The tachykinin, substance P, has long been associated with transmission of noxious stimuli. However, relatively little is known about signal transduction pathways subserving peptidergic regulation in sensory neurons. To investigate whether cyclic AMP (cAMP) could be a potential second messenger subserving substance P expression, dorsal root ganglion neurons were grown in culture in the presence of agents that increase content of cAMP. In developing neurons, forskolin increased substance P content and survival almost threefold. Antinerve growth factor (NGF) blocked the effect of NGF but not forskolin, suggesting that increased cAMP acts directly and not via increased secretion of NGF from Schwann cells and fibroblasts. In adult neurons, which do not require supplemental trophic factors for survival, NGF and forskolin had similar effects on substance P levels. Neither agent had any effect on somatostatin content of either developing or mature sensory neurons. 8-bromo cAMP and isobutyl methylxanthine duplicated the action of forskolin. Further, all three agents increased expression of preprotachykinin mRNA. Forskolin appeared to increase both total and neuron-specific expression of message as well as the number of neurons expressing mRNA. Our results suggest that cAMP directly regulates substance P content in sensory neurons from adult and neonatal rats.