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At least 469 records · Page 26Linked to original sources
PubMed1996

Kappa opioid receptor agonists inhibit sigma-1 (sigma 1) receptor binding in guinea-pig brain, liver and spleen: autoradiographical evidence.

The present study examined whether the kappa-opioid agonists U50,488H (trans-(+/-)-3,4-dichloro-N-methyl-N[-2-(1-pyrrolidinyl)- cyclohexyl]-benzeacetamide methane sulphonate), bremazocine, spiradoline and ICI 197067 bind to sigma sites in guinea-pig tissues using in vitro, semi-quantitative receptor autoradiography and receptor binding, and compared the binding profile so obtained with those for several selective sigma ligands. Guinea-pigs were killed and their brians, livers and spleens were removed, tissue sections cut and processed for sigma binding site autoradiography using (+)-[3H]-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)-[3H]-3-PPP), or tissue was wiped and determined by liquid scintillation. Serial slide-mounted sections were incubated with 9-10 concentrations (1 nM-10 microM) of kappa opioids and their potency to inhibit (+)-[3H]-3-PPP binding compared with that of the sigma ligands haloperidol, DTG (1,3 di(o)-tolylguanidine), (+)-3-PPP, (+) and (-)pentazocine, SR 31742A and rimcazole (n = 3, duplicate determinations). Binding of (+)-[3H]-3-PPP to untreated, matched serial tissue sections was used as control. Kd values were estimated in brain, liver and spleen using quantitative, saturation binding analysis, IC50 values were determined from the binding data obtained by slide wiping experiments for each drug, and Ki values were calculated using the Cheng-Prussoff equation. All four kappa opioids inhibited (+)-[3H]-3-PPP binding to sigma 1-receptors with order of potency: brain: U50,488H = spiradoline > bremazocine > ICI 197067; liver: spiradoline > U50,488H > ICI 197067 > bremazocine; spleen: U50,488H > spiradoline > ICI 197067 > bremazocine. By comparison, the sigma ligands inhibited (+)-[3H]-3-PPP binding to matched, serial slide-mounted brain tissue sections (similar results in liver and spleen) with order of potency: SR 31742A > haloperidol > (+)pentazocine > (+)-3-PPP > DTG > (-)pentazocine > rimcazole. (+)-[3H]-3-PPP autoradiography confirmed these binding data. It is concluded that the kappa opioids tested moderately inhibit (+)-[3H]-3-PPP binding to sigma 1-receptors in guinea-pig brain, liver and spleen tissue with Ki values comparable to some selective sigma ligands and therefore are not opioid selective.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1996

Diabetes alters mu and kappa opioid binding in rat brain regions: comparison with effects of food restriction.

Diabetic rats display changes in opioid pharmacology and brain regional levels of opioid peptides and prodynorphin mRNA. Previous investigations of opioid receptor binding, carried out in whole-brain homogenates, have, however, failed to detect changes. In the present study, quantitative autoradiography was used to measure mu and kappa opioid receptor binding in discrete brain regions of streptozotocin-treated diabetic rats. Measurement was limited to regions that previously displayed opioid binding changes in chronically food-restricted rats, since our primary aim is to identify brain mechanisms that mediate adaptive responses to persistent metabolic need and adipose depletion. Diabetics displayed strong trends or statistically significant changes which matched seven of the thirteen binding changes observed in food-restricted rats. In no case did diabetics display changes in the opposite direction. The two statistically significant changes common to food-restricted and diabetic rats are increased kappa binding in the medial preoptic area and decreased mu binding in the lateral habenula. The possible functional significance of these changes is discussed.

Animals↗
PubMed1977

Changes in striatal dopamine metabolism during precipitated morphine withdrawal.

