Paracetamol-Induced Hypothermia Is Independent of Cannabinoids and Transient Receptor Potential Vanilloid-1 and Is Not Mediated by AM404

Abstract

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 paracetamolinduced 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.

Paracetamol sharpens reflection and spatial memory: a double-blind randomized controlled study in healthy volunteers

“…Subsequent action on cannabinoid receptors type 1 (CB1) and calcium channels, such as Ca(v) 3.2 modulate descending serotonergic pathways, and a number of other factors, including transient receptor potential cation channel member A1 receptors, have been described 9,11. Hypothermic/antipyretic effects have been largely studied and it appears in animals that APAP action on temperature is independent of the cascade of events leading to analgesia 12. Cognitive-affective changes with APAP have been studied in animals and an improved cognitive performance,13 an anxiolytic effect14 involving cannabinoid mechanism, and a potentiation of antidepressant and anticompulsive effect have been described 15.…”

Is prostaglandin E2 (PGE2) involved in the thermogenic response to environmental cooling in healthy humans?

“…The efficiency in which PGE 2 (via EP 3 receptor activation in the POA) raises T C during fever would make this a useful mechanism for humans to defend their T C in cold environments or environments set beneath the TNZ. This theory is supported by evidence in animal models [21,[35][36][37], and humans [38][39][40][41][42], whereby COX inhibitors (and thus reduced PGE 2 synthesis) have been shown to cause dose dependent T C reductions in the absence of fever or immune response (afebrile). In the following sections, afebrile animal and human studies that have used COX/PGE 2 inhibitors during cold stress, and its effect on T C regulation, will be discussed.…”

“…decreases in plasma free fatty acid [37]. When ACT was administered intravenously (160-300 mgÁkg À1 ) in afebrile mice housed at 22°C, which is beneath their TNZ [43], T C was reduced by $3°C [21,35,44]. Interestingly, it was shown via ELISA that when the maximum T C reduction was reached (where the dose was 300 mgÁkg À1 ), this coincided with a 96% decrease in whole brain PGE 2 concentrations [21].…”

Paracetamol: Update on its Analgesic Mechanism of Action

“…Interestingly, the involvement of the FAAH metabolic pathway and cannabinoid system is specifically related to their antinociceptive action and not to their hypothermic/antipyretic action [63,64].…”