Abstract
In recent years, there has been increasing interest in hypothermia induced by paracetamol for therapeutic purposes, which, in some instances, has been reported as a side effect. Understanding the mechanism by which paracetamol induces hypothermia is therefore an important question. In this study, we investigated whether the novel metabolite of paracetamol, N-(4-hydroxyphenyl)arachidonylamide (AM404), which activates the cannabinoid (CB) and transient receptor potential vanilloid-1 (TRPV1) systems, mediates the paracetamol-induced hypothermia. The hypothermic response to 300 mg/kg paracetamol in CB1 receptor (CB1R) and TRPV1 knockout mice was compared to wild-type mice. Hypothermia induced by paracetamol was also investigated in animals pretreated with the CB1R or TRPV1 antagonist 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperdinyl-1H-pyrazole-3-carboxamide trifluoroacetate salt (AM251) or 4′-chloro-3-methoxycinnamanilide (SB366791), respectively.
In CB1R or TRPV1 knockout mice, paracetamol induced hypothermia to the same extent as in wild-type mice. In addition, in C57BL/6 mice pretreated with AM251 or SB366791, paracetamol induced hypothermia to the same extent as in control mice. AM404 failed to induce hypothermia at pharmacological doses. Inhibition of fatty acid amide hydrolase (FAAH), which is involved in the metabolism of paracetamol to AM404, did not prevent the development of hypothermia with paracetamol. Paracetamol also induced hypothermia in FAAH knockout mice to the same extent as wild-type mice. We conclude that paracetamol induces hypothermia independent of cannabinoids and TRPV1 and that AM404 does not mediate this response. In addition, potential therapeutic value of combinational drug-induced hypothermia is supported by experimental evidence.
Footnotes
This work was supported by the Research Advisory Board of Barts and the London Hospitals. S.S.A. was supported by the Leverhulme Trust and the William Harvey Research Foundation.
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.111.038638.
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ABBREVIATIONS:
- COX
- cyclooxygenase
- AM404
- N-(4-hydroxyphenyl)arachidonylamide
- CB1R
- cannabinoid receptor-1
- FAAH
- fatty acid amide hydrolase
- PGE2
- prostaglandin E2
- TRPV1
- transient receptor potential vanilloid-1
- WIN55-212,2
- (R)-(+)-[2,3-dihydro-5-methyl-3[(4-morpholinyl)methyl]pyrrolo [1,2,3-de]-1,4-benzoaxzinyl]-(1-naphthalenyl)methanone mesylate salt
- AM251
- N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide
- SB366791
- 4′-chloro-3-methoxycinnamanilide
- URB597
- cyclohexyl carbamic acid 3′-carbamoyl-biphenyl-3-yl ester
- SC560
- 5-(4-chloro-phenyl)-1-(4-methoxyphenyl)-3-trifluoromethylpyrazole
- ANOVA
- analysis of variance.
- Received February 11, 2011.
- Accepted May 26, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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