Adenosine agonists, N6-cyclohexyladenosine (CHA), N6-cyclopentyladenosine (CPA), N6-phenylisopropyladenosine (PIA), 5'-N-ethylcarboxamidoadenosine (NECA), 5'-N-methylcarboxamidoadenosine (MECA) and 2-chloroadenosine (CADO), produced a dose-related inhibition of acetylcholine (ACh)-induced writhing in mice. The antinociceptive potency of adenosine agonists was comparable to that of morphine. Adenosine agonists were 10-1000 times more potent when given i.c.v. than p.o., suggesting a central site of action. Theophylline antagonized the antinociceptive activity of R-PIA in the writhing assay, suggestive of an adenosine receptor-mediated event. The sedative/ataxic properties of adenosine agonists were evaluated using a rotorod assay. Adenosine agonists impaired performance on the rotorod in doses comparable to and in some cases lower than those active in the ACh writhing assay. The results of the present study suggest that adenosine agonists attenuate nociceptive responding to a chemical stimulus through a central purinergic mechanism. The ability of adenosine agonists to inhibit ACh-induced writhing may be secondary to their sedative/ataxic properties.