Role of transient receptor potential vanilloid‐1 (TRPV1) and cannabinoid CB1 receptors in paracetamol induced antinociception and hypothermia in mice

Abstract

Paracetamol is one of the most popular and widely used analgesic antipyretics; however, its mode of action has not been clear. It was recently shown that paracetamol is metabolized in the brain and the spinal cord to form the potent TRPV1 agonist N‐acylphenolamine (AM‐404). AM‐404 is also an inhibitor of the cellular uptake of the endogenous cannabinoid, anandamide. This study was designed to study the contribution of TRPV1 and CB1 receptors in the antinociceptive and hypothermic effects of paracetamol in mice. Capsazepine, a TRPV1 antagonist, significantly reversed the antinociceptive effect of paracetamol in the formalin test, when administered i.p. at a dose of 10 mg/kg. A higher dose (30 mg/kg), however, failed to reverse the paracetamol induced antinociceptive effect. In contrast, the higher dose partially blocked paracetamol induced hypothermia but not the lower dose. Furthermore, AM‐251, a cannabinoid CB1 receptor antagonist, when administered i.p. at a dose of 10 mg/kg, reversed the antinociceptive effect of paracetamol in the formalin test and blocked paracetamol induced hypothermia after 2 hours of paracetamol injection. In conclusion, both TRPV1 and CB1 receptors are involved in paracetamol induced antinociception in mice. Hypothermia, however, might involve other mediators and further studies are needed to investigate this point.