MODULATION OF OPIATE RESPONSES IN BRAIN NORADRENERGIC NEURONS BY THE CYCLIC-AMP CASCADE - CHANGES WITH CHRONIC MORPHINE

It has been recently reported that the cyclic AMP cascade substantiall y modulates excitatory amino acid(17,42) and d-aminobutyric acid(34) r esponses in central neurons. Furthermore, interactions between the cyc lic AMP system and opiate receptors have been well documented.(10,12,1 3,27,37) The modification of neuronal responsiveness to opiates throug h such a second messenger system could be important in both normal fun ctioning of opioid neurotransmitter systems and in opiate abuse. As th e noradrenergic nucleus locus coeruleus receives a prominent endogenou s opioid innervation(14,32,41) and is thought to be important in brain mechanisms of opiate abuse,(1,9,16) we examined opiate responses in l ocus coeruleus neurons following activation of the cyclic AMP cascade. We report that opiate responses of locus coeruleus neurons are enhanc ed by forskolin, an activator of adenylate cyclase, and by intracellul ar 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 potentiation response s to the a(2), adrenoceptor agonist, clonidine, but did not consistent ly potenticoeruleus neurons from rats chronically treated with morphin e.