It has been recently reported that the cyclic AMP cascade substantially modulates excitatory amino acid and d-aminobutyric acid responses in central neurons. Furthermore, interactions between the cyclic AMP system and opiate receptors have been well documented. The modification of neuronal responsiveness to opiates through such a second messenger system could be important in both normal functioning of opioid neurotransmitter systems and in opiate abuse. As the noradrenergic nucleus locus coeruleus receives a prominent endogenous opioid innervation and is thought to be important in brain mechanisms of opiate abuse, we examined opiate responses in locus coeruleus neurons following activation of the cyclic AMP cascade. We report that opiate responses of locus coeruleus neurons are enhanced by forskolin, an activator of adenylate cyclase, and by intracellular application of cyclic AMP. This potentiation of the opiate response was blocked by protein kinase inhibitors, which also depressed opiate responses below baseline values. Forskolin also potentiated responses to the a2 adrenoceptor agonist, clonidine, but did not consistently potentiate opiate responses in locus coeruleus neurons from rats chronically treated with morphine.