Cyclic AMP Analogues Potentiate k-Opiate and Attenuate ?2-Adrenoceptor Agonist Effects on Intrasynaptosomal Free Calcium

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Abstract
The intrasynaptosomal free calcium concentration ([Ca2+]i) was measured in quin2-loaded synaptosomes prepared from rat cerebral cortex. Membrane-permeant cyclic adenosine-3′,5′-monophosphate (cAMP) analogues [8-bromo-cyclic adenosine-3′,5′-monophosphate (8-Br-cAMP) and dibutyryl-cyclic adenosine-3′,5′-monophosphate (db-cAMP)] increased [Ca2+]i in a dose-dependent manner; The maximal increases were ˜50% for 8-Br-cAMP and 35% for db-cAMP and occurred at ˜10 μM with both analogues. Clonidine (1 μM) alone reduced [Ca2+]i by 26.5%; db-cAMP and 8-Br-cAMP attenuated this reduction to 14.2 and 8.2%, respectively. In contrast, the reduction (19.9%) in [Ca2+]i induced by the preferential k-opiate agonist dynorphin A(1–13) was not attenuated by the cAMP analogues; in fact, db-cAMP and 8-Br-cAMP potentiated the effect of dynorphin A(1–13) (1 μM), producing decreases in [Ca2+]i of 33.6 and 29.6%, respectively. We conclude that although aradrenergic and k-opiate receptors both reduce [Ca2+]i, the α2-adrenoceptor-mediated response and the k-opiate receptor-mediated response involve different effector mechanisms. It appears that pre-synaptic α2-adrenoceptor agonist effects are linked to reductions in adenylate cyclase activity and cAMP production and a resultant increase in Ca2+ sequestration, Ca2+-channel blockade, or both. On the other hand, the k-opiate-mediated effects possibly involve an increase in cAMP production and a blockade of Ca2+ entry.