OPIATE RECEPTORS AND THEIR INTERACTIONS WITH ADENYLATE CYCLASE IN MAMMALIAN BRAIN
WALCZAK, STANLEY A.
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Monkey amygdala was utilized to directly compare the interaction of opioid compounds with binding sites and with receptor-coupled adenylate cyclase (AC). AC activity of amygdala homogenates was doubled in the presence of dopamine (10 (mu)M). This stimulation was inhibited by morphine, etorphine and several enkephalin analogs. Antagonism by naloxone, inactivity of dextrorphan, and the relative inhibitory potencies of opioids indicated that the effects on AC involved the classically described stereospecific opiate receptors. Metabolites of 1-(alpha)-acetyl-methadol (LAAM), but not LAAM itself, inhibited the amygdala AC system, consistent with the hypothesis that the actions of LAAM in vivo require metabolic activation. Preincubation of the homogenate, or freezing the tissue prior to assay destroyed opiate inhibition, but not the dopamine effect. Apparently, the narcotic receptor interaction is distinct from, and more labile than that of the dopamine receptor. In other studies, etorphine and D-ala('2)-met-enkephalin caused a significant decrease in the threshold for activation of AC by guanyl nucleotides, whereas morphine has no effect.;The primate amygdala was shown to contain saturable, stereospecific opiate binding sites. A biphasic plot was observed, consistent with the presence of two classes of binding sites. There was a relatively good correlation between the IC(,50)'s of the more potent compounds in the AC system and the K(,i)'s in the binding studies. The theophylline present in the AC buffer system had a differential effect on binding of agonists. Theophylline decreased the affinity of "(mu) type" agonists (e.g. morphine) at opiate receptor binding sites presumably coupled to AC. In four discrete areas of rat brain, both sodium and GTP inhibited agonist binding with little effect on antagonist binding; these effects were marked and approximately additive. It is proposed that two distinct levels of GTP modulation may exist for those receptors coupled to AC, one at the receptor binding level and one at the level of interaction with AC. GTP would modulate only at the receptor level those receptors not coupled to AC.
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