morphinans and 16-methylcyprenorphine

The antiarrhythmic activities of 16-methylcyprenorphine (M8008), nor-binaltorphimine (NBT) and naltrexone, which are relatively specific opioid receptor antagonists for delta, kappa and mu receptors, respectively, were examined during the 30 min following coronary artery occlusion in anaesthetised rats. The haemodynamic and electrocardiographic effects of the opioid receptor agonists [D-Ala2,D-Leu5]enkephalin (DADLE) (relatively selective for delta receptors), ICI-204448 (kappa) and glyol (mu) were also investigated over the 30-90 min post ligation period. When administered intravenously 5 min before ligation, M8008 (0.5 mg kg-1 and 2.5 mg kg-1) reduced the number of ventricular ectopic beats but had no effect on the incidence or duration of ventricular fibrillation. NBT and naltrexone were not antiarrhythmic at a dose of 0.5 mg kg-1 but at 2.5 mg kg-1 (a concentration at which both drugs block kappa receptors) the number of ventricular ectopic beats, the incidence of ventricular fibrillation and mortality were all reduced. All of the opioid receptor agonists caused a transient decrease in heart rate and in arterial blood pressure but none exhibited an arrhythmogenic effect. These studies suggest that the delta and kappa opioid receptor antagonists used may be antiarrhythmic as a result of blockade of the action of endogenously released peptides acting on these receptors or that they have a non-specific 'direct' antiarrhythmic action.

Topics: Animals; Arrhythmias, Cardiac; Coronary Disease; Coronary Vessels; Electrophysiology; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, Leucine-2-Alanine; Enkephalins; Hemodynamics; Male; Morphinans; Naltrexone; Narcotic Antagonists; Pyrrolidines; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu

The cardiac electrophysiological effects of 16-methylcyprenorphine (M8008), nor-binaltorphimine (NBT) and naltrexone, which are relatively specific opioid antagonists for delta, kappa and mu receptors, respectively, were studied in paced (1.5 Hz) sheep Purkinje fibres in vitro. M8008 (1 ng ml-1-10 micrograms ml-1) caused a concentration-dependent reduction in the maximum rate of depolarisation of phase 0 (MRD) and in the action potential duration measured at 50% repolarisation, APD50. Neither NBT (10 ng ml-1-10 micrograms ml-1) nor naltrexone (1 ng ml-1-10 micrograms ml-1) produced any significant effect on the cardiac action potential. In the presence of a physiological salt solution modified to mimic some of the changes that occur during myocardial ischaemia (i.e. hypoxia, acidosis, hyperkalaemia), M8008 caused a more marked reduction in MRD and prolonged rather than shortened APD50. These results suggest that the reported antiarrhythmic activity of M8008, but not NBT or naltrexone, may be, at least in part, explained by a direct cardiac electrophysiological action.

Topics: Acidosis; Action Potentials; Animals; Coronary Disease; Hyperkalemia; Hypoxia; Morphinans; Naltrexone; Narcotic Antagonists; Purkinje Fibers; Sheep

In this study it has been shown that the unexpected increase in food consumption, produced by the alpha 2-adrenoceptor antagonist idazoxan (10 mg/kg, i.p.) in rats, was significantly attenuated by small doses of the opioid antagonist (-)-naloxone (0.1, 1 mg/kg, i.p.) and totally inhibited by a small dose of naltrexone (1 mg/kg, i.p.). On the other hand, idazoxan-induced feeding was not affected by (+)-naloxone (0.1, 1 mg/kg, i.p.), which is inactive at opioid receptors. In addition, idazoxan-induced food consumption was not blocked by the delta-opioid antagonist, naltrindole (0.1, 1 mg/kg, i.p.) nor by the mu/delta-antagonist, RX8008M (16-methyl cyprenorphine; 0.1, 1 mg/kg, i.p.), which clearly discriminates between mu/delta- and kappa-opioid receptor function in vivo. These findings suggest that idazoxan may lead to the release of endogenous opioid peptides, which subsequently stimulate feeding by activation of kappa-, as opposed to mu- or delta-opioid receptors. This response is unlikely to be due to alpha 2-adrenoceptor blockade, since other highly selective alpha 2-adrenoceptor antagonists do not increase food intake and, instead may reflect the high affinity of idazoxan for non-adrenoceptor idazoxan binding sites.

Topics: Adrenergic alpha-Antagonists; Animals; Dioxanes; Dose-Response Relationship, Drug; Eating; Endorphins; Idazoxan; Indoles; Male; Morphinans; Naloxone; Naltrexone; Narcotic Antagonists; Rats; Rats, Inbred Strains

The effects of novel opioid antagonists on the behavioural syndrome induced by electroconvulsive shock (ECS) in rats have been examined and compared with those of the established agent naloxone. A single ECS produced catalepsy and significantly increased tail immersion response times during the 15 min following the seizure. These responses were inhibited by a low dose of naloxone (1 mg kg-1, i.p.) and also by RX8008M (16-methylcyprenorphine; 1 mg kg-1, i.p.) which blocks mu- and delta- but not kappa-opioid receptor function. In comparison, the antinociception and catalepsy induced by ECS was not attenuated by the selective delta-receptor antagonist naltrindole (1 mg kg-1, i.p.). These results suggest that ECS-induced antinociception and catalepsy may be mediated by endogenous opioids acting at mu-opioid receptors and are consistent with biochemical studies showing the release of beta-endorphin in both animals and man following this procedure.

