Centre for Biochemical Pharmacology, William Harvey Research Institute, Barts and London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
Drug Metab Dispos. 2011 Sep;39(9):1689-95. doi: 10.1124/dmd.111.038638. Epub 2011 May 31.
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 CB(1) receptor (CB(1)R) and TRPV1 knockout mice was compared to wild-type mice. Hypothermia induced by paracetamol was also investigated in animals pretreated with the CB(1)R 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 CB(1)R 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.
近年来，人们对扑热息痛（acetaminophen）诱导的低温治疗产生了浓厚的兴趣，在某些情况下，这被报道为一种副作用。因此，了解扑热息痛诱导低温的机制是一个重要的问题。在这项研究中，我们研究了扑热息痛的新代谢物 N-(4-羟基苯基)花生四烯酰胺（AM404）是否通过激活大麻素（CB）和瞬时受体电位香草酸 1 型（TRPV1）系统来介导扑热息痛引起的低温。将 300mg/kg 扑热息痛在 CB1 受体（CB1R）和 TRPV1 敲除小鼠中的低温反应与野生型小鼠进行比较。还研究了在预先用 CB1R 或 TRPV1 拮抗剂 1-(2,4-二氯苯基)-5-(4-碘苯基)-4-甲基-N-1-哌啶基-1H-吡唑-3-甲酰胺三氟乙酸盐（AM251）或 4'-氯-3-甲氧基肉桂酰胺（SB366791）预处理的动物中扑热息痛诱导的低温。在 CB1R 或 TRPV1 敲除小鼠中，扑热息痛引起的低温与野生型小鼠相同。此外，在预先用 AM251 或 SB366791 预处理的 C57BL/6 小鼠中，扑热息痛引起的低温与对照小鼠相同。在药理学剂量下，AM404 未能引起低温。抑制脂肪酸酰胺水解酶（FAAH），该酶参与扑热息痛向 AM404 的代谢，并不会阻止扑热息痛引起的低温发展。扑热息痛在 FAAH 敲除小鼠中也引起与野生型小鼠相同程度的低温。我们得出的结论是，扑热息痛诱导的低温独立于大麻素和 TRPV1，并且 AM404 不介导这种反应。此外，实验证据支持联合药物诱导低温的潜在治疗价值。