Precipitation of withdrawal in morphine tolerant/dependent rats by either naloxone or the partial agonist ZK 48491 caused a significant increase in the contration of striatal DA, which persisted for at least 1 h. During the same time the probenecid-induced accumulation of HVA and DOPAC was reduced in the striatum in relation to probenecid-treated tolerant/dependent controls. 20 min after precipitation of withdrawal by naloxone, the striatal concentration of 3-methoxytyramine was decreased by about 40%, while the activity of the DA metabolizing enzymes, MAO and COMT, remained unchanged. Naloxone-precipitated withdrawal was, further, found to delay the depletion of striatal DA caused by inhibition of synthesis 90 min after alpha-methyl-p-tyrosine treatment. All these results provide evidence for a decreased release of DA from the striatum during precipitated morphine withdrawal.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1982

Beneficial action of a new opiate antagonist (Win 44,441-3) in hemorrhagic shock.

The new opiate antagonist Win 44,441-3 (-)-isomer was infused intravenously in cats at a rate of 2 mg . kg-1 . h-1 to determine its effect in hemorrhagic shock. Hemorrhaged cats treated with Win 44,441-3 maintained post reinfusion mean arterial blood pressure (MABP) at a higher value compared to cats receiving only the vehicle. Final MABP was 70 +/- 11 mm Hg for cats receiving vehicle compared to 103 +/- 7 mm Hg for cats receiving Win 44,441-3. These values represent 60 +/- 9% and 85 +/- 6% of initial MABP for the vehicle- and Win 44,441-3-treated cats respectively. Win 44,441-2 (+)-isomer, the inactive stereoisomer of Win 44,441-3, was also infused at 2 mg . kg-1 . h-1 in cats subjected to hemorrhagic shock. The final pressure in this group was 72 +/- 8 mm Hg which is 61 +/- 8% of the initial pressure for this group. Win 44,441-3 and Win 44,441-2 were both ineffective in moderating increases in circulating lysosomal hydrolase activity in shocked cats. Neither isomer stabilized lysosomal membranes or retarded proteolysis in vitro. Plasma myocardial depressant factor was significantly reduced by the opiate antagonist, Win 44,441-3 during shock. Our results show that the systemic infusion of an opiate antagonist improves the hemodynamic state of cats subjected to hemorrhagic shock while the (+)-isomer which lacks opiate antagonist activity produces no such improvement.

Animals↗
PubMed1982

Autoradiographic localization of opiate kappa-receptors in the guinea-pig brain.

Opiate binding sites of the kappa-subtype were visualized in guinea-pig brain sections using in vitro autoradiography. kappa-Binding sites, defined as [3H](-)-bremazocine binding in the presence of high concentrations of [D-Ala2,MePhe4,Gly-ol5]enkephalin and [D-Ala2,D-Leu5]enkephalin, were found in the cortical laminae V and VI, hippocampal dentate gyrus, and lateral habenulae. The distribution of kappa-sites in the guinea-pig differs considerably from the distribution of mu- and delta-sites which others have found in the rat.

Animals↗
PubMed1982

The choice of opiate receptor subtype by neo-endorphins.

The choice of opiate receptor subtype by alpha- and beta-neo-endorphin was studied in isolated preparations. Neo-endorphins had significant inhibitory actions on the electrically evoked contractions of guinea-pig ileum, mouse vas deferens and rabbit ileum as well as on the rabbit vas deferens which had been shown to contain kappa-receptors exclusively. Mr 2266, a relatively specific kappa-receptor antagonist, was more effective than naloxone, a relatively mu-receptor antagonist, to antagonize the agonist actions of neo-endorphins in either the guinea-pig and rabbit ileum or in the rabbit vas deferens. By contrast, in the mouse vas deferens, the effectiveness of Mr 2266 to antagonize the agonist actions of neo-endorphins was low and similar to that of naloxone. The potencies of neo-endorphins relative to that of ethylketocyclazocine, a representative kappa-receptor agonist, in the guinea-pig ileum were similar to those in the rabbit ileum but were significant different from those in the mouse vas deferens. The data indicate that neo-endorphins act as kappa-receptor agonists in either the guinea-pig and rabbit ileum or in the rabbit vas deferens while in the mouse vas deferens they act on opiate receptor subtypes other than kappa- and mu-receptors.

Animals↗
PubMed1983

Opioid antagonists and drinking: evidence of kappa-receptor involvement.

