The effect of the adenine nucleotides on procaine-induced conduction block in rats was investigated in vivo and in vitro. Both adenine and cyclic nucleotides significantly shortened the duration of sciatic nerve blocks in rats without affecting the frequency, degree of block or time of onset. Adenosine 5'-triphosphate (ATP) and N6, O2' dibutyryl 3':5'-monophosphate (db-cyclic AMP) were most effective. In isolated sciatic nerve preparations, the adenine nucleotides (ATP, adenosine 5'diphosphate (ADP), adenosine 5'monophosphate (AMP)) rapidly reversed procaine-induced depression of the action potential. These results suggest that local anesthetic effects may be mediated through interference with the physiological functions of the nucleotides.