TRPV1 receptors and an inhibitor of cellular anandamide uptake, which leads to increased levels of endogenous cannabinoids; moreover, it inhibits cyclooxygenases in the brain, albeit at concentrations that are probably not attainable with analgesic doses of paracetamol. CB 1 receptor antagonist, at a dose level that completely prevents the analgesic activity of a selective CB 1 receptor agonist, completely prevents the analgesic activity of paracetamol. Thus, paracetamol acts as a pro‐drug, the active one being a cannabinoid. These findings finally explain the mechanism of action of paracetamol and the peculiarity of its effects, including the behavioral ones. Curiously, just when the first CB 1 agonists are being introduced for pain treatment, it comes out that an indirect cannabino‐mimetic had been extensively used (and sometimes overused) for more than a century.

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          Author and article information

          Journal
          CNS Drug Rev
          CNS Drug Rev
          10.1111/(ISSN)1527-3458
          CNS
          CNS Drug Reviews
          Blackwell Publishing Ltd (Oxford, UK )
          1080-563X
          11 January 2007
          Fall-Winter 2006
          : 12
          : 3-4 ( doiID: 10.1111/cns.2006.12.issue-3-4 )
          : 250-275
          Affiliations
          [ 1 ]Division of Toxicology and Clinical Pharmacology University of Modena and Reggio Emilia, Italy
          [ 2 ]Department of Biomedical Sciences, Section of Pharmacology, University of Modena and Reggio Emilia, Italy
          [ 3 ]Section of Pharmacology and Pharmacognosy, Department of Pharmacological Sciences, University of Chieti “G. D'Annunzio,” Italy
          Author notes
          [* ]Address correspondence and reprint requests to: Alfio Bertolini, M.D., Professor of Clinical Pharmacology and Director of the Division of Toxicology and Clinical Pharmacology, University of Modena and Reggio Emilia — Policlinico di Modena, Largo del Pozzo, 71, I‐41100 Modena, Italy;
 Tel.: +39 (059) 422‐4064; Fax: +39 (059) 422‐4069; E‐mail: bertolini.alfio@ 123456unimore.it
          Article
          PMC6506194 PMC6506194 6506194 CNS250
          10.1111/j.1527-3458.2006.00250.x
          6506194
          17227290
          Page count
          References: 235, Pages: 26
          Categories
          Reviews
          Custom metadata
          2.0
          Fall/Winter 2006
          Converter:WILEY_ML3GV2_TO_NLMPMC version:5.6.2.1 mode:remove_FC converted:03.05.2019

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