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Biomedical subjects

E L Way

Publications and source records attributed to E L Way.

At least 91 records · Page 5Linked to original sources
PubMed1979

Effect of morphine on calcium uptake by lysed synaptosomes.

The effect of morphine on the uptake of 45Ca++ was studied in lysed synaptosomes obtained from homogenates of whole mouse brain. The addition of morphine, 10(-6) M, to the incubation medium or acute administration of 10 or 20 mg/kg s.c. resulted in a decrease in 45Ca++ uptake; this decrease was observed only in the presence of ATP (3 mM). In contrast, after morphine pellet implantation (72 hr) to induce tolerance and physical dependence, an enhancement of lysed synaptosomal 45Ca++ uptake occurred; the increase was obtained in the presence but not in the absence of ATP. The enhancement of Ca++ uptake appears to be related with the degree of tolerance and dependence development since a linear relationship was noted between the time of morphine pellet implantation and the increase in 45Ca++ uptake by lysed synaptosomes. The acute inhibitory action on 45Ca++ uptake by morphine was prevented in vitro by naloxone, 1.9 x 10(-8) M, and in vivo by 2 mg/kg of naloxone s.c. and the chronic enhancing action of morphine by the simultaneous implantation of a naloxone pellet with the morphine pellet. The present findings lend further support to our previous reports in which we suggest that alterations in Ca++ flux may be involved with morphine analgesia, tolerance and physical dependence.

Animals↗
PubMed1979

Effect of morphine on synaptosomal Ca++ uptake.

The effect of morphine on the uptake of 45Ca++ was studied in synaptosomes from mouse brain using two procedures, centrifugation and filtration. The addition of morphine (1.7 x 10(-7) or 3.4 x 10(-7) M) reduced 45CA++ uptake by either technique, although the basal 45Ca++ uptake by the filtration method was approximately 7-fold higher than that by the centrifugation procedure. Similar effects were obtained after acute morphine treatment with 10 mg/kg s.c. Previous naloxone in vitro treatment (1.9 x 10(-8) M) or in vivo administration (2 mg/kg s.c.) reversed the morphine inhibition of the 45Ca++ uptake. On the other hand, after the animal was rendered tolerant and dependent by morphine pellet implantation, an enhancement of the synaptosomal 45Ca++ uptake was observed. It is concluded that changes in Ca++ fluxes in synaptosomes observed after acute and chronic morphine treatment may be involved with morphine pharmacological action related with analgesia, tolerance and physical dependence.

Animals↗
PubMed1978

Single-dose tolerance to antinociception, and physical dependence on beta-endorphin in mice.

beta-Endorphin (B-EN) injected intracerebroventricularly in mice produced a rapid onset, dose-dependent antinociceptive effect. The median analgesic dose (AD50) 30 min following administration was found to be 270 ng/mouse (3.7 nmoles/kg). B-EN produced an acute, single-dose tolerance which was characterized by its dose dependence and the time course of its development. Single-dose tolerance development was demonstrable with doses twice or more the AD50. Tolerance was maximal at about 12 h following the priming dose and disappeared within 48 h. Tolerance was accompanied by some degree of physical dependence as noted by signs of naloxone-precipitated withdrawal similar to those elicitable in the morphine-dependent state. Tolerance development to B-EN was blocked by the simultaneous administration of naloxone and also by pretreatment with 0.35 mg/kg actinomycin D or 30 mg/kg cycloheximide 30 min before B-EN. It appears that single-dose tolerance to B-EN was initiated by processes similar to those involved with tolerance resulting from chronic administration of morphine.

Analgesics↗
PubMed1978

Effects of hypothyroidism on the response of the rat colon to morphine.

Isolated terminal colon strips obtained from rats, made hypothyroid by methimazole treatment, were almost completely insensitive to the contractile effects of morphine as compared to strips from control animals. This low morphine sensitivity was accompanied by a significant (40%) reduction in the tissue sulfatide content. Although colon strips from hypothyroid rats showed a reduction of the contractile effects of acetylcholine, the decrease was considerably less than that noted for morphine. The addition of 6.6 X 10(-5) M tri-iodothyronine to colons from hypothyroid rats largely restored the tissue sensitivity to morphine. These results suggest that sulfatides could be linked to the in vitro effects of morphine in the colon.

Acetylcholine↗
PubMed1978

Tolerance, dependence and lethality in morphine-dependent mice after repeated oral administration of methadone.

