u-50488 and ketazocine

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 1,5-dimethyl 3,7-diaza-3,7-dimethyl-9-oxo-2,4-di-2-pyridine-bicyclo[3.3.1]nonane-1,5-dicarboxylate, HZ2, has a high and selective affinity for the kappa opioid receptor and an antinociceptive activity comparable to morphine. In addition, it is characterized by a long duration of action and a high oral bioavailability. QSAR studies within series of kappa agonists revealed a chair-boat conformation of a double protonated HZ2 characterized by an almost parallel orientation of the C9 carbonyl group and the N7-H group and at least one aromatic ring to be the pharmacophoric arrangement. Structural variations showed that the pyridine rings in 2 and 4 position can be replaced with p-methoxy-, m-hydroxy- and m-fluoro-substituted phenyl rings. However, all other substituents have to be kept the same for a high affinity to the kappa receptor.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics, Opioid; Animals; Brain; Carboxylic Acids; Ethylketocyclazocine; Models, Molecular; Molecular Structure; Pyridines; Quantitative Structure-Activity Relationship; Rats; Receptors, Opioid, kappa

This report concerns the synthesis and preliminary pharmacological evaluation of a novel series of kappa agonists related to the morphinan (-)-cyclorphan (3a) and the benzomorphan (-)-cyclazocine (2) as potential agents for the pharmacotherapy of cocaine abuse. Recent evidence suggests that agonists acting at kappa opioid receptors may modulate the activity of dopaminergic neurons and alter the neurochemical and behavioral effects of cocaine. We describe the synthesis and chemical characterization of a series of morphinans 3a-c, structural analogues of cyclorphan [(-)-3-hydroxy-N-cyclopropylmethylmorphinan S(+)-mandelate, 3a], the 10-ketomorphinans 4a,b, and the 8-ketobenzomorphan 1b. Binding experiments demonstrated that the cyclobutyl analogue 3b [(-)-3-hydroxy-N-cyclobutylmethylmorphinan S(+)-mandelate, 3b, MCL-101] of cyclorphan (3a) had a high affinity for mu, delta, and kappa opioid receptors in guinea pig brain membranes. Both 3a,b were approximately 2-fold more selective for the kappa receptor than for the mu receptor. However 3b (the cyclobutyl analogue) was 18-fold more selective for the kappa receptor in comparison to the delta receptor, while cyclorphan (3a) had only 4-fold greater affinity for the kappa receptor in comparison to the delta receptor. These findings were confirmed in the antinociceptive tests (tail-flick and acetic acid writhing) in mice, which demonstrated that cyclorphan (3a) produced antinociception that was mediated by the delta receptor while 3b did not produce agonist or antagonist effects at the delta receptor. Both 3a,b had comparable kappa agonist properties. 3a,b had opposing effects at the mu receptor: 3b was a mu agonist whereas 3a was a mu antagonist.

Topics: Acetic Acid; Animals; Benzomorphans; Brain; Dose-Response Relationship, Drug; Ethylketocyclazocine; Guinea Pigs; In Vitro Techniques; Injections, Intraventricular; Male; Mice; Mice, Inbred ICR; Morphinans; Morphine; Narcotic Antagonists; Pain; Pain Measurement; Reaction Time; Receptors, Opioid, kappa; Receptors, Opioid, mu