Diprenorphine, naloxone, MR-2266-BS and WIN-44,441-3 were compared for their ability to antagonize morphine analgesia and to decrease deprivation-induced drinking in rats. Diprenorphine and naloxone were markedly more potent (32x) than MR-2266-BS and WIN-44,441-3 in antagonizing the analgesic effects of morphine. In contrast, diprenorphine, naloxone and MR-2266-BS decreased deprivation-induced drinking over a similar dose range. The doses required to reduce fluid consumption were higher than those necessary to antagonize morphine. WIN-44,441-3 was ineffective in decreasing drinking. The relatively similar potencies of diprenorphine, naloxone and MR-2266-BS for decreasing deprivation-induced drinking suggest that the effect on drinking involves antagonist activity at a kappa-opioid receptor.

Animals↗
PubMed1983

[3H]Mr 2034 labels a high affinity opioid kappa-receptor not accessible to naloxazone.

Saturation binding studies with [3H]Mr 2034, an opioid kappa-agonist, were carried out using brain homogenates from naloxazone-pretreated rats (200 mg/kg subcutaneously 16 hours before killing). [3H]Mr 2034 showed unaffected binding characteristics, compared to membrane homogenates of untreated controls. However, in contrast to this finding, naloxazone blocked the high affinity binding of other tritiated opioid agonists and antagonists, among them the kappa-agonist [3H]ethylketocyclazocine. Displacement studies with [3H]dihydromorphine, [3H]ethylketocyclazocine and [3H]Mr 2034 in brain membrane homogenates from untreated rats and using various opioid agonists and antagonists indicated that these substances are capable of differentiating between the two kappa-ligands [3H]ethylketocyclazocine and [3H]Mr 2034, too.

Animals↗
PubMed1984

Kappa-opiates and urination: pharmacological evidence for an endogenous role of the kappa-opiate receptor in fluid and electrolyte balance.

In prehydrated rats, the administration of kappa-opiate agonists such as bremazocine, ethylketocyclazocine or compound Upjohn-50,488 produced a dose-dependent increase in urine output and decreased the concentration of Na+ and K+ in the urine as compared to that of saline-treated rats. The diuretic effect of bremazocine lasted at least 3 h. The increase in urine output was independent of the hydration state of the rat since in non water-loaded animals, bremazocine produced proportionally as much diuresis and a decrease in the output of urine electrolytes of about the same magnitude as that observed in the prehydrated animals treated with the opioid. In contrast to the diuretic action of kappa-opiate agonists, the administration of antagonists with high affinity for the kappa-opiate receptor (Win 44,441 or Mr 2266) decreased dose dependently the output of urine and reduced very significantly the total output of Na+ and K+. Whereas 2 mg/kg naloxone did not block the bremazocine-induced urinary effects, 1 mg/kg Win 44,441 or Mr 2266 antagonized competitively the renal activity of bremazocine. The results are interpreted to suggest that the kappa-opiate receptor may be involved in the regulation of fluid and electrolyte balance.

Animals↗
PubMed1984

Tripeptides acting on opioid receptors in rat colon.

The tripeptides SD-34 and SD-25 induced atropine-, guanethidine-, antihistaminics-resistant but naloxone-sensitive contractions of isolated rat distal colon. They appeared to act on an opioid receptor, probably of the mu subtype, distinct from those for methionine enkephalin and morphine, because the pA2 values of naloxone for the peptides were similar to those for mu-agonists but different from those for methionine enkephalin and morphine, and because the peptides caused contractions of colon that had been desensitized to morphine. Mr 2266, a supposed kappa-antagonist, inhibited the actions of the peptides, ethylketocyclazocine and dynorphin at concentrations much lower than those inhibiting the actions of methionine enkephalin and morphine. Thus these peptides seem to act on the mu- and/or kappa-receptors. The actions of the tripeptides were inhibited by methysergide and methylergometrine, but not by the 5-HT2 antagonist ketanserin, and were not affected by 5-HT or substance P autodesensitization . Thus their actions do not seem to involve 5-HT, histamine, ACh or substance P. It seems likely that the tripeptides, through opioid receptors, directly activate the muscle, or remove some inhibitory modulation of myogenic activity, thus causing contractions.

