Pharmacological treatments were used to estimate trans-synaptic regulation of opioid peptide gene expression occuring at specific neurotransmitter receptors. In vitro and in vivo studies have shown that different signal-transduction mechanisms regulate the transcription of proenkephalin, proopiomelanocortin and nerve growth factor mRNA. The activation of receptors coupled to adenylate cyclase elicited the increase of proenkephalin and nerve growth factor gene expression. Therefore, a cAMP-dependent mechanism was suggested to be involved in such regulation. However, the temporal delay between the elevation of the intracellular cAMP content and the increase in nerve growth factor and proenkephalin mRNAs prompted us to investigate whether additional mechanisms associated with the second messenger were operative in the regulation of the expression of these two genes. We report evidence that a protein(s), probably functioning as a trans-acting factor, might be involved in the regulation of nerve growth factor gene transcription. The characterization and isolation of these DNA regulatory proteins will provide the pharmacologist with valuable information for the development of new compounds in the therapy of mental disorders.