The effects of the optical isomers and the racemic form of ketocyclazocine (KC) were compared with morphine and U-50,488H in the chronic spinal dog. l-KC and dl-KC produced depression of nociceptive reflexes, miosis, relaxation of the nictitating membrane and sedation, whereas d-KC lacked pharmacological activity. Peak plasma levels and distribution phase half-lives for dl-, l- and d-KC were similar, indicating no major dispositional differences between the isomers of KC despite a trend for d-KC to have a longer elimination half-life, slower plasma clearance and a greater apparent volume of distribution than l-KC. Although a relatively low dose of naltrexone (0.01 mg/kg) was sufficient to shift morphine dose-effect curves to the right, this dose of naltrexone was not sufficient to shift the dose-effect curves of dl-KC to the right. A dose of 1 mg/kg of naltrexone was required, consistent with the view that the effects were mediated by kappa opioid receptors. The overall pharmacological profile of l-KC differed from that of the more selective kappa opioid agonist U-50,488H, which produced both stimulatory and sedative effects. Neither l-KC nor U-50,488H produced pharmacological profiles typical of the sigma agonist d-N-allylnormetazocine or phencyclidine. The data suggest that the pharmacological activity of KC resides in the l-enantiomer, that the effects are kappa opioid receptor-mediated and that the binding of d-KC to haloperidol-sensitive sigma receptors does not produce N-allylnormetazocine- or phencyclidine-like actions in the dog.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Behavior, Animal; Dogs; Dose-Response Relationship, Drug; Drug Administration Schedule; Ethylketocyclazocine; Female; Morphine; Naltrexone; Pyrrolidines; Receptors, Opioid; Receptors, Opioid, kappa; Receptors, sigma; Stereoisomerism; Time Factors

Gastric function was evaluated in rhesus monkeys during a continuous, s.c. infusion of three kappa agonists; dynorphin-(1-13), (trans-3,4-dichloro-N-methyl-N[2-(1-pyrrolidinyl)cyclohexyl] benzeneacetamide methanesulfonate hydrate) (U50,488H) and ketocyclazocine (KETO). A dye dilution technique was used to determine gastric fractional emptying rate, hydrogen ion, sodium ion and fluid secretion after the intragastric administration of a water meal. All agonists significantly inhibited fractional emptying rate after the water meal. The kappa receptor antagonist, (-)-(1R,5R,9R)-5,9-dimethyl-2-(3-furylmethyl)-2'-hydroxy-6,7-benzomor pha n methanesulfonate, prevented the inhibitory response to dynorphin-(1-13) and partially blocked the effect of KETO, but, at the dose used in the present study, was completely ineffective against the specific kappa agonist, U50,488H. This suggests that dynorphin-(1-13) and U50,488H may not bind to the same kappa receptor isotype. The partial antagonism of KETO by both naloxone and (-)-(1R,5R,9R)-5,9-dimethyl-2-(3-furylmethyl)-2'-hydroxy-6,7-benzomor pha n methanesulfonate is consistent with a kappa/mu effect of this compound. Naloxone, at the dose used in these studies, did not modify the response to U50,488H. In contrast to their inhibitory action on gastric emptying, the kappa agonists, dynorphin-(1-13) and U50,488H, did not alter acid secretion. The suppressive action of KETO on acid secretion may be due to activation of mu receptors. The inhibitory effect of dynorphin-(1-13) on sodium output was blocked by (-)-(1R,5R,9R)-5,9-dimethyl-2-(3-furylmethyl)-2'-hydroxy-6,7-benzomor pha n methanesulfonate, suggesting a role for kappa agonists in the control of nonparietal secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Antihypertensive Agents; Cyclazocine; Dynorphins; Ethylketocyclazocine; Gastric Acid; Gastric Emptying; Macaca mulatta; Male; Narcotics; Peptide Fragments; Pyrrolidines; Receptors, Opioid; Receptors, Opioid, kappa; Sodium

The effects of various subtype-selective opioid agonists and antagonists on the phosphoinositide (PI) turnover response were investigated in the rat brain. The kappa-agonists U-50,488H and ketocyclazocine produced a concentration-dependent increase in the accumulation of IP's in hippocampal slices. The other kappa-agonists Dynorphin-A (1-13) amide, and its protected analog D[Ala]2-dynorphin-A (1-13) amide also produced a significant increase in the formation of [3H]-IP's, whereas the mu-selective agonists [D-Ala2-N-Me-Phe4-Gly5-ol]-enkephalin and morphine and the delta-selective agonist [D-Pen2,5]-enkephalin were ineffective. The increase in IP's formation elicited by U-50,488H was partially antagonized by naloxone and more completely antagonized by the kappa-selective antagonists nor-binaltorphimine and MR 2266. The formation of IP's induced by U-50,488H varies with the regions of the brain used, being highest in hippocampus and amygdala, and lowest in striatum and pons-medulla. The results indicate that brain kappa- but neither mu- nor delta-receptors are coupled to the PI turnover response.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Brain; Cyclazocine; Dynorphins; Enkephalins; Ethylketocyclazocine; Male; Phosphatidylinositols; Pyrrolidines; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, kappa

