tan-67 and norbinaltorphimine

We investigated whether delta- and kappa-opioid agonists alter myocardial function, intracellular Ca(2+) concentration ([Ca(2+)](i)), and myofilament Ca(2+) sensitivity in intact guinea pig beating hearts and whether these effects are mediated by an opioid receptor. Intact guinea pig hearts were perfused with modified Krebs Ringer solution containing delta- (TAN-67) and kappa- (ICI-199441) opioid agonists in the absence and presence of delta- (BNTX) and kappa- (nor-BNI) opioid antagonists, respectively, while functional variables and [Ca(2+)](i) were recorded. TAN-67 (1 microM) and ICI-199441 (1 microM) decreased heart rate (P < 0.05). TAN-67 (1 microM) and ICI-199441 (1 micro M) decreased available [Ca(2+)](i) without changing developed left ventricular pressure (LVP) (P < 0.05). TAN-67 (1 microM) and ICI-199441 (1 microM) also caused a leftward shift in the curve of developed LVP as a function of available [Ca(2+)](i) (P < 0.05). ICI-199441 (1 microM) produced a steeper slope in the relation curve compared with baseline (P < 0.05). BNTX (1 microM) and nor-BNI (1 microM) blocked the effects of TAN-67 and ICI-199441, respectively. delta- and kappa-opioid agonists enhance myofilament Ca(2+) sensitivity despite decreasing available [Ca(2+)](i) in intact isolated guinea pig hearts, and these effects are mediated by delta- and kappa-opioid receptor stimulation.. Our results indicate that delta- and kappa-opioid agonists enhance myofilament Ca(2+) sensitivity despite decreasing available intracellular Ca(2+) concentrations in intact isolated guinea pig beating hearts, and these effects are mediated by delta- and kappa-opioid receptor stimulation.

Topics: Actin Cytoskeleton; Animals; Benzylidene Compounds; Blood Pressure; Calcium; Coronary Circulation; Guinea Pigs; Heart; Heart Rate; In Vitro Techniques; Kinetics; Naltrexone; Narcotic Antagonists; Pyrrolidines; Quinolines; Receptors, Opioid, delta; Receptors, Opioid, kappa; Stimulation, Chemical; Ventricular Function, Left

The present study was designed to investigate the role of the endogenous opioid system in the development of ethanol-induced place preference in rats exposed to conditioned fear stress (exposure to an environment paired previously with electric foot shock), using the conditioned place preference paradigm. The administration of ethanol (300 mg/kg, i.p.) with conditioned fear stress induced significant place preference. Naloxone (1 and 3 mg/kg, s.c.), a non-selective opioid receptor antagonist, significantly attenuated this ethanol-induced place preference. Moreover, the selective mu-opioid receptor antagonist beta-funaltrexamine (3 and 10 mg/kg, i.p.) and the selective delta-opioid receptor antagonist naltrindole (1 and 3 mg/kg, s.c.) significantly attenuated ethanol-induced place preference. In contrast, the selective kappa-opioid receptor antagonist nor-binaltorphimine (3 mg/kg, i.p.) significantly enhanced ethanol-induced place preference. Furthermore, 75 mg/kg ethanol (which tended to produce place preference) combined with the mu-opioid receptor agonist morphine (0.1 mg/kg, s.c.) or the selective delta-opioid receptor agonist 2-methyl-4aalpha-(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12aalpha- octahydroquinolino [2,3,3,-g] isoquinoline (TAN-67; 20 mg/kg, s.c.), at doses which alone did not produce place preference, produced significant place preference. However, co-administration of the selective kappa-opioid receptor agonist trans-3,4-dichloro-N-(2-(1-pyrrolidinyl)cyclohexyl)benzenacetamide methanesulfonate (U50,488H; 0.3 and 1 mg/kg, s.c.) with ethanol (300 mg/kg, i.p.) dose dependently attenuated ethanol-induced place preference. Moreover, conditioned fear stress shifted the response curve for the aversive effect of U50,488H to the left. These results suggest that mu- and delta-opioid receptors may play critical roles in the rewarding mechanism of ethanol, and that kappa-opioid receptors may modulate the development of the rewarding effect of ethanol under psychological stress.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Behavior, Animal; Central Nervous System Depressants; Conditioning, Psychological; Ethanol; Fear; Male; Morphine; Naloxone; Naltrexone; Narcotic Antagonists; Quinolines; Rats; Rats, Sprague-Dawley; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Stress, Psychological

