The previous demonstration of an increase and redistribution of adenylate cyclase activity in injured peripheral nerve suggests that an increase in neuronal cyclic AMP concentration could play a role in peripheral nerve regeneration. We report our finding that accumulating adenylate cyclase activity was translated into a twofold increase in cyclic AMP concentration in the regenerating nerve stump, coincident with the initiation and elongation of regenerative nerve sprouts. We sought to magnify the role of cyclic AMP in regeneration by using forskolin, a robust activator of adenylate cyclase, to produce an additional increase in neuronal cyclic AMP in situ. Forskolin in vitro produced an approximately 40-fold greater elevation in neuronal cyclic AMP than an equimolar (10(-5] concentration of isoprenaline. Moreover, the elevated cyclic AMP concentration persisted for at least 60 min in the continued presence of forskolin. Daily injection of forskolin into the dorsal lymph sac of Rana pipiens, or delivery of forskolin through an implanted osmotic pump produced a sustained 40% increase in the rate of sensory nerve regeneration in freeze-lesioned sciatic nerves. We conclude that an increase in cyclic AMP concentration and, presumably, the activation of appropriate protein kinases stimulates regenerative nerve growth following trauma.