Selective kappa antagonist properties of nor-binaltorphimine in the rat mes seizure model
Abstract
The opioid antagonist properties of nor-binaltorphimine (nor-BNI; 17,17′-Bis (cyclopropylethyl)-6,6′,7,7′-tetradehydro-4,5:4′,5′- diepoxy-6,6′-(imino)[7,7′-bimorphinan]-3,3′,14,14′-tetrol) were evaluated in the rat maximal electroshock (MES) seizure model. Following s.c. or i.c.v. pretreatment, nor-BNI selectively antagonized the anticonvulsant effects of the kappa opioid U50,488, significantly increasing its ED50 by 2.3 and 4.5 fold, respectively. In contrast, pretreatment with nor-BNI (s.c. or i.c.v.) failed to antagonize the anticonvulsant effects of the selective mu opioid, DAMGO. At the doses and injection routes used, nor-BNI itself had no apparent effect on overt behavior or MES-induced convulsions. These data support the earlier suggestion that the anticonvulsant effects of U50,488 are mediated by kappa opioid receptors and confirm 1) the selectivity of nor-BNI as a kappa antagonist and 2) its applicability as a pharmacological tool in the differentiation of multiple opioid receptors.
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2008, European Journal of PharmacologyWe aimed to further define the pathway mediating the inhibitory effects of κ-opioid receptor stimulation on Ca2+ transients and hypertrophic responses to β1-adrenoceptor stimulation. We determined the effects of Trans-(±)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-benzeneacetamid methanesulfonate salt (U50,488H), a selective κ-opioid receptor agonist, on the enhancement of spontaneous Ca2+ transients and the induction of hypertrophy by isoprenaline, a β-adrenoceptor agonist, in cultured neonatal ventricular myocytes. The results were compared with those found with KN93, a selective Ca2+/calmodulin-dependent kinase (CaMKII) inhibitor, propranolol, a β-adrenoceptor antagonist, and verapamil, a L-type Ca2+ channel antagonist. Hypertrophy of cardiomyocytes was characterized by increases in (i) total protein content; (ii) cell size; and (iii) [3H]leucine incorporation. 10 μmol/l isoprenaline increased all three parameters. We also determined the expression of nuclear CaMKIIδ in response to U50,488H in the presence or absence of isoprenaline. To determine whether the effects of U50,488H were receptor-mediated, its effects were also measured following blockade of the κ-opioid receptor with nor-binaltorphimine. κ-Opioid receptor stimulation suppressed the stimulatory effect of isoprenaline on Ca2+ transients and cardiac hypertrophy, as did KN93, propranalol and verapamil. U50,488H also suppressed the expression of nuclear CaMKIIδB in the presence, but not in the absence of isoprenaline. These results suggest that the inhibitory effect of κ-opioid receptor stimulation on β1-adrenoceptor stimulation may also involve CaMKIIδ.
κ-opioid receptor stimulation inhibits cardiac hypertrophy induced by β<inf>1</inf>-adrenoceptor stimulation in the rat
2007, European Journal of PharmacologyTo test the hypothesis that κ-opioid receptor stimulation inhibits cardiac hypertrophy induced by β1-adrenoceptor stimulation, we determined the effects of trans-(±)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-benzeneacetamide methanesulfonate salt (U50,488H), a selective κ-opioid receptor agonist, on cardiac hypertrophy induced by isoprenaline, a selective β-adrenoceptor agonist, in neonatal ventricular myocytes upon blockade of β2-adrenoceptor. Hypertrophy of cardiomyocytes was determined by increases in (i) total protein content; (ii) [3H]leucine incorporation; and iii) cell size. 10 μmol/l isoprenaline increased all three parameters. The effects were abolished by 2 μmol/l propranolol, a β-adrenergic receptor antagonist, or 300 nmol/l CGP20712A, a β1-adrenoceptor antagonist, but not by 100 nmol/l ICI118,551, a β2-adrenoceptor antagonist. The effects were also abolished by Rp-cAMPs 100 μmol/l, a protein kinase A inhibitor and not by pertussis toxin 5 mg/l. The effects of isoprenaline in the presence or absence of ICI118,551 were also abolished by 1 μmol/l U50,488H. The inhibitory effects of U50,488H were abolished by 1 μmol/l nor-binaltorphimine, a selective κ-opioid receptor antagonist. U50,488H also abolished the increases in the amplitude and frequency of the spontaneous intracellular Ca2+ transient induced by 10 μmol/l isoprenaline in the presence or absence of ICI118,551, an effect also abolished by nor-binaltorphimine. In conclusion the results show that κ-opioid receptor stimulation abolished both the cardiac hypertrophy and enhanced amplitude and frequency of the spontaneous intracellular Ca2+ transient induced by β1-adrenoceptor stimulation.
Norbinaltorphimine
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The dynamic relationship between mu and kappa opioid receptors in body temperature regulation
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On the mechanism of anticonvulsant effect of tramadol in mice
2005, Pharmacology Biochemistry and BehaviorThe present study was conducted to examine the effects of tramadol, an atypical opioid on convulsive behaviour in maximal electroshock (MES) seizure test on mice. Moreover, an attempt was also made to investigate the role of possible receptor mechanisms involved. MES seizures were induced via transauricular electrodes (60 mA, 0.2 sec). Seizure severity was determined by (1) the duration of tonic hindlimb extensor (THE) phase and by (2) mortality due to electroconvulsions. Intraperitoneal (i.p.) administration of tramadol dose-dependently (10–50 mg/kg) decreased the duration of THE phase of MES. The anticonvulsant effect of tramadol was antagonized by the opioid antagonists, naloxone in high dose, and MR2266, a selective kappa antagonist but not by naltrindole, a delta opioid antagonist. Coadministration of either γ-aminobutyric acid (GABA)-ergic drugs (diazepam, GABA, muscimol and baclofen) or N-methyl-d-aspartate (NMDA) receptor antagonist, MK801 with tramadol augmented the anticonvulsant effect of the latter drug. By contrast, flumazenil, a central benzodiazepine (BZD) receptor antagonist, counteracted the diazepam-induced facilitation of anti-MES effect of tramadol. Similarly, δ-aminovaleric acid (DAVA), a GABAB receptor antagonist, abolished the facilitatory effect of baclofen, a GABAB agonist on anti-MES action of tramadol. These BZD–GABAergic antagonists, flumazenil or DAVA, on their own also antagonized the anti-MES effect of tramadol administered alone. No significant effect on mortality was observed in any of the studied groups. Taken together, the current results have demonstrated a possible role for multitude of important neurotransmitter systems, i.e., opioid (kappa), GABAA–BZD receptors system, GABAB receptors and NMDA channel involvement in the antielectroshock effect of tramadol in mice.