Animals↗
PubMed1984

Cardiac slowing induced by peripheral kappa-opiate receptor stimulation in rats.

The cardiovascular effects of ethylketocyclazocine were studied in rats anaesthetized with pentobarbital and artificially ventilated. Ethylketocyclazocine (1 mg X kg-1 i.v.) induced a fall in heart rate and blood pressure. The bradycardia and the hypotension were not altered by bilateral vagotomy and atropine, but were inhibited by naloxone and Mr 2266 BS. Ethylketocyclazocine always induced bradycardia in beta-adrenoreceptor-blocked and pithed animals. This bradycardia was prevented by Mr 2266 BS. These results would suggest that a direct peripheral action may occur at kappa-sites, located on the heart after intravenous injection of ethylketocyclazocine in the rat.

Adrenergic beta-Antagonists↗
PubMed1985

Characterization of dynorphin A-induced antinociception at spinal level.

Dynorphin A (DYN A) injected intrathecally in the rat produced a significant elevation of the nociceptive threshold, measured by the tail flick test. The highest dose of DYN A (25 nmol) produced maximal elevation of tail flick latency to radiant heat together with hindlimb paralysis and tail flaccidity lasting several hours, thus confirming several previous reports. A lower dose of DYN A (12.5 nmol) produced only a smaller, not constant, short-lasting change in the nociceptive threshold. The vocalization test (electrical stimulation of the tail) gave a different result: the time course curve showed that the antinociceptive effect had worn off 60 min after DYN A 25 nmol. Thus it can be assumed that the prolonged depression of the tail flick reflex was related to motor dysfunction and did not completely reflect the animal's response to painful stimuli. Tolerance to the antinociceptive and motor effects developed after the chronic intrathecal infusion of DYN A with osmotic minipumps. Intrathecal MR 1452 (30 nmol), a purported kappa-receptor blocker, fully prevented the effects of DYN A but not morphine-induced antinociception. Naloxone antagonized DYN A only at a 4 fold higher dose. MR 1452 (90 nmol) administered after DYN A reversed the elevation of the vocalization threshold while tail flick latency remained unmodified. Analysis by high performance liquid chromatography of intrathecally injected radiolabelled DYN A revealed that DYN A was largely broken down about 10 min after its administration. Our results seem to indicate that DYN A in the spinal cord causes alterations in nociception and motor function, clearly distinguishable in time and both mediated by an opioid receptor, probably of the kappa type. However, different mechanism(s), possibly non-opioid in nature, may contribute to the prolonged depression of the tail flick.

Analgesia↗
PubMed1985

Vagally mediated reflex and cardiac slowing induced by loperamide in rats.

The intravenous injection of loperamide induced an immediate fall in blood pressure and heart rate in anaesthetized rats. Both effects were inhibited by the opiate antagonists naloxone and MRZ 2266 BS. Bilateral vagotomy also inhibited both effects whereas atropine only reduced the bradycardia, but the combination of atropine and tertatolol suppressed the bradycardia. A high dose of loperamide induced bradycardia in pithed rats. This effect was prevented by MRZ 2266 BS but not by naloxone. It is concluded that loperamide can elicit a vagally mediated reflex involving vagal and sympathetic mechanisms and could stimulate cardiac opiate receptors, probably kappa, both effects leading to bradycardia.

Animals↗
PubMed1985

Effect of mu and kappa opioid receptor agonists on rat plasma corticosterone levels.

The effect of several mu and kappa opioid receptor agonists on rat plasma corticosterone levels, measured using radioimmunoassay, was investigated. The mu agonists, morphine and fentanyl, and the kappa agonists, U-50,488, tifluadom and bremazocine, all produced dose-related increases in rat plasma corticosterone levels. The effects of both fentanyl and U-50,488 were reversed by naloxone, indicating an action at opioid receptors. Pretreatment of the rats with the irreversible, mu-selective antagonist, beta-funaltrexamine, reduced the effect of fentanyl, but not that of U-50,488, indicating that both mu and kappa opioid receptors are involved in mediating this effect.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1985

Conversion of dynorphin-(1-9) to [Leu5]enkephalin by the mouse vas deferens in vitro.