The present study examined whether the renal sympathetic nerves contribute to the renal excretory responses produced by kappa opioid receptor agonist administration in conscious spontaneously hypertensive rats (SHR). Intravenous infusion of the kappa opioid receptor agonists, ketocyclazocine (KC) and U-50488H, produced increases in urine flow rate. KC and U-50488H infusion also resulted in a marked and sustained antinatriuresis which was promptly reversed by low-dose naloxone (50 micrograms/kg i.v.), thus suggesting an opioid receptor-mediated action of both agonists. Although these kappa agonists did not produce changes in glomerular filtration rate or renal plasma flow, efferent renal sympathetic nerve activity increased with the same time course as the antinatriuretic response. To investigate whether the decrease in urinary sodium excretion was mediated via the increase in efferent renal sympathetic nerve activity, experiments were repeated in SHR with prior bilateral renal denervation. These studies demonstrated that similar renal excretory responses (diuresis and a naloxone reversible antiinatriuresis occurred during infusion of KC and U-50488H in renal denervated as were seen in intact SHR. These studies indicate that the renal excretory responses to the kappa opioid agonists KC and U-50488H are not mediated through changes in renal hemodynamics or via a pathway requiring intact renal innervation. Because an antinatriuretic response was observed in renal denervated SHR, this suggests that kappa opioid receptor agonists may influence the renal tubular reabsorption of sodium by additional naloxone-sensitive mechanisms independent of intact renal innervation.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Cyclazocine; Diuresis; Ethylketocyclazocine; Hemodynamics; Hypertension; Kidney; Male; Pyrrolidines; Rats; Rats, Inbred SHR; Receptors, Opioid; Receptors, Opioid, kappa; Sympathetic Nervous System

The effects of several mu and kappa opioid agonists were examined alone and in combination with the opioid antagonist quadazocine in squirrel monkeys responding under a schedule of shock titration. Under this procedure, shock was scheduled to increase once every 15 sec from 0.01 to 2.0 mA in 30 steps. Five responses on a lever during the 15-sec shock period terminated the shock for 15 sec, after which the shock resumed at the next lower intensity. The intensity below which the monkeys maintained the shock 50% of the time (median shock level) and the rate of responding in the presence of shock were determined under control conditions and after administration of the mu agonists, l-methadone and fentanyl and the kappa agonists, bremazocine, ethylketocyclazocine, ketocyclazocine and U50,488. When examined alone, intermediate doses of mu and kappa agonists increased median shock level. At the highest doses of these compounds responding was eliminated and shock rose to its peak intensity. When the mu and kappa agonists were examined in combination with quadazocine, dose-effect curves for median shock level and for rate of responding were shifted to the right in a dose-dependent fashion. A comparison of the pA2 values for quadazocine on median shock level and on rate of responding revealed similar values for the two measures; however, pA2 values differed depending on the agonist examined. That is, the pA2 values for quadazocine in combination with l-methadone and fentanyl on median shock level were 7.43 and 7.61, respectively; whereas the pA2 value for quadazocine in combination with bremazocine and U50,488 were 6.53 and 6.43, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesia; Animals; Azocines; Benzomorphans; Cyclazocine; Dose-Response Relationship, Drug; Ethylketocyclazocine; Fentanyl; Male; Methadone; Narcotic Antagonists; Pyrrolidines; Receptors, Opioid; Receptors, Opioid, kappa; Receptors, Opioid, mu; Saimiri

