The locus coeruleus is innervated by proopiomelanocortin (POMC)-derived peptide immunoreactive fibres. The biological effects of ( melanocyte-stimulating hormone (aMSH) and [-endorphin on second messengers (cAMP, inositol phosphates) and gene transcription were studied in the locus cceruleus-derived cell line CATH.a. RT-PCR analysis revealed the presence of four MSH receptor subtypes (1, 3, 4 and 5). Activation of these receptors by diacetyl alphaMSH stimulated cAMP accumulation in a dose-dependent manner (EC50: 4 x 10(-9) M). Diacetyl alphaMSH stimulated transcription from reporter genes driven by the c-fos or tyrosine hydroxylase promoter. This effect was abolished when protein kinase A was inactivated with a dominant inhibitory mutant. RT-PCR analyses revealed the presence of delta-, but not mu-and kappa-opioid receptor. Pharmacological analysis showed that beta-endorphin (EC50: 2.5 x 10(-8)M), but not N-acetyl beta-endorphin, antagonized the biological effect of diacetyl alphaMSH on cAMP production and gene transcription. Since N-acetylation regulates the biological activity of alphaMSH and beta-endorphin in an opposite manner, we propose a model where the rate of secretion dictated by the bioelectric activity of the presynaptic neuron modulates POMC-derived peptide maturation and the resulting biological signal sensed by the postsynaptic plate.