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At least 847 records · Page 47Linked to original sources
PubMed1991

Differential antagonism of U69,593- and bremazocine-induced antinociception by (-)-UPHIT: evidence of kappa opioid receptor multiplicity in mice.

The effect of pretreatment with the kappa receptor nonequilibrium antagonist, (-)-UPHIT (1S,2S-trans-2-isothiocyanato-4,5-dichloro-N-methyl-N-[2-(1-pyrrol idinyl) cyclohexyl]benzeneacetamide), on U69,593 [(5 alpha,7 alpha,8 beta)-(-)-N-methyl-N-(7-(1-pyrrolidinyl)-1-oxaspiro(4,5) dec-8-yl)benzeneacetamide]- and bremazocine-induced antinociception was examined in mice. Both U69,593 and bremazocine produced antinociception in the warm water tail-flick test after i.c.v. administration. Pretreatment with the kappa antagonist, nor-binaltorphimine, at doses shown not to affect [D-Ala2, NMePhe4, Gly-ol]enkephalin- (mu-agonist) or [D-Pen2, D-Pen5]enkephalin (delta-agonist)-induced antinociception, significantly attenuated the effects of U69,593 and bremazocine, suggesting actions of these agonists at kappa receptors. Furthermore, beta-funaltrxamine (mu antagonist) and ICI 174,864 [N,N,-diallyl-Tyr-(alpha-aminoisobutyric acid)2-Phe-Leu-OH] (delta antagonist), had no effect on U69,593 or bremazocine in this test providing further evidence of kappa receptor-mediated activity. Pretreatment with (-)-UPHIT produced no effect alone and a long-lasting (up to 48 hr) antagonism of U69,593, but not bremazocine, antinociception. The antagonist actions of (-)-UPHIT did not alter the antinociceptive effects of [D-Ala2, NMePhe4, Gly-ol]enkephalin or [D-Pen2, D-Pen5]enkephalin. These data suggest that (-)-UPHIT is a selective, long-lasting kappa antagonist which can differentially antagonize the antinociception produced by these two kappa agonists. These data provide evidence in vivo supportive of kappa receptor subtypes in the mouse, and suggest that (-)-UPHIT may be a useful probe for the exploration of kappa receptor heterogeneity.

Analgesics↗
PubMed1991

Prevention of hyperthermia-induced convulsions in immature rat by MR-2266, a kappa antagonist.

The opioid receptor subtypes involved in hyperthermia-induced convulsions were studied by testing different opioid receptor-selective antagonists in unrestrained 15-day-old rats. Saline-injected animals exposed to an ambient temperature of 40 degrees C showed a gradual increase in body temperature reaching a maximum of 40.4 +/- 0.2 degrees C at 60 min. At this time all rat pups had convulsions and died. Similar results were obtained when the animals were pretreated with beta-funaltrexamine or 1 mg/kg ICI-154129. However, the injection of 10 mg/kg ICI-154129 prevented hyperthermia-induced convulsions (only 20% of the rats showed generalized convulsions at 90 min). Rats treated with the kappa antagonist MR-2266 also showed an increase in rectal temperature. However, none of the animals had convulsions or died. These results suggest that the kappa-opioid receptors are involved in convulsions induced by hyperthermia.

Animals↗
PubMed1990

The possible involvement of alpha-adrenoceptors in the intestinal effect of nalbuphine in mice.

In the present study, intestinal motility was measured by the transit of charcoal meal through the small intestine in mice. Nalbuphine, given subcutaneously, caused a dose-dependent inhibition of the intestinal transit in mice. This inhibitory effect of nalbuphine was antagonized by prior s.c. administration of naloxone and MR2266. In addition, the inhibitory effect of nalbuphine was also suppressed by prior administration of yohimbine, an alpha 2-adrenoceptor antagonist, and phentolamine, an antagonist for both alpha 1- and alpha 2-adrenoceptors. Unlike morphine, the intestinal inhibitory effect of nalbuphine was also antagonized by prazosin, a selective alpha 1-adrenoceptor antagonist. However, prior administration of propranolol did not alter this effect of nalbuphine. These adrenoceptor antagonists by themselves, at the doses used, had no effect on the rate of intestinal transit of a charcoal meal in mice. These results suggest that both alpha 1- and alpha 2-adrenoceptors may be involved in the intestinal effect of nalbuphine while beta-adrenoceptors do not appear to play any significant role in this aspect of nalbuphine's action.

Animals↗
PubMed1990

Different motor actions of dynorphins and nonpeptide kappa opioid receptor agonists in the isolated rat colon.

