Morphine sulfate stimulates the adenylate cyclase in mouse caudate nuclei.

Abstract

The effect of several concentrations of morphine on the activity of adenylate cyclase [ATP pyrophosphate-lyase (cyclizing); EC 4.6.1.1] was measured in homogenates of caudate nuclei of mice. Morphine stimulated the enzyme at 500 MM and inhibited slightly at 5 MM. Morphine stimulation was blocked by naloxone. Depending on its dose, morphine also increased or decreased the stimulating effect of dopamine on the dopamine-sensitive adenylate cyclase activity of caudate homogenate. Like dopamine, morphine's effect on the adenylate cyclase activity was increased or decreased, respectively, by retreating the animals with poly(I)poly(C) or with chlorampbenicol. Thus, both dopamine and morphine appear to act on the same receptor. This "new" receptor differs from the one described by Snyder et al. and others, who demonstrated only binding affinity and no enzymatic activity. These data indicate that certain functions of the opiates might be mediated through the dopamine-sensitive adenylate cyclase of the caudate nuclei, which are the dopamine receptors in the brain.Levodopa(L-dopa, L-3-4-dihydroxyphenylalanine) has been reported to relieve pain caused by bone metastases of breast cancer (1, 2) and other cancers (3). Recent microphysiological studies have shown that lamina V cells in the spinal dorsal horn take part in the integration and transmission of noxious stimuli to brain (4). Both levodopa and morphine inhibit the activities of the lamina V cells of the dorsal horn of the rabbit (5), and both are analgesic. We have found that feeding levodopa to mice promoted longevity (6, 7) and increased the dopaminesensitive adenylate cyclase [ATP pyrophosphate-lyase (cyclizing); EC 4.6.1.1] activity without changing the basal cyclase activity in the caudate nuclei of these mice (8). When morphine pellets (75 mg of morphine base) were implanted subcutaneously in rats for 5 days, the dopamine-sensitive adenylate cyclase activity increased, but the basal cyclase remained steady (9).The above findings suggested to us that dopamine and morphine may act on the same receptors in the nervous system, particularly those in the caudate nuclei. We, therefore, investigated competition between morphine and dopamine on the dopamine-sensitive adenylate cyclase. We also tested the effect of these compounds on another enzyme important in dopamine metabolism, monoamine oxidase [amine:oxygen oxidoreductase (deaminating) (flavin-containing) MATERIALS AND METHODSAnimals. Swiss Albino Hale Stoner male mice, 5-7 weeks old, weighing 22-27 g, were housed six to a cage in an air-conditioned room with a light-to-darkness cycle of 12 hr. Purina laboratory chow and water were given ab libitum. Three hours before the effects of morphine and dopamine were measured, some animals were pretreated with either chloramphenicol (1.5 mg/g of body weight by gastric tube twice) or the doublestranded RNA poly(I)-poly(C) (1.5 ,Ag/g of body weight) which, respectively, decreased or increased the effects of levodopa both on behavior of intact animals and the dopami...

Demonstration and Characterization of Opiate Inhibition of the Striatal Adenylate Cyclase

“…The absolute dependence on GTP for enkephalin activity suggested that the presence of guanine nucleotide in the tissue slices but not in homogenate was the cause for the divergent results. The reported stimulation of the adenylate cyclase by heroic concentration of morphine (Pun et al, 1975;Dismukes and Daly, 1975;Tang and Cotzias, 1978) could be due to the nonspecific ionic effect of the cationic drug molecule similar to that of the monovalent cations. The apparent sitmulation of striatal adenylate cyclase by 10 pwdextrorphan could be an example of cationic drug stimulation of striatal adenylate cyclase.…”

“…However, opiate inhibition of the brain adenylate cyclase has been equivocal. There are reports in the literature demonstrating that (a) opiate inhibited the adenylate cyclase in striatal homogenates (Collier and Roy, 1974), monkey amygdalal homogenate (Walczak et al, 1979), and striatal slices (Minneman and Iversen, 1976); (b) opiate stimulated adenylate cyclase activity (Dismukes and Daly, 1975;Puri et al, 1975;Tang and Cotzias, 1978); and (c) opiate had no effect on the enzymatic activity (Bonnet, 1975;Tell et al, 1975; Katz and Catravas, 1977). It is only in the neuroblastoma x glioma hybrid NGlO8-15 cells that opiate attenuation of the intracellular cAMP level by inhibition of the enzyme adenylate cyclase has been demonstrated (Sharma et a]., 1975a(Sharma et a]., , 1977Traber et al, 1975;Brandt et a].…”

Purine involvement in morphine antinociception

“…However, stimulation of adenylate cyclase by opiates (Puri et al, 1975;Tang & Cotzias, 1978) and no effect on this enzymatic activity (Katz & Catravas, 1977) have also been reported. Ho et al (1973) found that prior administration of cyclic AMP to mice or rats antagonized morphine analgesia.…”