R. A. Harris

Opiate binding to cerebroside sulfate: a model system for opiate-receptor interaction.

Abstract Cerebroside sulfate was shown to bind etorphine and levorphanol with high affinity. The relative potency of narcotic analgesics in preventing the binding of levorphanol to cerebroside sulfate correlated well with their reported analgetic activity. The data indicate similarities between cerebroside sulfate and a purified opiate receptor from mouse brain which has been reported to be a proteolipid. Some preliminary animal data also imply the involvement of CS in opiate action We, therefore, propose that CS may serve as a useful “receptor” model for the study of opiate-receptor interaction in vitro .

Effects of morphine tolerance and dependence on Mg++ dependent ATPase activity of synaptic vesicles.

Abstract The effect of morphine on ATPase of synaptic plasma membranes (SPM) and synaptic vesicles isolated from the mouse brain was studied. The activity of synaptic vesicle Mg ++ -dependent ATPase from mice rendered morphine tolerant and dependent by pellet implantation was 40% higher than that from placebo implanted mice. However, the activities of Mg ++ -dependent ATPase and Na + , K + activated ATPase of SPM of tolerant and nontolerant mice were not significantly different. The activity of synaptic vesicular Mg ++ -dependet ATPase was dependent on the concentration of Mg ++ but not of Ca ++ ; maximum activity was obtained with 2 mM MgCl 2 . On the other hand, Mg ++ -dependent ATPase activity of SPM was dependent on both Mg ++ and Ca ++ , activity being maximum using 2 mM MgCl 2 and 10 −5 M CaCl 2 . It is suggested that this stimulation of ATPase activity may alter synaptic transmission and may thus be involved in some aspects of morphine tolerance and dependence.

EFFECT OF CALCIUM AND LANTHANUM IN MORPHINE ANALGESIA AND TOLERANCE

Abstract A series of experiments were initiated to study the influence of calcium on morphine action. The analgetic effect of morphine in non-tolerant and tolerant mice was found to be antagonized by intraventricular calcium and enhanced by the cation chelator EGTA. Elevation of brain bioamines by monoamine oxidase inhibition (pargyline) or reducing brain catecholamine by chemical sympathectomy (6-hydroxydopamine) failed to alter the calcium effect. Enhancing calcium influx with the ionophore X537A also decreased morphine analgesia while inhibition of calcium binding to and movement across cell membrane by lanthanum greatly augmented morphine analgesia. Interestingly, lanthanum per se produced analgesia in both mice and rats and the action was inhibited by the narcotic antagonist, naloxone. Moreover, the analgetic sensitive sites in the CNS to lanthanum and morphine were both found to be in the periventricular and periaqueductal gray areas. Cross tolerance between lanthanum and morphine was noted and lanthanum attenuated the withdrawal syndrome in morphine-dependent mice. The development of tolerance to morphine was accompanied by an increased level of calcium in synaptosomes and a decrease in high affinity calcium binding to the synaptosomal plasma membrane fraction but not to the other membrane fractions studied. The effects suggest that chronic morphine treatment decreases the availability of calcium binding sites on the inner surface of the synaptosomal membrane.