Dynorphin 1-17 has been suggested to be the endogenous ligand for kappa opioid receptors. In this study motor effects of dynorphin 1-17, its N-terminal fragments d-Pen2,d-Pen5-enkephalin (DPDPE) and d-Ser2-[Leu5]enkephalin-Thr (DSLET) without or with pretreatment with naloxone, (-)-2-(furylmethyl)-noretacocine (Mr 2266) or tetrodotoxin (TTX) on the isolated rat colon were compared with those of nonpeptide kappa opioid receptor agonists. Intraluminal pressure changes were measured by perfusion manometry in preparations maintained in a standard organ bath. Dynorphin 1-17, 1-9, 1-8, 1-6, [Leu5]enkephalin, DPDPE and DSLET dose dependently stimulated the tone in the proximal, middle and distal colon with the maximum response at 10(-6) to 10(-5) M. The stimulation produced by Tyr-Gly-Gly-Phe and Tyr-Gly-Gly was 60 and 600 times less potent, respectively. Concentrations of 10(-10) to 10(-6) M des-Tyr1-[Leu5]enkephalin, dynorphin 3-13, 6-17, 1-methyl-2-(3-thienylcarbonyl)-amino-ethyl-5-(2-fluorophenyl)-H-2,3 dihydro-1,4-benzodiazepine, trans-(+/-)-3,4-dichloro-N-methyl-N-(2-(1-pyrrolidinyl) cyclohexyl)-benzene- acetamide-methane sulfonate and (5a,7a,8B)-(-)-N-methyl-(7-(1-pyrrolidinyl)-1-oxaspiro(4,5)-dec-8- yl) benzeneacet-amide produced no changes in motor activity of the rat colon. Only doses exceeding 10(-6) M of the latter three substances stimulated colonic tone. This action was inhibited neither by naloxone nor by Mr 2266. In contrast, the stimulation by dynorphin 1-17 and 1-6 was inhibited to a greater extent by naloxone than by Mr 2266.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1990

Characterization of kappa opioid binding using dynorphin A1-13 and U69,593 in the rat brain.

Previous studies of kappa opioid binding sites have suggested heterogeneous binding to this class of opioid receptors. To further investigate kappa receptor heterogeneity, we analyzed the binding properties of various "kappa-selective" ligands in rat brain homogenates. Displacement assays were carried out using [3H]bremazocine in the presence of various displacing ligands under mu and delta receptor-blocked conditions. Homologous displacement of [3H]bremazocine produced "shallow" displacement which best fit a two-site model of drug-receptor interaction. Dynorphin A1-13 and U69,593 exhibited similar biphasic displacement of [3H]bremazocine. Maximal displacement by these ligands, however, represented only approximately 55% of total [3H]bremazocine binding, which suggests the existence of a third component of [3H]bremazocine binding. Biphasic displacement by dynorphin A1-13 was detected in tissue throughout the brain and the spinal cord, whereas the dynorphin-resistant component of [3H]bremazocine binding was uniquely absent in the spinal cord. U50,488H, tifluadom and ethylketocyclazocine appeared to displace from additional, dynorphin-insensitive sites, as their maximal displacement exceeded that seen with either dynorphin A1-13 or U69,593. These results strongly suggest the existence of at least three components of non-mu, non-delta [3H]bremazocine binding in the rat brain: two with differential affinity for dynorphin A1-13 and U69-593 (kappa-1 and kappa-2 sites), and a third (termed here R1) that was further resolved into two binding sites by bremazocine. Preliminary analysis of the R1 component using naloxone revealed one high-affinity site, which may be opiate in nature, and a second site whose binding properties closely resemble those of the sigma receptor described by others.

Analgesics↗
PubMedDate not supplied

Morphine inhibits the ethanol-induced gastric damage in rats.

Morphine (0.1-2 mg/kg)--administered either orally (p.o.) or subcutaneously (s.c.)--inhibited the acidified ethanol-induced gastric damage in a dose-dependent manner. However, when morphine was given intracerebroventricularly no inhibition was observed. Naloxone (0.5 mg/kg, s.c. and p.o.) blocked the protective action of morphine. Bremazocine (0.05-1 mg/kg, p.o., s.c.) did not influence the ethanol-induced mucosal necrosis in a significant manner, but decreased (in the dose of 0.5 mg/kg, p.o., s.c.) the protective action of morphine. Morphine (1 mg/kg, s.c.) also reduced the ethanol-induced enhanced vascular permeability of gastric mucosa and naloxone (0.5 mg/kg, s.c.) inhibited this effect too. Indomethacin (10 mg/kg, p.o.) and the sulfhydryl alkylator N-ethylmaleimid (50 mg/kg, s.c.) decreased the protective action of morphine, suggesting a possible involvement of mucosal prostaglandins and sulfhydryls in the effect of morphine on ethanol-induced gastric erosions.

