Opiate- and alpha 2-adrenoceptor-induced hyperpolarizations of locus ceruleus neurons in brain slices: reversal by cyclic adenosine 3':5'-monophosphate analogues.

The purpose of this study was to investigate the ionic and second messenger mechanisms underlying the hyperpolarizations induced by the selective alpha 2-adrenoceptor agonist clonidine and the opiate agonist morphine in the locus ceruleus. Intracellular recordings were carried out in rat brain slices, and drugs at known concentrations were administered in the perfusate. The cyclic adenosine 3':5'-monophosphate (cAMP) analogues 8-bromo-cAMP and dibutyryl cAMP, while not altering basal activity, reversed the hyperpolarizations induced by clonidine or morphine. In contrast, administration of the parent compound adenosine failed to affect these responses. These results are consistent with previous biochemical studies suggesting that alpha 2-adrenergic and opiate agonists might signal their actions by reducing intracellular cAMP levels. Under manual voltage clamp, both clonidine and morphine elicited outward currents. The algebraic sum of the individual currents elicited by morphine and clonidine significantly exceeded the actual current elicited by their co-administration. This nonadditivity, as well as the observation that cAMP analogues reverse the morphine- and clonidine-induced hyperpolarizations, suggests that these compounds hyperpolarize locus ceruleus neurons through a shared ionic mechanism the activation of which might be signaled by a decrease in intracellular cAMP.