The effects of adenosine, adenosine analogues (N6-cyclohexyladenosine (CHA), L-N6-phenylisopropyladenosine (L-PIA), D-N6-phenylisopropyladenosine (D-PIA), N6-methyladenosine and 2-chloroadenosine), adenine, inosine, hypoxanthine, cyclic AMP and its analogue the dibutyryl cyclic AMP (db cyclic AMP), and methylxanthines (theophylline, caffeine and isobutylmethylxanthine (Ibmx) on compound action potentials were investigated in de-sheathed sciatic nerve preparations of the frog. Adenosine and its analogues enhanced, in a concentration-dependent manner, the inhibitory action of tetrodotoxin (TTX) on nerve conduction. The order of potencies was: CHA greater than D-PIA greater than L-PIA greater than N6-methyladenosine greater than 2-chloroadenosine greater than adenosine. The adenosine metabolites, inosine and hypoxanthine, were inactive on TTX-induced axonal blockade. Adenine enhanced the inhibitory action of TTX on nerve conduction, but was less effective than adenosine. db Cyclic AMP, but not cyclic AMP, mimicked the inhibitory effect of adenosine on nerve conduction. Methylxanthines did not antagonize the effect of adenosine on TTX-induced axonal block and in high concentrations also mimicked the effect of adenosine on nerve conduction. The possibility of adenosine acting on TTX-induced axonal block through an adenosine receptor positively coupled to adenylate cyclase is discussed.