Influence of fentanyl,levorphanol and pethidine on the release of noradrenaline from rat brain cortex slices

Summary In slices of rat brain cortex preincubated with (–)-³H-noradrenaline, the influence of fentanyl, levorphanol and pethidine on the efflux of tritium was investigated. The spontaneous outflow of tritium was not changed by low, and was accelerated by high concentrations of the drugs. The overflow of tritium evoked by electrical stimulation at 3 Hz was diminished by 10^–8–10^–7 M fentanyl and by 10^–7–10^–6 M levorphanol, but was augmented by 10^–5 M levorphanol. Naloxone prevented the inhibitory effect of fentanyl and levorphanol. In contrast to fentanyl and levorphanol, pethidine did not decrease, but at concentrations of 10^–6–10^–5 M greatly increased the stimulation-induced overflow of tritium. However, the increase was abolished, and the stimulation-evoked overflow slightly reduced, after the re-uptake of noradrenaline had been blocked by cocaine. It is concluded that fentanyl, levorphanol and pethidine share with morphine the ability to inhibit the release of transmitter from cerebrocortical noradrenaline neurones evoked by nerve impulses.     

Comparison of opioid agonists in maintaining responding and in suppressing morphine withdrawal in rhesus monkeys

Sixteen opioid agonists were studied for their capacity both to maintain responding previously reinforced by codeine and to suppress the withdrawal syndrome induced by morphine deprivation in rhesus monkeys. All compounds, which included examples from each of the major chemical families of opioids, maintained responding at rates above those maintained by saline. There were differences among the compounds in the maximal response rates maintained, and large differences in their potencies in maintaining responding. In morphine-dependent monkeys, the abstinence signs that developed 14 h after the last morphine dose were suppressed completely by all of the compounds except codeine. There was a strong positive correlation (r=0.92) between the potency of a compound in maintaining drug-reinforced responding and the potency of the compound in suppressing the morphine withdrawal syndrome.     

Levorphanol use: past,present and future

Levorphanol is a potent opioid analgesic that was first approved for use in the United States in 1953. Levorphanol is approved for use in moderate to severe pain where an opioid analgesic is appropriate. Levorphanol has a wide range of activities including mu opioid agonism, delta agonism, kappa1 and kappa3 receptor agonism, N-methyl-d-aspartate receptor antagonism and reuptake inhibition of both norepinephrine and serotonin. This multimodal profile might prove effective for pain syndromes that are refractory to other opioid analgesics, such as central and neuropathic pain and opioid-induced hyperalgesia. Levorphanol is well suited as a first-line opioid and can also be used during opioid rotation. It has no known effect on the cardiac QT interval or drug–drug interactions involving hepatic cytochrome P450s enzymes. In these regards, levorphanol may offer a superior safety profile over methadone and other long-acting opioids. Despite its prospective value of multiple mechanisms of action and the potential for treating various types of pain, levorphanol use has been largely supplanted by other recently approved opioids. Its waning use over the years has caused it to be referred to as the “Forgotten Opioid” and resulted in what some consider its underutilization. In fact, levorphanol is relatively unfamiliar to most prescribers. The purpose of this review is to inform practitioners about the attributes of this opioid and reintroduce it to clinicians as an option for treating moderate to severe pain when alternative treatment options are inadequate, not indicated or contraindicated.     

Potentiation of opioid — Induced cataracts by catecholamines injected into the mouse brain

Summary The cataractogenic effect of parenteral levorphanol was increased by the injection of catecholamines into the mouse brain. Although l-epinephrine potentiated this effect most strongly, the potency of dl-isoproterenol unexpectedly equaled that of l-norepinephrine. Phenoxybenzamine, however, blocked the effect of l-norepinephrine, whereas pronethalol failed to inhibit dl-isoproterenol. That dl-isoproterenol may act indirectly is supported by the finding that treatment of the mouse with reserpine blocked the potentiation induced by dl-isoproterenol but did not inhibit the action of the pressor catecholamines.     

Stereospecific interaction between alcohol and opiates mediated by the mu high-affinity binding receptor

Experiment 1 revealed that preexposure to morphine blocked ethanol-induced CTA, and that conversely, preexposure to ethanol blocked morphine-induced CTA. In experiment 2, naloxazone injected 4.5 hr before the preexposure drug significantly reversed the interaction between morphine and ethanol. The results of Experiment 3 showed that preexposure to levorphanol blocked both morphine- and ethanol-induced CTAs while dextrorphan at the same dose did not affect the CTAs. These findings are discussed in terms of the involvement of the opiate receptors and their ligands in opiate-ethanol interaction.     

Discriminative stimulus effects of cyclorphan: selective antagonism with naltrexone

The opioid antagonist, naltrexone, was used to identify some of the receptor mechanisms responsible for the discriminative stimulus effects of cyclorphan in the pigeon. Subjects were trained to discriminate 10 mg/kg IM injections of either morphine or dextrorphan from saline injections in a two key drug discrimination procedure in which responding was maintained by food presentation. The dextrorphan-trained birds generalized tol-cyclorphan at 10 mg/kg; naltrexone did not alter thel-cyclorphan dose-response curve for this effect. In the morphine-trained group,l-cyclorphan produced only partial generalization, and naltrexone greatly increased the dose ofl-cyclorphan necessary to produced only These results are consistent with the conclusion that in morphine-trained pigeons the partial generalization tol-cyclorphan is mediated by opioid receptors. Moreover, limited intrinsic efficacy at mu opioid receptors may be the characteristic ofl-cyclorphan that prevents full generalization in morphine-trained pigeons.d-Cyclorphan produced partial generalization in both groups, but the involvement of opioid receptor mechanisms could not be confirmed, as 1 mg/kg naltrexone did not antagonized-cyclorphan in either group.     

