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At least 523 records · Page 29Linked to original sources
PubMed1995

kappa-Opioid receptor agonist protects against ischemic reduction of 2-deoxyglucose uptake in morphine-tolerant rats.

We examined the effects of mu-opioid receptor agonist and antagonists, and kappa-opioid receptor agonist on the hypoxia/hypoglycemia-induced reduction in 2-deoxyglucose uptake of rat hippocampal slices. Naloxone, a mu-opioid receptor antagonist and (5,7,8)-(+)-3,4-dichloro-N-methyl-N-(7,8,1-pyrrolidinyl)-1-oxaspirol+ ++ (4,5)dec-8-yl)-benzeneacetamide methanesulfonate, U-62,066E, a kappa-opioid receptor receptor agonist, showed neuroprotective actions against the hypoxia/hypoglycemia-induced deficit in glucose uptake. In contrast, morphine exhibited an exacerbating action. These results suggest that blockade of mu-opioid receptor- and stimulation of kappa-opioid receptor-mediated functions has a protective role against the hypoxia/hypoglycemia-induced decreases in glucose metabolism in hippocampal slices. Chronic administration of morphine (10 mg/kg) for 9 days affected neither the basal nor the hypoxia/hypoglycemia-induced reduction in 2-deoxyglucose uptake. Rats treated with morphine chronically exhibited not only tolerance to the analgesic effect but also tolerance to the exacerbating action. However, chronic morphine did not modify U-62,066E-induced neuroprotection. These findings indicate that the receptor mechanisms of neuroprotection produced by the activation of kappa-opioid receptors may not be involved in mu-opioid receptor function.

Analgesics↗
PubMed1988

Opposite effects of kappa-opioid agonists on gastric emptying of liquids and solids in dogs.

The influence of oral (p.o.) administration of kappa-(U-50488, tifluadom) and mu- (morphine, DAGO) opioid substances on gastric emptying of liquids and solids in a standard canned dog food meal was evaluated using a double-radiolabeled technique in dogs fitted with gastric cannulas. One hour after feeding, 28.6% +/- 3.6% (mean +/- SD) of the solid phase and 27.1% +/- 8.6% of the liquid phase of the meal had been emptied. Both U-50488 and tifluadom given orally (0.01-0.1 mg/kg) significantly increased (p less than 0.05) the 1-h emptying of the solid phase of the meal by 23.1%-49.6%. In contrast, both drugs significantly reduced emptying of liquids. These effects were not reproduced when similar doses were given intravenously. Oral administration of morphine or DAGO (0.01-0.1 mg/kg) did not affect gastric emptying, whereas an inhibited emptying of solids was observed for morphine at a higher dose (1 mg/kg p.o.). At a dose of 100 micrograms/kg i.v. both naloxone and MR 2266 (0.1 mg/kg) abolished the effects of orally administered U-50488 on gastric emptying of solids and liquids. It is concluded that kappa- but not mu-agonists act locally to alter gastric emptying of a standard meal in dogs, having opposite effects on solid and liquid phases. A selective local stimulation of kappa mucosal or submucosal receptors of the gastroduodenal area may explain such effects.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1987

Opioid kappa-receptor agonists suppress sexual behaviors in male rough-skinned newts (Taricha granulosa).

Four experiments were performed to evaluate a possible opioid involvement in the regulation of sexual behavior (amplectic clasping of a female) in intact adult male rough-skinned newts (Taricha granulosa) during the breeding season. It was found that an ip injection of bremazocine, a kappa-receptor opiate agonist, can markedly reduce sexual activity and that an ip injection of naloxone can reverse this inhibition in a dose-dependent fashion. In contrast, in male newts that were sexually inactive before treatment, injections of naloxone failed to induce sexual behavior, suggesting that opioid mechanisms do not normally exert a tonic inhibition of amphibian sexual behavior. In addition, an injection of ethylketocyclazocine (another kappa-receptor agonist), but not morphine (a mu-receptor agonist) suppressed sexual behaviors of male newts. These results indicate that opioid mechanisms that include kappa-type opioid receptors may contribute to the regulation of sexual behavior in nonmammalian vertebrates.

Analgesics↗
PubMed1990

Effects of drugs interacting with opioid receptors during normal perfusion or ischemia and reperfusion in the isolated rat heart--an attempt to identify cardiac opioid receptor subtype(s) involved in arrhythmogenesis.