The purpose of this study was to establish the ethanol-induced place preference in rats exposed to foot shock stress using the conditioned place preference paradigm. We also investigated the role of the endogenous opioid system in the development of the ethanol-induced place preference. The administration of ethanol (300 mg/kg, i.p.) with foot shock stress, but not without such stress, induced a marked and significant place preference. Naloxone (1 and 3 mg/kg, s.c.), a non-selective opioid receptor antagonist, significantly attenuated the ethanol-induced place preference. Moreover, the selective mu-opioid receptor antagonist beta-funaltrexamine (3 and 10 mg/kg, i.p.) and selective delta-opioid receptor antagonist naltrindole (1 and 3 mg/kg, s.c.), but not the selective kappa-opioid receptor antagonist nor-binaltorphimine (1 and 3 mg/kg, i.p.), significantly attenuated the ethanol-induced place preference. Furthermore, 150 mg/kg ethanol (which tended to produce a place preference, although not significantly) combined with each dose (that did not produce a place preference) of the mu-opioid receptor agonist morphine (0.1 mg/kg, s.c.) or selective delta-opioid receptor agonist 2-methyl-4aalpha-(3-hydroxyphenyl)-1,2,3,4,4a,5,12, 12aalpha-octahydroquinolino [2,3,3-g] isoquinoline (TAN-67; 20 mg/kg, s.c.), but not the selective kappa-opioid receptor agonist trans-3, 4-dichloro-N-(2-(1-pyrrolidinyl)cyclohexyl)benzenacetamide methanesulfonate (U50,488H; 1 mg/kg, s.c.), produced a significant place preference. These data indicate that stress may be important for development of the rewarding effect of ethanol, and that mu- and delta-opioid receptors may be involved in the rewarding mechanism of ethanol under stressful conditions.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Behavior, Animal; Dose-Response Relationship, Drug; Electric Stimulation; Ethanol; Exploratory Behavior; Foot; Injections, Intraperitoneal; Injections, Subcutaneous; Male; Morphine; Naloxone; Naltrexone; Narcotics; Quinolines; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta; Receptors, Opioid, mu

The effects of selective mu-, delta- and kappa-opioid receptor agonists and antagonists on the discriminative stimulus properties of methamphetamine were examined in rats that had been trained to discriminate between methamphetamine (0.4 mg/kg) and saline. Methamphetamine produced a dose-related increase in methamphetamine-appropriate responses in all of the rats. In generalization tests, neither morphine (a mu-opioid receptor agonist: 0.3-10 mg/kg) nor 3,4-dichloro-N-[2-(1-pyrrolidinyl)cyclohexo]benzeneacetamide (U50,488H: a kappa-opioid receptor agonist: 1.0-8.0 mg/kg) generalized to the discriminative stimulus properties of methamphetamine. A newly synthesized non-peptide selective delta-opioid receptor agonist 2-methyl-4aalpha-(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12aalpha- octahydroquinolino(2,3,3,-g)isoquinoline (TAN-67: 32 mg/kg) partially generalized (70% methamphetamine-appropriate responses) to the discriminative stimulus properties of methamphetamine. In combination tests, pretreatment with the mu- and kappa-opioid receptor antagonists, beta-funaltrexamine (9.0 mg/kg) and nor-binaltorphimine (10 mg/kg), respectively, had little or no influence on the discriminative stimulus properties of methamphetamine. In contrast, pretreatment with naltrindole (a non-selective delta-opioid receptor antagonist: 3.0 mg/kg) or naltriben (a selective delta2-opioid receptor antagonist: 1.0 mg/kg), but not with 7-benzylidenenaltrexone (a selective delta1-opioid receptor antagonist: 0.5 and 1.0 mg/kg), significantly attenuated the discriminative stimulus properties of methamphetamine. However, naltrindole (3.0 mg/kg) did not significantly attenuate the discriminative stimulus properties of methamphetamine at a higher training dose (1.0 mg/kg). Our findings may have some bearing on the relative importance of the role of delta-opioid (especially delta2-opioid) receptors in the discriminative stimulus properties of a low dose of methamphetamine.

Topics: Animals; Benzylidene Compounds; Central Nervous System Stimulants; Discrimination, Psychological; Dose-Response Relationship, Drug; Male; Methamphetamine; Naltrexone; Quinolines; Rats; Rats, Inbred F344; Receptors, Opioid, delta