TY - JOUR T1 - Paracetamol-induced hypothermia is independent of cannabinoids and transient receptor potential vanilloid-1 and is not mediated by AM404 JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.111.038638 SP - dmd.111.038638 AU - Samir S Ayoub AU - Gareth Pryce AU - Michael P Seed AU - Christopher Bolton AU - Roderick J Flower AU - David Baker Y1 - 2011/05/31 UR - http://dmd.aspetjournals.org/content/early/2011/05/31/dmd.111.038638.abstract N2 - 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, AM404, which activates the cannabinoid (CB) and transient receptor potential vanilloid-1 (TRPV1) systems, mediates the paracetamol-induced hypothermia. The hypothermic response to 300mg/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 pre-treated with the CB1R or TRPV1 antagonists AM251 or 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 pre-treated 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. Additionally, potential therapeutic value of combinational drug-induced hypothermia is supported by experimental evidence. ER -