Cardiac opioid receptors have been shown to be involved in the genesis of arrhythmias during ischemia and reperfusion. The present study was aimed at elucidating the receptor subtype(s) involved in arrhythmogenesis. Two series of experiments were conducted. In the first, effects of prototype opioid agonists, namely, (D-Ala2, NMe4, Gly-ol)-Enkephalin (DAGO), U50,488H and (D-Pen2, Pen5)-Enkephalin (DPDPE) and (D-Ala2, D-Leu2)-Enkephalin (DADLE), representing mu-, kappa- and delta-agonists, respectively, in disturbing the normal cardiac rhythm in the isolated perfused rat heart were investigated. Both DAGO and U50,488H were arrhythmogenic, whereas the effects of the delta-agonists, DPDPE and DADLE at a same dose range (44-396 nmol/heart) as that of DAGO were almost negligible. U50,488H was by far the most potent as it induced ventricular arrhythmias including frequent PVC and VT even at a dose (44 nmol/heart) at which other agonists either produced no or negligible effect. In the second series of experiments, the antiarrhythmogenic effects of mu-antagonist (naloxone) and kappa-antagonist (MR 2266) against arrhythmias arising during ischemia and reperfusion were compared. The effects of MR 2266 were significantly greater than that of naloxone. Results of the present study suggest that the cardiac kappa-receptors are the most likely receptor-subtype involved in arrhythmogenesis during ischemia and reperfusion.

Animals↗
PubMedDate not supplied

In vivo modulation of small bowel motility by morphine and D-Ala2 D-Leu5 enkephalin.

The effects of morphine and D-Ala2 D-Leu5 enkephalin (DADLE) on intestinal motility were studied in conscious dogs with chronically implanted electrodes. In fed dogs, the normal pattern of irregular spike activity was interrupted by morphine and DADLE; both induced regular spike activity whilst DADLE also induced quiescence. Mr2266 and naloxone abolished the regular spike activity response to morphine and DADLE, but not the quiescence induced by DADLE. Mr2267 had no antagonistic action. Nalorphine methiodide induced a morphine-like response; lower doses had no agonistic action but abolished the response to morphine. The results suggest that regular spike activity induced by morphine and DADLE is a mu receptor effect, whilst the quiescence induced by DADLE may be a delta receptor effect. Morphine appears to have a peripheral site of action.

Animals↗
PubMedDate not supplied

Increased immunoreactive dynorphin and leu-enkephalin in posterior pituitary of obese mice (ob/ob) and super-sensitivity to drugs that act at kappa receptors.

Posterior pituitaries of obese mice (ob/ob) contained significantly more immunoreactive dynorphin (P less than .01) and leu-enkephalin (P less than .01) than their lean littermates. Drinking in obese mice was stimulated by 0.3%, and feeding by 10%, of the dose of ethylketocyclazocine, a kappa receptor agonist, needed to produce extra feeding and drinking in lean mice. Obese mice also showed greater and longer lasting suppression of ingestion after MR-2266, a kappa antagonist, than did lean mice. MR-2266 was much more effective than naloxone in suppressing schedule-induced polydipsia in rats. These results indicate that kappa receptors are involved in feeding and drinking and that obesity is associated with changes in these receptors and their ligands.

Analgesics, Opioid↗
PubMedDate not supplied

Mu opiate isoreceptors: differentiation with kappa agonists.

In vivo pharmacological data support the concept of mu (mu) isoreceptors in the rat CNS. The mu 1 receptor mediates analgesia and regulation of cholinergic neurons. Naloxazone may be a specific antagonist of this receptor type. In contrast, the mu 2 receptor is responsible for respiratory depression and regulation of nigrostriatal dopaminergic neurons. In this case, the kappa agonists EKC and MR-2034 appear to be specific mu 2 antagonists.

Acetylcholine↗
PubMedDate not supplied

Autoradiographic localization of kappa opiate receptors to deep layers of the cerebral cortex may explain unique sedative and analgesic effects.

The pharmacologically defined kappa drug 3H-ethylketazocine (3H-EKC) and 3H-bremazocine bind to unique sites, but also to mu and delta receptors. By displacing mu and delta interactions with morphine and D-Ala2, D-Leu5-enkephalin (DADL) respectively we have visualized selective receptors for 3H-EKC and 3H-bremazocine. These two kappa ligands are localized to sites different from mu and delta receptors labeled with 3H-dihydromorphine (3H-DHM) and 3H-DADL. The highest density and most selective localization of putative kappa receptors occurs in layers V and VI of the cerebral cortex. Cells in these layers project to the thalamus, regulating sensory input to the cortex. These deep cortical kappa receptors may account for the unique sedative and analgesic actions of kappa opiates.

Analgesics↗
PubMedDate not supplied

Differing stereospecificities distinguish opiate receptor subtypes.

