Adenosine administered to humans has been reported to induce pain after intravenous administration. On the other hand adenosine analogues have been shown to possess antinociceptive effects after peripheral and intrathecal administration in animals. The aim of the present study was to investigate the effect of peripheral administration of adenosine agonists with different affinities for the A1 and A2 adenosine receptors on a persistent pain stimulus using the formalin test. The drugs chosen were, R-phenylisopropyl-adenosine (R-PIA) with high affinity for the A1 receptor, N-ethylcarboxamide-adenosine (NECA) with almost equal affinity for the A1 and A2 receptor and 2-(2-aminoethylamino)-carbonylethylphenylethylamino-adenosin e (APEC) with high affinity for the A2 receptor. The drugs were mixed with formalin and administered subcutaneously into the dorsal hind paw in mice to study the local effects. They were also injected separately from the formalin solution in different paws to evaluate the systemic effect. The total time of licking the injected paw during the first 5 min. was recorded. In high doses all compounds reduced the licking activity, but a low dose of APEC (1 microM) injected together with the formalin solution had an algesic effect. All effects were antagonized by theophylline. These results suggests that A1 adenosine receptors mediate a local peripheral antinociceptive effect and the involvement of local peripheral A2 receptors in the enhancement of the algesic response.