Administration, Oral↗
PubMed1990

Discriminative stimulus properties of U50,488 and morphine: effects of training dose on stimulus substitution patterns produced by mu and kappa opioid agonists.

By using a two-lever drug discrimination task, four groups of rats were trained to discriminate either a low (3.0 mg/kg) and a high (5.6 mg/kg) training dose of the kappa opioid agonist U50,488 [trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolindinyl)cyclohexyl] benzeneacetamine methanesulfonate hydrate] or a low (3.0 mg/kg) and a high (10 mg/kg) training dose of the mu opioid agonist morphine from water. The stimulus effects of the high training dose of U50,488 were shared by the kappa agonists bremazocine and ethylketocyclazocine (i.e., these drugs produced at least 80% drug-appropriate responding), but not by the mu agonists morphine, fentanyl and l-methadone or the nonopioid compounds d-amphetamine, pentobarbital and phencyclidine. Conversely, the stimulus effects of the high training dose of morphine were shared by other mu agonists, but not by the kappa agonists or the nonopioid compounds examined. Similarities in the stimulus effects of morphine and U50,488 occurred, however, when mu and kappa agonists were examined in rats trained to discriminate relatively low training doses of morphine or U50,488 from water. At the low training dose of morphine, complete substitution was obtained with the mu agonists tested as well as the kappa agonist ketocyclazocine. In these rats, intermediate (approximately 70% drug-appropriate responding) levels of substitution were obtained with the kappa agonists bremazocine and ethyylketocyclazocine. Similarly, at the low training dose of U50,488 both the mu and kappa agonists examined substituted completely. Asymmetrical substitution occurred between U50,488 and morphine at the low training doses, with morphine substituting completely for the low training dose of U50,488 and U50,488 failing to substitute for the low training dose of morphine. The rank order of potency for naloxone as an antagonist of the stimulus effects of morphine and U50,488 was; 3.0 mg/kg of morphine greater than 10 mg/kg of morphine greater than 3.0 mg/kg of U50,488 = 5.6 mg/kg of U50,488. The present results indicate that training dose is an important determinant of the different levels of cross-substitution obtained between mu and kappa agonists, and that a greater pharmacological specificity of drug-induced discriminative stimuli can be obtained when relatively high training doses of mu and kappa opioid agonists are used to establish the discrimination.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1990

Reconstitution of solubilized delta-opiate receptor binding sites in lipid vesicles.

Delta-opiate receptors have been solubilized with the non-ionic bile salt detergent digitonin from NG108-15 cell membranes and reconstituted into lipid vesicles. Specific opiate binding was restored to soluble receptor preparations after supplementation with a brain lipid extract, and dilution below the effective detergent concentration. Saturable and specific opiate binding was measured for both membrane and vesicle preparations; dissociation constants (Kd) obtained from saturation isotherms of [3H]bremazocine binding were 1.3 and 4.2 nM, respectively. Relative affinity (IC50) values of ligand binding measured for subtype-selective agonists confirmed that a delta-opiate binding site interaction was recovered in vesicle preparations. Changes in agonist binding affinity noted for these experiments were explained by dissociation of the GTP-binding protein Gi from the receptor in detergent. The recovery of solubilized opiate receptors was nearly quantitative, and strictly dependent upon the total brain lipid preparation used in the reconstitution. Ligand binding was incompletely recovered after substituting pure, vesicle-forming phospholipid preparations. [3H]Bremazocine binding was also reconstituted after lectin affinity chromatography of solubilized receptor preparations, using conditions which likely effect the removal of endogenous lipid cofactors. A photoaffinity cross-linking methodology was employed to verify recovery of the delta-opiate receptor after its solubilization from membranes and reconstitution. Two membrane-associated proteins (50 and 70 kDa) were covalently tagged with an azido analog of beta-endorphin(Leu5) in cell membranes and subsequently identified by immunoblotting with antisera directed against this opioid. Labeling of the 50-kDa polypeptide was prevented by coincubating assay samples with a relative excess of (D-Pen2,5)enkephalin. This opioid binding polypeptide was also present in solubilized/reconstituted receptor preparations.

Animals↗
PubMed1989

Opioid- and phencyclidine-like discriminative effects of ditolylguanidine, a selective sigma ligand.