Mice were rendered tolerant to and dependent on morphine via a morphine pellet implantation. Three days later methadone hydrochloride was administered at a dose of 100mg/kg per os 3 hours after pellet removal and then daily for a total of 5--6 days. This dose of methadone was shown to exhibit a high efficacy for the blockade of morphine abrupt withdrawal jumping and only minimal toxicity. Under these conditions, the level of analgetic tolerance with respect to morphine and methadone and the level of dependence as measured by the naloxone ED50 were initially elevated by the morphine treatment. However, upon substitution with oral methadone these levels declined with time at a rate which did not differ from that of a group of mice receiving only water after morphine pellet removal. Despite these findings, the methadone treatment was associated with an increasing tolerance to methadone lethality during the administration of this narcotic which was nearly double that of a similarly treated water control group by the sixth day. This observation could not be explained by an elevation in the level of cellular tolerance rendered by the methadone treatment since the morphine LD50 was not elevated following identical treatment with morphine and then methadone. The significance of these results is discussed with respect to the role of methadone administration and its metabolism in the modification of tolerance and dependence.

Administration, Oral↗
PubMed1978

Possible involvement of cerebroside sulfate in opiate receptor binding.

Cerebroside sulfate (CS) appears to fulfill most of the structural requirements of a hypothetical opiate receptor. It possesses many of the properties that are thought to be necessary for the identification of an "opiate receptor," exhibiting high affinity and stereoselective binding to a number of narcotic drugs. Although these properties are insufficient to establish identity of the receptor, it is highly significant that the affinity of this binding can be correlated with the analgetic potency of these drugs in both man and rodents. CS is an endogenous component of brain tissue, and a partially purified opiate receptor from mouse brain has been found to be CS. Other experiments indicate that reduced availability of brain CS decreases the analgetic effects of morphine and this is accompanied by a reduction in number of binding sites, suggesting that the interaction of opiates with CS observed in vitro may also have importance in vivo. CS was also found to be a component of the opiate receptor after marking with 125I-labeled diazosulfanilic acid. The possibility that CS or the SO4-2 group of this lipid may be the "anionic site" of the opiate receptor should be considered.

Animals↗
PubMed1978

Evidence for the involvement of cerebroside sulfate in opiate receptor binding: Studies with Azure A and jimpy mutant mice.

The role of cerebroside sulfate in opiate action and binding was studied by examining the effect of decreasing the availability of the glycolipid in vivo on morphine analgetic activity and receptor affinity. Available cerebroside sites were decreased either by injecting Azure A at a dose with selective high affinity for sulfo-lipids, or by using "jimpy" mice, a genetic leukodystropic mutant mouse with a deficiency in brain sulfatides. Injections of Azure A (4.4 MG/KG) intracerebroventricularly produced a 2-fold increase in the AD50 of morphine (tail-flick test) within 2 hr. The genetic mutation also resulted in a decreased sensitivity to morphine; the morphine AD50 was 6- to 11-fold higher in jimpy mice than in their normal littermates. Azure A produced a dose-dependent inhibition of opiate binding to synaptosomal plasma membranes. There was 85% inhibition of [3H]morphine binding with 0.2 micrometer Azure A, and 40% inhibition of [3H]naloxone binding with 5 micrometer Azure A. The inhibition of morphine binding was competitive and was demonstrated to be different from that elicited by Na+. Synaptic membranes from jimpy mice exhibited a decrease in number of binding sites for morphine. Binding of Azure A to cerebroside sulfate, associated with or in the proximity of the receptor sites, was suggested by the fact that in the presence of 0.2 micrometer Azure A, no inhibition of [3H]morphine binding to synaptosomal plasma membranes of jimpy mice could be demonstrated whereas 31% inh-bition was observed in membranes from control littermates. Based on the findings, it is concluded that cerebroside sulfate strategically located may have a role in binding morphine and mediating its effects.

Animals↗
PubMed1978

Effects of acute and chronic morphine treatments on calcium localization and binding in brain.

Acute subcutaneous injection of 25 mg/kg of morphine in rats decreased synaptosomal CA++ levels by 29% without altering the Ca++ content of other subcellular fractions. In contrast, chronic morphine treatment of mice or rats by pellet implantation selectively increased synaptosomal Ca++ levels by almost 100%. This increase in Ca++ induced by morphine was blocked by simultaneous chronic administration of naloxone. The binding of low concentrations (10(-7)-10(-5) M) of 45Ca++ to synaptic plasma membranes was increased by acute morphine treatment and decreased by chronic administration. The binding of higher concentrations (10(-3) M) of 45Ca++ to synaptic vesicles was also increased by acute morphine treatment and decreased by chronic treatment. Changes in binding were not observed with other subcellular fractions. It is suggested that these highly selective changes in Ca++ levels and binding may represent mechanisms by which acute morphine treatment interferes with synaptic transmission and by which chronic administration overcomes these effects, resulting in tolerance and dependence.

Animals↗