Arsenic reduces the antipyretic activity of paracetamol in rats: Modulation of brain COX-2 activity and CB1 receptor expression

• We examined whether arsenic reduces the antipyretic activity of paracetamol.
• Arsenic did not induce pyrexia, but inhibited paracetamol's antipyretic effect.
• Arsenic reduced decrease in COX-2 activity and cytokine release by paracetamol.
• Arsenic reversed paracetamol-mediated cannabinoid CB1 receptor up-regulation.
• Reduction in antipyretic effect may relate to COX and CB1 receptor modulation.

We examined whether subacute arsenic exposure can reduce paracetamol-mediated antipyretic activity by affecting COX pathway and cannabinoid CB1 receptor regulation. Rats were preexposed to elemental arsenic (4 ppm) as sodium arsenite through drinking water for 28 days. Next day pyrexia was induced with lipopolysaccharide and paracetamol's (200 mg/kg, oral) antipyretic activity was assessed. The activities of COX-1 and COX-2, the levels of PGE2, TNF-α and IL-1β and expression of CB1 receptors were assessed in brain. Arsenic inhibited paracetamol-mediated antipyretic activity. COX-1 activity was not affected by any treatments. Paracetamol decreased COX-2 activity, levels of PGE2, TNF-α and IL-1β and caused up-regulation of CB1 receptors. Arsenic caused opposite effects on these parameters. In the arsenic-preexposed rats, paracetamol-mediated effects were attenuated, while CB1 receptor up-regulation was reversed to down-regulation. Results suggest that elevated COX-2 activity and reduced CB1 expression could be involved in the arsenic-mediated attenuation of the antipyretic activity of paracetamol.