Paired stereoisomers of compounds active at the proposed mu, kappa and sigma classes of opiate receptors display differing stereoselectivity patterns at the receptor subtypes. The (-) isomers of cyclazocine and SKF-10047 are far more potent than the (+) isomers as displacers of [3H]dihydromorphine from receptors. However, the (-) isomers are only moderately more potent than the (+) isomers at displacing [3H]ethylketocyclazocine from kappa receptors in an assay controlled for radioligand binding to mu receptors, and the (+) and (-) isomers are similar in potency for displacement of [3H]phencyclidine (PCP) from sigma receptors. At the sigma/PCP receptor, (+) ketamine proved four times as potent as (-) ketamine, while the dioxalan derivative dexoxadrol is far more potent than its nearly inactive enantiomer levoxadrol. The results for the sigma/PCP receptor are in agreement with those of behavioral studies. Stereospecificity patterns may provide support for the concept of the opiate receptor subclasses as biochemically distinct entities.

Animals↗
PubMed1983

Catatonic or hypotonic immobility induced in mice by intracerebroventricular injection of mu or kappa opioid receptor agonists as well as enkephalins or inhibitors of their degradation.

The intracerebroventricular injections in mice of the mu receptor agonists morphine and fentanyl induced an immobility state (the animals staying motionless with the head down on a 45 degree inclined plane) which was apparently hypertonic (catatonia ?) or at least enabled them to remain hanging on a horizontal wire with their forepaws. In similar conditions, injections of the kappa receptor agonists ketocyclazocine and bremazocine induced an immobility state which was hypotonic, in contrast with the preceding one. In a similar way to the mu agonists, Met-enkephalin or Leu-enkephalin injected i.c.v. in association with the inhibitor of enkephalinase thiorphan induced an apparently hypertonic immobility which was easily antagonized by naloxone. The association of thiorphan with bestatin (an inhibitor of aminopeptidases involved in enkephalins inactivation) produced similar results. In contrast, the hypotonic immobility induced by the kappa receptor agonists required relatively high doses of naloxone to be antagonized. The opiate antagonist MR 2266 antagonized equipotent doses of all the above mentioned agents with a similar efficacy. From these data it is suggested that enkephalins could induce an apparently tonic immobility by stimulating mu receptors and that endogenous enkephalins could be involved in a tonic mediation modulating the locomotor activity or regulating the muscular tone.

Animals↗
PubMed1983

A comparative study of the respiratory depressant and analgesic effects of bremazocine, a kappa-agonist.

The respiratory depression and analgesia induced by a kappa-agonist, bremazocine, were studied by the ED50 ratios and the apparent pA2 values of the interaction with naloxone. The ratio between the ED50 in respiratory depression and analgesia (i.c.v.) was very high compared to that of other mu- and delta-agonists, indicating its small activity on the respiratory center. pA2 values were 7.33 and 7.20 for analgesia and respiratory depression, respectively, after i.c.v. administration. After s.c. injection, the pA2 value for analgesia was 6.16. The results confirm the involvement of different opiate receptors in the mediation of supraspinal and spinal analgesia. The results suggest that bremazocine may induce analgesia by interacting with different types of receptors located at different levels of the CNS. This property and the low activity on the respiratory center make drugs like bremazocine good candidates in the search for safer opiate analgesics.

Analgesia↗
PubMed1983

Antinociceptive profile of dynorphin in the rat.

Morphine, bremazocine, dynorphin(1-17) and two of its fragments (1-13) and (1-8) all increased nociceptive pressure thresholds in the rat after intracerebroventricular administration. Morphine also increased nociceptive heat thresholds in the hotplate test at similar dose-levels. In contrast, bremazocine and the dynorphins were totally inactive against the noxious heat stimulus. This profile of antinociceptive activity is typical of kappa receptor agonists.

Analgesics↗
PubMed1983

Effects of naloxone and Mr 1452 on stress-induced changes in nociception of different stimuli in rats.

The effects of naloxone and Mr 1452 on nociceptive responding to heat and pressure following restraint stress were examined. Thresholds for heat and pressure were determined using standard tail immersion and paw pressure tests. Restraint produced significant analgesia to heat but hyperalgesia to pressure. Naloxone reduced this heat analgesia but had no effect on stress-induced hyperalgesia to pressure. Mr 1452 also attenuated the heat analgesia but in contrast to naloxone it potentiated the hyperalgesia to pressure. These results suggest a differential involvement of mu- and k-opioid systems in the mediation of stress-induced changes in nociception.

Animals↗