The sigma binding site in brain has affinity for psychotomimetic opioids, phencyclidine (PCP) and antipsychotic drugs, and is a separate entity from the PCP receptor. In order to demonstrate a behavioral correlate of sigma binding, rats were trained to discriminate between s.c. injections of saline and 3.0 mg/kg of ditolylguanidine (DTG), a selective and high affinity sigma ligand, and tested for generalization to novel drugs. The rats generalized dose dependently and completely or almost completely to PCP and related drugs and to mu, kappa and sigma opioid agonists. A separate group of rats trained to discriminate saline from 2.0 mg/kg of PCP generalized completely to DTG, confirming the commonalities in the discriminative effects of these drugs. DTG-like discriminative effects of opioid enantiomers showed no consistent stereoselectivity. Discriminative effects of the DTG training dose were neither mimicked by haloperidol and (-)-butaclamol, which have high affinity for the sigma site, or by the opioid antagonist naltrexone. Order of potency in producing DTG-like discriminative effects did not correlate with published reports of relative drug affinity for the sigma site or the PCP receptor. Although the discriminative effects of DTG have commonalities with those of several types of opioid and PCP-like drugs, their pharmacologic characteristics are different from the pharmacologic characteristics of opioid and PCP receptors as well as from those of the sigma binding site.

Animals↗
PubMed1989

Differential cross-tolerance to opioid agonists in morphine-tolerant pigeons responding under a schedule of food presentation.

Effects of the opioid agonists morphine, l-methadone, ethylketazocine, U50,488 [trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl]benzeneacetamide methanesulfonate hydrate], cyclazocine and bremazocine, and the nonopioid chlorpromazine were determined in pigeons responding under a fixed-ratio 30 schedule of food presentation before, during and after chronic morphine administration. Before chronic morphine administration, all drugs produced dose-dependent decreases in response rates. After daily administration of up to 56 mg/kg of morphine for 7 weeks, dose-effect curves for the mu agonists morphine and l-methadone, as well as the mu/kappa agonist ethylketazocine shifted to the right approximately 1 1/4, 3/4 and 1/2 log units, respectively. In contrast, dose-effect curves for the mixed agonist/antagonists cyclazocine and bremazocine each shifted to the left approximately 3/4 log unit, whereas dose-effect curves for the kappa agonist U50,488 and the nonopioid chlorpromazine did not shift during chronic morphine administration. Dose-effect curves for all drugs except bremazocine returned to their prechronic positions within the period 3 to 8 weeks after termination of chronic morphine administration. The present study demonstrates that repeated administration of morphine produces tolerance to its rate-decreasing effects as well as cross-tolerance selective to other opioids possessing mu agonist properties. The cross-tolerance to ethylketazocine observed in morphine-tolerant pigeons corroborates studies of the discriminative stimulus effects of ethylketazocine in pigeons, suggesting that in this species ethylketazocine possesses predominantly mu agonist properties.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1989

Mu- and delta-opioid receptor-mediated inhibition of adenylate cyclase activity stimulated by released endogenous dopamine in rat neostriatal slices; demonstration of potent delta-agonist activity of bremazocine.

Rat neostriatal slices were superfused with medium containing 0.1 to 30 microM of the dopamine (DA)-releasing agent D-(+)-am-phetamine (AMPH) and the D-2 DA receptor antagonist (-)-sulpiride (10 microM) in the absence or presence of mu-, delta-, and kappa-selective opioids. AMPH dose-dependently enhanced the cyclic AMP production, as measured by its efflux from striatal slices, whereas simultaneous blockade of D-2 DA receptors by (-)-sulpiride strongly potentiated this effect. Both the mu-opioid receptor selective agonist [D-Ala2,MePhe4,Gly-ol5]enkephalin (0.01-3 microM) and the delta-opioid receptor selective agonist [D-Phe2-D-Pen5]enkephalin (DPDPE, 0.01-3 microM) inhibited the cyclic AMP efflux, stimulated by 10 microM AMPH in the presence of (-)-sulpiride, by 70 to 80%. The highly selective kappa-opioid receptor agonist U 50,488 (trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrol-idinyl)- cyclohexyl]benzeneacetamide methanesulfonate hydrate) (0.01-1 microM) had no effect. In contrast, the purported kappa-opioid receptor agonist bremazocine (3-300 nM) inhibited the stimulated adenylate cyclase activity to a similar extent as did [D-Ala2-MePhe4,Gly-ol5]enkephalin and DPDPE. Moreover, the selective irreversible delta-antagonist fentanyl isothiocyanate reversed both the inhibition caused by DPDPE and that caused by bremazocine, whereas the kappa-selective antagonist norbinaltorphimine showed no differences in its potency to antagonize the inhibitory effects of the different opioid agonists. The results indicate that opioids, by activating mu- or delta-, but not kappa-opioid receptors may cause a profound inhibition of adenylate cyclase activity stimulated by activation of (postsynaptic) D-1 DA receptors upon the (presynaptic) release of DA.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