Acetaminophen: Antipyretic or hypothermic in mice? In either case, PGHS-1b (COX-3) is irrelevant

Acetaminophen (AC) reduces the core temperatures (Tc) of febrile and non-febrile mice alike. Evidence has been adduced that the selectively AC-sensitive PGHS isoform, PGHS-1b (COX-3), mediates these effects. PGHS-1b, however, has no catalytic potency in mice. To resolve this contradiction, AC was injected intravenously (i.v.) into conscious PGHS-1 gene-sufficient (wild-type (WT)) and -deficient (PGHS-1−/−) mice 60 min before or after pyrogen-free saline (PFS) or E. coli LPS (10 μg/kg) i.v. Tc was monitored continuously; brain and plasma PGE2 levels were determined hourly. AC at <160 mg/kg did not affect Tc when given before PFS or LPS; at 160 mg/kg, it caused a ∼2.5 °C Tc fall in 60 min. LPS given after AC (all doses) induced a ∼1 °C fever, not different from that in AC-untreated mice. But this rise was insufficient to overcome the hypothermia of the 160 mg/kg-treated mice; their Tc culminated 1 °C below baseline. LPS given before AC similarly elevated Tc ∼1 °C. This rise was reduced to baseline in 30 min by 80 mg AC/kg; Tc rebounded to its febrile level over the next 30 min. At 160 mg/kg, AC reduced Tc to 4 °C below baseline in 60 min, where it remained until the end of the experiment. WT and PGHS-1−/− mice responded similarly to all the treatments. The basal brain and plasma PGE2 levels of PFS mice and the elevated plasma levels of LPS mice were unchanged by AC at 160 mg/kg; but the latter's brain levels were reduced at 1 h, then recovered. Thus, AC could exert an anti-PGHS-2 effect when this enzyme is upregulated in the brain of febrile mice. The hypothermia it induces in non-febrile mice, therefore, is due to another mechanism. PGHS-1b is not involved in either case.