Caffeine inhibits antinociception by acetaminophen in the formalin test by inhibiting spinal adenosine A ₁ receptors

The present study examined effects of caffeine on antinociception by acetaminophen in the formalin test in mice. It demonstrates that caffeine 10 mg/kg inhibits antinociception produced by acetaminophen 300 mg/kg i.p. against phase 2 flinches. Chronic administration of caffeine in the drinking water (0.1, 0.3 g/l) for 8 days also inhibits the action of acetaminophen. The selective adenosine A ₁ receptor antagonist DPCPX 1 mg/kg i.p. mimics the action of caffeine, but the selective adenosine A _2A receptor antagonist SCH58261 3 mg/kg i.p. does not. While acetaminophen produced the same effect in mice that were +/+, +/- and -/- for adenosine A ₁ receptors, inhibition of antinociception by caffeine was seen only in +/+ and +/- mice. A higher dose of caffeine, 40 mg/kg, produced an intrinsic antinociception against formalin-evoked flinches, an effect also seen when caffeine was administered intrathecally. SCH58261 30 nmol, but not DPCPX 10 nmol, also produced antinociception when administered intrathecally indicating involvement of adenosine A _2A receptors in spinal antinociception. Caffeine reversal of acetaminophen results from actions in the spinal cord, as intrathecal DPCPX 10 nmol inhibited antinociception by systemic acetaminophen; this was also observed in +/+ but not in -/- adenosine A ₁ receptor mice. We propose that spinal adenosine A ₁ receptors contribute to the action of acetaminophen secondarily to involvement of descending serotonin pathways and release of adenosine within the spinal cord. Inhibition of acetaminophen antinociception by doses of caffeine relevant to dietary human intake levels suggests a more detailed consideration of acetaminophen-caffeine interactions in humans is warranted.