Caffeine induces central cholinergic analgesia.

The antinociceptive effect of caffeine was examined by using the hot-plate, abdominal constriction tests in mice and the tail flick and paw-pressure tests in rats. Caffeine (1–5 mg kg–1 s.c. in mice; 2.5–5 mg kg–1 i.p. in rats) produced significant antinociception in both species which was prevented by atropine (5 mg kg–1 i.p.), pirenzepine (0.1 mg per mouse i.c.v.), hemicholinium-3 (1 mg/ mouse i.c.v.) and N6-cyclopentyladenosine (5 mg/mouse i.c.v.), but not by naloxone (1 mg kg–1 i.p.), CGP 35348 (100 mg kg–1 i.p.), a-methyl p-tyrosine (100 mg kg–1 i.p.) and reserpine (2 mg kg–1 i.p.). Intracerebroventricular injection of caffeine in mice at doses (2.5–5 mg per mouse) which were largely ineffective by parenteral routes, induces an antinociception whose intensity equalled that obtainable s.c. or i.p. In the antinociceptive dose-range, caffeine did not produce any behavioural impairment as revealed by the rotarod and Irwing tests. On the basis of the above data, it can be postulated that caffeine exerts an antinociceptive effect mediated by central amplification of cholinergic transmission.