Topics: Analgesia; Animals; Catalepsy; Electroshock; Indoles; Injections, Intraperitoneal; Male; Morphinans; Naltrexone; Narcotic Antagonists; Rats; Rats, Inbred Strains; Receptors, Opioid

Use of selective delta opioid antagonists provide evidence that the delta receptor within the brain seems an integrated part in the mediation of respiratory depression induced by a potent analgesic like fentanyl. Low doses of the delta antagonists RX-8008M (3-6 micrograms/kg) as well as ICI 174,864 (3-6 micrograms/kg) reversed fentanyl-related respiratory depression (arterial blood gases) in the unanesthetized canine. Opioid-induced blockade of afferent sensory nerve volleys (amplitude height of the somatosensory-evoked potential) could be reversed only by a high dose (9 micrograms/kg) of RX-8008M. Depression of amplitude height of the SEP could not be reversed by ICI 174,864 over the whole dose range (3-6-9 micrograms/kg). In comparison, naloxone (1-5-10 micrograms/kg) not only reversed depression of PaO2, it also reversed the blockade of afferent sensory nerve impulses in the low (5-micrograms/kg)-dose range. A highly selective delta antagonist may have a therapeutic value in reversing opioid-related respiratory depression, resulting in little or no attenuation of analgesia.

Topics: Analgesia; Animals; Dogs; Enkephalin, Leucine; Evoked Potentials, Somatosensory; Fentanyl; Morphinans; Narcotics; Receptors, Opioid; Respiration

Three opioid antagonists (MR2266, 16-methyl cyprenorphine and nor-binaltorphimine) were tested independently for their ability to suppress the intake of a highly palatable saccharin and glucose (S/G) solution after central administration. MR2266 is an equally potent antagonist at kappa (kappa) and mu (mu) opioid receptors. Nor-binaltorphimine (N-BNI) and 16-methyl cyprenorphine (M80) are two recently developed opioid antagonists that were chosen based upon their ability to act more selectively than naloxone at kappa and delta (delta) opioid receptor types, respectively. Prior research has demonstrated that when dissolved in acid and administered centrally, MR2266 (20 micrograms) fails to suppress S/G intake. Because all three antagonists are rather insoluble in water, they were dissolved in dimethyl sulfoxide (DMSO). Rats with chronic ventricular cannula were allowed to consume S/G for a 0.5 hr bout. They received a single intracerebroventricular (ICV) injection of antagonist (MR2266: 0, 10, 20 and 40 micrograms; M80: 0, 5, 10, 20 and 40 micrograms or N-BNI: 0, 1, 3, and 10 micrograms) 10 min prior to the start of the drinking bout. Administration of DMSO alone failed to alter drinking relative to saline, whereas each antagonist significantly attenuated S/G intake. We conclude that, when dissolved in DMSO, these antagonists suppress drinking by blockade of opioid receptors.

Topics: Animals; Benzomorphans; Drinking Behavior; Female; Glucose; Injections, Intraventricular; Morphinans; Naltrexone; Narcotic Antagonists; Rats; Rats, Inbred Strains; Saccharin

1. Ethylketocyclazocine (EKC) and U50,488H have been employed widely as kappa-receptor agonists in the study of opioid receptor systems. However, the quantification of their agonism in terms of affinities and relative efficacies has not been investigated. 2. In this study, operational model-fitting was used to analyse the effects of irreversible receptor alkylation by beta-chlornaltrexamine (beta-CNA) on the kappa-receptor mediated effects of EKC and U50,488H in the isolated, coaxially stimulated ileum of the guinea-pig. 3. EKC produced monophasic inhibitory concentration-effect curves which were readily amenable to analysis. In contrast U50,488H produced biphasic curves characterized by a higher potency phase of agonism that was susceptible to antagonism by 16-methylcyprenorphine (RX8008M) and a lower potency phase that was apparently non-opioid in nature. 4. Analysis of the kappa-receptor-mediated effects of both agonists indicated that EKC has fifteen fold higher affinity than U50,488H and that the two agonists possess similar intrinsic efficacies.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Binding, Competitive; Cyclazocine; Electric Stimulation; Ethylketocyclazocine; Guinea Pigs; In Vitro Techniques; Male; Models, Biological; Morphinans; Muscle, Smooth; Naltrexone; Narcotic Antagonists; Pyrrolidines; Receptors, Opioid; Receptors, Opioid, kappa

