ketazocine and tifluadom

Evidence from studies which utilise either opiate receptor agonists and antagonists strongly indicate a role for endorphinergic mechanisms in the control of feeding responses. Two means by which these compounds may exert an effect on feeding can be singled-out. Firstly, emerging evidence suggests that the process of achieving satiety (terminating a meal, or choice of a commodity) may be accelerated following treatments with opiate receptor antagonists. Secondly, the preference for highly palatable solutions (sweet solutions have received most attention) in two-bottle tests is blocked after injection of opiate receptor antagonists. This finding has been interpreted in terms of the abolition of the reward or incentive quality associated with the particularly attractive flavour. These two mechanisms of action may represent two aspects of a single, fundamental process. Following an introduction to rat urination model of in vivo kappa agonist activity, the consistent effect of several kappa agonists (including the highly selective U-50,488H) to stimulate food consumption is described. Recognising that members of the dynorphin group of endogenous opioid peptides are kappa receptor ligands, some with a high degree of selectivity, and the evidence the dynorphins and neo-endorphins produce hyperphagia in rats is particularly interesting. Such lines of evidence lead to the hypothesis that peptides of the dynorphin group may act endogenously to promote the expression of normal feeding behaviour.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Benzodiazepines; Benzomorphans; Butorphanol; Choice Behavior; Cyclazocine; Diuresis; Drinking; Dynorphins; Eating; Endorphins; Ethylketocyclazocine; Humans; Morphine; Narcotic Antagonists; Phenazocine; Pyrrolidines; Receptors, Opioid; Receptors, Opioid, kappa; Satiety Response

The purpose of the present study was to evaluate the interrelation between behavioural effects of kappa-opiates and cerebral neurochemical correlates in rats. Administration of the kappa-opiates tifluadom (2.5 mg/kg i.p.) or ketazocine (5 mg/kg i.p.) caused a marked initial decrease in locomotor activity lasting about 15-20 min, followed by an increase in locomotor activity at about 40 min after drug administration. At 15 min after i.p. injections of the same drugs 3,4-dihydroxyphenylacetic acid concentrations, measured by HPLC, were slightly increased in the nucleus accumbens, but unchanged in the striatum; dopamine concentrations were unchanged in both regions. The rates of glucose utilization, determined by quantitative [14C]2-deoxyglucose autoradiography, were mainly unchanged except for the nucleus accumbens, which showed an increased glucose utilization after both drugs given i.v. Tifluadom also decreased rates of glucose utilization in the caudate nucleus and parietal, sensorimotor, olfactory and frontal cortices. The above-mentioned effects on behaviour and local cerebral glucose utilization could be prevented by naloxone (3 mg/kg). The data suggest that changes in locomotor activity, neurotransmitter metabolism and neuronal activity in the nucleus accumbens are interrelated and that opiate-induced akinesia is mediated via the nucleus accumbens.

Topics: Animals; Benzodiazepines; Brain; Corpus Striatum; Cyclazocine; Dopamine; Ethylketocyclazocine; Glucose; Male; Motor Activity; Nucleus Accumbens; Rats; Rats, Inbred Strains

The purpose of this study was to investigate further the kappa opioid receptor selectivity of the field-stimulated isolated rabbit vas deferens preparation and to study the profile of a series of kappa agonists in this tissue. Agonists acting at mu, delta and sigma receptors were without detectable effect in the rabbit vas deferens. But a number of kappa agonists, including bremazocine, tifluadom, ethylketocyclazocine, ketocyclazocine, U-50,488 and Win 42,610 all depressed contractions, producing parallel dose-response curves. Mr 2034 generally produced a shallower dose-response curve and achieved a lower maximum effect, thus acting like a partial agonist. The effect of ethylketocyclazocine was not reduced by the irreversible mu antagonist, beta-funaltrexamine, confirming that it is not acting via mu receptors. Another group of drugs, including nalorphine, butorphanol and proxorphan, which produce an agonist action via kappa receptors in the guinea-pig ileum and mouse vas deferens, were antagonists in the rabbit vas deferens, suggesting that this tissue will only respond to high efficacy kappa agonists.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Benzodiazepines; Benzomorphans; Butorphanol; Cyclazocine; Ethylketocyclazocine; In Vitro Techniques; Male; Muscle Contraction; Muscle, Smooth; Nalorphine; Naloxone; Pyrrolidines; Rabbits; Receptors, Opioid; Receptors, Opioid, kappa; Receptors, Opioid, mu; Vas Deferens

Several opioid antagonists have previously been shown to decrease drinking. The data have suggested that this was due to an antagonist action at kappa opioid receptors rather than mu or delta opioid receptors. Kappa agonists have a marked diuretic effect through suppression of vasopressin release. Antagonism of this kappa receptor-mediated effect can be used as an in vivo test for determining kappa-receptor antagonist activity. The potencies of opioid antagonists for antagonizing the diuretic effects of the kappa agonist bremazocine do not correlate directly with the potencies for decreasing deprivation-induced drinking. Further work should investigate the receptor specificity for effects on drinking and kappa-mediated diuresis.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Benzodiazepines; Benzomorphans; Butorphanol; Clonidine; Cyclazocine; Drinking; Ethylketocyclazocine; Naloxone; Pyrrolidines; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, kappa; Urination; Vasopressins

A large body of evidence has suggested a role for the endogenous opiates and their receptors in the regulation of appetite. In this study, we report on the effects of tifluadom, a noval opiate with a benzodiazepine-like structure and preferential activity at the kappa opiate receptor, on ingestive behaviors. Tifluadom increases food intake in rats without altering water intake. Tifluadom's effect on feeding is more potent than that of morphine or ketocyclazocine and equivalent to that of butorphanol. The effect is partially resistant to naloxone antagonism. Tifluadom is more potent when administered subcutaneously than when given intraperitoneally. These data provide further support for the concept that kappa opiate receptors represent an important component of the natural feeding drive.

Topics: Animals; Benzodiazepines; Butorphanol; Cyclazocine; Drinking Behavior; Ethylketocyclazocine; Feeding Behavior; Male; Morphine; Naloxone; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, kappa

Recent studies have suggested a role for the kappa opiate receptor and its endogenous ligand, dynorphin, in the central regulation of appetite. In this study we found that the ob/ob mouse was mildly resistant to the ability of three kappa agonists, viz, butorphanol, tifluadom, and ketocyclazocine to induce food intake. In addition, we could find no change in ir-dynorphin levels in 7 areas for the central nervous system. These findings do not provide evidence for a role of kappa opioid feeding system in the pathogenesis of obesity in the ob/ob mouse.

Topics: Animals; Appetite; Benzodiazepines; Body Weight; Butorphanol; Cyclazocine; Dose-Response Relationship, Drug; Drinking; Eating; Ethylketocyclazocine; Male; Mice; Mice, Obese; Receptors, Opioid; Receptors, Opioid, kappa