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

Abstract

Acetaminophen (AC) reduces the core temperatures ( T c) 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. T c was monitored continuously; brain and plasma PGE 2 levels were determined hourly. AC at <160 mg/kg did not affect T c when given before PFS or LPS; at 160 mg/kg, it caused a ∼2.5 °C T c 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 T c culminated 1 °C below baseline. LPS given before AC similarly elevated T c ∼1 °C. This rise was reduced to baseline in 30 min by 80 mg AC/kg; T c rebounded to its febrile level over the next 30 min. At 160 mg/kg, AC reduced T c 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 PGE 2 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.