The effects of 16-Me cyprenorphine (M80) on the antinociception produced by reexposing rats to a chamber associated with footshock (1 mA, 0.75 sec) 24 hr earlier was assessed with the formalin test. In Experiment 1, intracerebroventricular administration of M80 dose-dependently (0.5-8 micrograms) reversed conditional analgesia. Experiment 2 demonstrated that M80 (5 micrograms) had no effect on baseline pain sensitivity, but completely reversed conditional analgesia. Experiment 3 demonstrated that 0.25 micrograms DAGO, 3.5 micrograms DPDPE, and 28 micrograms U50,488H all produced equivalent levels of antinociception on the formalin test. The 5 micrograms dose of M80 completely reversed the antinociception produced by DPDPE but did not influence that produced by DAGO or U50,488H. These data suggest, that at the doses employed, M80 is a selective delta-opioid receptor antagonist and that delta-receptors are involved in conditional fear-induced analgesia.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Conditioning, Operant; Enkephalin, D-Penicillamine (2,5)-; Enkephalins; Fear; Female; Formaldehyde; Injections, Intraventricular; Morphinans; Pain Measurement; Pyrrolidines; Rats; Receptors, Opioid; Receptors, Opioid, delta

1. The irreversible opioid receptor antagonist beta-chlornaltrexamine (beta-CNA) has been shown previously to have agonist activity in the guinea-pig ileum preparation. However, the receptor type or types mediating this effect have not been established. 2. In this study, the agonism of beta-CNA was investigated by use of the competitive antagonist 16-methylcyprenorphine (RX8008M). Non-cumulative concentration-effect curves for beta-CNA were displaced in a non-parallel fashion indicating that the agonism was mediated by both mu- and kappa-receptors. 3. In principle, expression of agonism by an irreversible receptor antagonist could compromise its use in estimating agonist dissociation constants (pKAs) due to desensitization operating in addition to receptor inactivation. For kappa-receptors, this possibility was checked by use of ethylketocyclazocine (EKC) to mimic the agonist effects of beta-CNA and test whether subsequent EKC concentration-effect curves were displaced. For mu-receptors it was necessary to perform more involved experiments in which [D-Ala2, MePhe4, Gly-ol5]enkephalin (DAGOL) was used as a standard agonist and its pKA was estimated under different conditions of beta-CNA incubation. 4. These analyses indicated that neither the mu- nor the kappa-receptor-mediated agonism of beta-CNA was associated with appreciable receptor desensitization. In turn it was concluded that the usefulness of beta-CNA as a pharmacological tool for the estimation of mu- and kappa-opioid receptor agonist dissociation constants is not compromised by the agonist effects that the compound demonstrates at these receptors.

Topics: Animals; Cyclazocine; Drug Interactions; Electric Stimulation; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalins; Ethylketocyclazocine; Guinea Pigs; Ileum; In Vitro Techniques; Male; Morphinans; Muscle, Smooth; Naltrexone; Narcotic Antagonists; Receptors, Opioid; Receptors, Opioid, kappa; Receptors, Opioid, mu

The effect of the opioid antagonist, 16-methylcyprenorphine (RX8008M), on the antinociceptive action of the mu-selective agonist, morphine, and the kappa-selective agonist, U50488H, has been investigated in the mouse abdominal constriction test. RX8008M produced a dose-dependent antagonism of the antinociceptive effect of morphine, but did not antagonize the response to U50488H. RX8008M should prove a useful probe for the in-vivo characterization of the receptor selectivity of opioid drugs.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; In Vitro Techniques; Male; Mice; Morphinans; Morphine; Muscle Contraction; Narcotic Antagonists; Pyrrolidines

The present study compared the effects of two opioid antagonists, beta-funaltrexamine (beta-FNA) and 16-methyl cyprenorphine (RX8008M) on the antinociception produced by a range of opioid agonists in the abdominal constriction test in the mouse and the paw pressure test in the guinea-pig. Both antagonists produced large shifts in the dose-response curves to the mu-agonists, morphine and fentanyl, confirming their mu-antagonist activity. Neither antagonist produced any antagonism of the antinociceptive effects of the selective kappa-agonists U50488, U69593 and tifluadom, in the mouse. However, RX8008M produced small shifts in the dose-response curves to these agonists in the guinea-pig, which seems more likely to reflect mu-receptor activity of the agonists in the guinea-pig than lack of selectivity of the antagonists. Both beta-FNA and RX8008M produced some antagonism of bremazocine, ethyl-ketocyclazocine, proxorphan and butorphanol, indicating that these agonists have a prominent mu-receptor component to their antinociceptive actions.

Topics: Abdomen; Animals; Guinea Pigs; Male; Mice; Morphinans; Muscle Contraction; Naltrexone; Narcotic Antagonists; Narcotics; Nociceptors; Pain

16-Me cyprenorphine (RX 8008M) has been investigated in a number of isolated tissue preparations and found to be a pure opioid antagonist with Ke values at the delta, mu and kappa receptors of 0.73, 1.77 and 59.6 nM respectively. Comparisons of the mu, kappa and delta Ke values with a number of other antagonists in the mouse vas deferens have been made and show that the 16-Me substituent results in a marked enhancement of delta activity, making RX 8008M the most selective non-peptide delta antagonist available at the present time.

Topics: Animals; Chemical Phenomena; Chemistry; Guinea Pigs; Ileum; Male; Mice; Morphinans; Rabbits; Rats; Receptors, Opioid; Receptors, Opioid, delta; Vas Deferens