Serotonergic System Does Not Contribute to the Hypothermic Action of Acetaminophen

Acetaminophen (AcAP), a widely-used antipyretic and analgesic drug, has been considered to exert its effects via central mechanisms, and many studies have demonstrated that the analgesic action of AcAP involves activation of the serotonergic system. Although the serotonergic system also plays an important role in thermoregulation, the contribution of serotonergic activity to the hypothermic effect of AcAP has remained unclear. In the present study, we examined whether the serotonergic system is involved in AcAP-induced hypothermia. In normal mice, AcAP (300 mg/kg, intraperitoneally (i.p.)) induced marked hypothermia (ca. -4°C). The same dose of AcAP reduced pain response behavior in the formalin test. Pretreatment with the serotonin synthesis inhibitor DL-p-chlorophenylalanine (PCPA, 300 mg/kg/d, i.p., 5 consecutive days) substantially decreased serotonin in the brain by 70% and significantly inhibited the analgesic, but not the hypothermic action of AcAP. The same PCPA treatment significantly inhibited the hypothermia induced by the selective serotonin reuptake inhibitor fluoxetine hydrochloride (20 mg/kg, i.p.) and the serotonin 5-HT₂ receptor antagonist cyproheptadine hydrochloride (3 mg/kg, i.p.). The lower doses of fluoxetine hydrochloride (3 mg/kg, i.p.) and cyproheptadine hydrochloride (0.3 mg/kg, i.p.) did not affect the AcAP-induced hypothermia. These results suggest that, in comparison with its analgesic effect, the hypothermic effect of AcAP is not mediated by the serotonergic system.