Discriminative stimulus effects of acute morphine followed by naltrexone in the squirrel monkey

Rationale. The discriminative stimulus effects of a combination of acute morphine followed by naltrexone have been described in rats. Objective. The purpose of this study was to extend observations to a non-human primate. Methods. Eight squirrel monkeys were trained in a discrete-trial avoidance/escape procedure to discriminate morphine (1.7 mg/kg, IM, 4 h) followed by naltrexone (0.1 mg/kg, IM, 0.25 h) (MOR→NTX) versus saline (1.0 ml/kg, IM, 4 h) followed by naltrexone (0.1 mg/kg, IM, 0.25 h) (SAL→NTX). Results. Seven subjects acquired the discrimination in an average of 108±14 sessions. MOR→NTX-appropriate responding increased as an orderly function of increasing dose of morphine (0.56–1.7 mg/kg) and of naltrexone (0.01–10 mg/kg). The discrimination was also dependent upon interval between morphine and naltrexone administration. The MOR→NTX cue was fully generalized to the combination of levorphanol (0.3 mg/kg) followed by naltrexone, but not to the non-opioid stereoisomer of levorphanol, dextrorphan (0.3 and 3.0 mg/kg) or the kappa-opioid-receptor-selective agonist U69,593 (0.3 mg/kg) followed by naltrexone. Naltrexone administered 15 min before morphine dose-dependently blocked MOR→NTX-appropriate responding. Conclusions. This is the first non-rodent study of the discriminative effects of MOR→NTX. MOR→NTX produces a unique interoceptive stimulus that is pharmacologically selective, requires occupation of opioid receptors, presumably mu, for some minimum period of time, and is reversible. This discrimination procedure might provide new insights into the early drug-receptor interactions that underlie the development of physical dependence upon morphine-like drugs. Electronic Publication     

Ingestive behaviour of the pigeon: Stereoselective influence of the opiate agonist levorphanol and its antagonism by naloxone

Four experiments evaluated the effect of levorphanol on ingestive behaviour of different groups of non-deprived pigeons. In experiments 1 and 2, levorphanol and its (+)stereoisomer dextrorphan were administered at three doses (0.25, 1 and 2 mg). As compared with control values, levorphanol dose-dependently reduced food intake. This anorexia persisted for at least 5 h post-injection. A late hyperdipsia was also observed. These changes were stereoselective, suggesting that they followed the binding of levorphanol to opiate receptors. In experiments 3 and 4, the anorexic effect of 1 mg levorphanol, but not its hyperdipsic effect, was partly antagonized by the concomitant administration of either 0.25 mg or 1 mg naloxone. Given alone at the dose of 1 mg, naloxone slightly and transiently reduced food, but not water, intake. These results are discussed in terms of the endorphinergic regulation of ingestive behaviour in birds.     

The stimulus properties of morphine and ethanol

The present investigation sought (a) to establish the efficacy of morphine and ethanol as discriminative stimuli when each is paired with the administration of saline and (b) to compare, in a qualitative sense, the stimulus properties of the two drugs. Additional experiments examined the effects of treatment with naloxone or l-propranolol upon morphine and ethanol-mediated discriminated responding. Finally, the stereospecificity of the stimuli produced by morphine was determined by a comparison, in morphine-trained rats, of levorphanol and dextrorphan. Discriminated responding developed rapidly in both the morphine and ethanol groups. In tests in which ethanol was administered to morphine-trained animals and vice versa, no similarity to stimulus properties was apparent. Antagonism of discriminated responding induced by morphine and ethanol was attempted using naloxone and l-propranolol. Naloxone blocked the actions of morphine but was without effect upon ethanol. No evidence of antagonism of either drug by propranolol was found. When a range of doses of levorphanol (0.1–3 mg/kg) and dextrorphan (3–100 mg/kg) was tested in morphine trained animals, only levorphanol was able to substitute for morphine. The present results suggest that the stimulus properties of morphine represent typical opiate effects.     

Opioid receptor subtype-specific cross-tolerance to the effects of morphine on schedule-controlled behavior in mice

Key-press responding of mice was maintained under a fixed-ratio (FR) 30-response schedule of food presentation. Successive 3-min periods during which the experimental chamber was illuminated and the schedule was in effect were preceded by 10-min time-out (TO) periods during which all lights were out and responses had no scheduled consequences. Intraperitoneal (IP) injections of saline or of cumulative doses of drugs were given at the start of each TO period. Successive saline injections had little or no effect on response rates, whereas the -opioid agonists morphine (0.1–10.0 mg/kg) and levorphanol (0.1–3.0 mg/kg), the -opioid agonist ethylketazocine (0.03–3.0 mg/kg), the mixed -/-opioid agonist metkephamid (0.1–10.0 mg/kg), and the nonopioid dissociative anesthetic ketamine (1.0–100.0 mg/kg) generally produced dose-related decreases in response rates. Following chronic administration of morphine (100.0 mg/kg/6 h), tolerance developed to the effects of morphine on rates of responding. In addition, a comparable degree of cross-tolerance developed to the effects of levorphanol and metkephamid. On the other hand, there was no evidence of cross-tolerance to the effects of ethylketazocine or ketamine. These results are consistent with the evidence suggesting that different opioid agonists exert their behavioral effects through distinct classes of opioid receptors.