Although it has been suggested pro-opiomelancortin (POMC)-related peptides widely distributed throughout brain may be neurotransmitters or neuromodulators, little is known about their secretion from neurons because it is difficult to study neurosecretion in vivo. Previous work has shown that POMC-related peptides in hypothalamus may be released in response to potassium-induced depolarization. However, little attention has been directed toward studying secretion of POMC-related peptides in extrahypothalamic brain. To demonstrate the possibility that POMC peptides in extrahypothalamic brain may also be neuroregulators and can be released in response to a specific stimulus, the release of derivatives of POMC, immunoreactive (IR) adrenocorticotropic hormone (ACTH) and IR-beta-endorphin, from dissociated amygdala and cortical brain cells was studied in response to potassium-induced depolarization. Depolarizing concentrations of potassium in the presence of calcium stimulated significant increments in release of IR-ACTH/IR-beta-endorphin by amygdala (111/105%) and cortical (162/136%) cells. Stimulated release occurred following an experimental paradigm used to stimulate release of classical neurotransmitters and neuropeptides and suggested POMC-related peptides could be neuroregulators in extrahypothalamic brain.