Caffeine antinociception: Role of formalin concentration and adenosine A₁ and A₂ receptors

Caffeine produces antinociception in the formalin test at lower doses than in thermal threshold tests. In this study, we examined (a) the effect of formalin concentration on the action of caffeine, and (b) the relative involvement of adenosine A₁ and A₂ receptors in the action of caffeine. Formalin 1%, 2% and 5% produces a concentration-dependent increase in flinching behaviour in rats. At 5% formalin, the EC₅₀ for caffeine in reducing phase 2 responses (16-60 min following formalin injection) is 40 mg/kg, but at 2%, this is reduced to 5 mg/kg. There is no further shift using 1% formalin. Caffeine has a more pronounced effect on phase 2A (16-36 min) than on phase 2, with significant effects being observed at lower doses. Both 8-cyclopentyltheophylline (A₁ selective) and 3,7-dimethyl-1-propargylxanthine (A, selective) produce a dose-related inhibition of 1.5% formalin flinching behaviours between 1-10 mg/kg. Both agents also produce locomotor stimulation over this dose range, but significant effects occur only at 10 mg/kg. These results indicate that antinociception by caffeine shows a high dependence on stimulus intensity. At 1-2% formalin, doses of caffeine that produce antinociception are now in the range that corresponds to normal human dietary and therapeutic intake levels. Both antinociception and locomotor stimulation appear to be dependent on activation of adenosine A₁ receptors, as effects of 3,7-dimethyl-1-propargylxanthine are observed only at a dose which blocks adenosine A₁ receptors in addition to A₂ receptors.