The inhibitory action of dynorphin-(1-9) on the electrically stimulated mouse vas deferens was seen to be antagonised by the delta-selective opioid antagonist ICI 174864. The observed delta-receptor mediated responses were partially, but not totally, prevented by peptidase inhibitors which protect the C- and N-termini of dynorphin-(1-9). [3H]Dynorphin-(1-9) is rapidly degraded by slices of vasa deferentia of the mouse. The major product of this metabolism co-elutes with [Leu5]enkephalin on reverse phase HPLC. It is concluded that a major component of the inhibitory effects of dynorphin-(1-9) on the mouse vas deferens is mediated by degradation to [Leu5]enkephalin which in turn acts through delta-receptors. It is possible that in other in vitro and in vivo systems, the effects produced by dynorphin-(1-9) might be similarly mediated by delta-receptor activation.

Animals↗
PubMed1985

The kappa opioid receptor and food intake.

Many studies have suggested a role of opioid receptors in the modulation of food intake. Several distinct classes of opioid receptors have been postulated. In an attempt to establish which opioid receptor(s) modulate feeding we studied the effect of the kappa agonist, bremazocine, on feeding and compared its effects to the preferential mu agonist, morphine, and the mixed kappa-sigma agonist, butorphanol and the kappa agonist, ethylketocyclazocine. Bremazocine increased feeding to the same extent as morphine and was less potent than the mixed agonist/antagonists. The bremazocine effect demonstrated a bell-shaped dose response curve. Daily administration of bremazocine or morphine enhances the effect on increasing food intake. However, this effect of daily injections on enhancing food intake is not present when animals receiving morphine are crossed over to bremazocine and vice versa. The bremazocine effect is enhanced by diprenorphine and not inhibited by naloxone. Low doses of the dopamine antagonist, haloperidol, enhance the bremazocine effect and higher doses inhibit it. Finally, using another kappa agonist, tifluadom, we showed that the effect on food intake is stereospecific. Our studies provided further evidence for a role for the kappa opioid receptor in feeding. However, they also suggest that more than one subpopulation of opioid receptors is involved in feeding modulation.

Animals↗
PubMed1985

A kappa-selective opioidergic pathway is involved in the reversal of a behavioural effect of adrenalectomy.

We have shown previously that adrenalectomized rats are immobile for only approximately 30% of a 5 min retest period, 24 h after an initial 15 min swimming exposure, compared with approximately 70% immobility for intact animals. The administration of ketocyclazocine, dynorphin-(1-17) or [Met5]enkephalin[Arg6,Phe7] immediately after initial exposure reversed the effect of adrenalectomy, whereas equimolar doses of morphine sulphate, [D-Ala2,D-Leu5]enkephalin and dynorphin-(1-8) were inactive. MR2266, a kappa-selective partial agonist/predominant antagonist, did not reverse immobility but antagonized the reversing effect of ketocyclazocine. In conjunction with our previous studies, we interpret these data to show that one of the opioidergic pathways for the incorporation of information post-stress is kappa-selective. This kappa selectivity in turn suggests a possible physiological role for prodynorphin-derived peptides in memory.

Adrenalectomy↗
PubMed1985

[3H]U-69593 a highly selective ligand for the opioid kappa receptor.

The selective kappa agonist U-50488 was recently discovered and characterized. In this study, the receptor binding properties of [3H]U-69593, an analog of U-50488, were characterized. [3H]U-69593 binds with high affinity (3 nM) to membranes prepared from guinea pig, mouse and rat brain. The number of kappa binding sites comprise only 13%, 9% and 4% of the total opioid sites, respectively. The benzmorphans, dynorphin, and compounds structurally related to U-50488 have high affinity for this kappa site.

Analgesics↗