Marked diuresis has previously been reported after administration of kappa opioid agonists. The present study shows that this effect is stereospecific; MR-2034 markedly increased urinary output over the dose range 0.08 to 1.25 mg/kg, whereas the opposite isomer, MR-2035, was markedly less potent. Bremazocine increased urinary output in Long-Evans hooded and Sprague-Dawley albino rats as well as lean and fatty Zucker rats. In the lean Zucker and the albino rats, bremazocine produced an inverted U-shaped diuretic dose-effect curve, an effect characteristic of kappa agonists with mu agonist activity. This pattern was not seen with the fatty Zucker rats or the Long-Evans hooded rats. The full kappa agonists bremazocine, ethylketazocine and U-50,488 increased urinary output under three different conditions of hydration: water loaded, normal hydration and water deprived. In contrast, the partial kappa agonists reliably only increase urinary output under the normal hydration condition. The diuretic effects of full and partial kappa agonists correlated with plasma vasopressin levels in water-deprived rats. The full kappa agonists (ethylketazocine, U-50,488, tifluadom and MR-2034) suppressed plasma vasopressin levels below the threshold of detectability of the radioimmunoassay, whereas the partial kappa agonists (nalorphine and butorphanol) suppressed vasopressin levels compared with control values but did not have the efficacy of the full kappa agonists. All these results support the hypothesis that kappa agonists produce their diuretic effect by suppression of plasma vasopressin levels.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Benzomorphans; Butorphanol; Cyclazocine; Diuresis; Drinking; Ethylketocyclazocine; Female; Male; Nalorphine; Pyrrolidines; Rats; Rats, Inbred Strains; Rats, Zucker; Receptors, Opioid; Receptors, Opioid, kappa; Stereoisomerism; Vasopressins; Water Deprivation

Pigeons were trained to discriminate a dose of either 4.2 mg/kg of U50,488 or 1.0 mg/kg of morphine from water using a two-key drug discrimination procedure. In U50,488-trained pigeons, the kappa agonist bremazocine occasioned drug-appropriate responding during substitution tests, whereas ethylketocyclazocine and ketocyclazocine occasioned intermediate levels of drug-appropriate responding up to and including doses that markedly suppressed response rates. The mu agonists morphine, l-methadone and fentanyl produced responding predominantly on the water-appropriate key. In morphine-trained pigeons, l-methadone, fentanyl, ethylketocyclazocine and ketocyclazocine, but not U50,488 and bremazocine, occasioned drug-appropriate responding. Nonopioid compounds, such as d-amphetamine, pentobarbital, phencyclidine and (+)-SKF 10,047 produced responding predominantly on the water-appropriate key in both U50,488- and morphine-trained pigeons. During tests of antagonism, a 0.1 and 1.0 mg/kg dose of naloxone antagonized completely the discriminative stimulus properties of the training dose of U50,488 and morphine, respectively. In addition, morphine displayed a substantially longer duration of action than U50,488, in that intermediate levels of drug-appropriate responding were evident as long as 4 hr after the administration of morphine and only 1 hr after the administration of U50,488. Over a period of approximately 8 months, the dose-effect curves for the discriminative stimulus properties of both drugs were unchanged. The present findings illustrate further the unique behavioral response of pigeons to the discriminative stimulus properties of the kappa agonists, and establishes that pigeons can discriminate between mu and some kappa agonists.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Columbidae; Cyclazocine; Dextroamphetamine; Discrimination Learning; Dose-Response Relationship, Drug; Ethylketocyclazocine; Female; Fentanyl; Methadone; Morphine; Naloxone; Phenazocine; Phencyclidine; Pyrrolidines; Time Factors

The effects of several opioid agonists and the opioid antagonist naloxone were examined in rats responding under a fixed-consecutive-number (FCN) schedule. Under this schedule, a reinforced response run consisted of responding eight or more times on one response lever, and then responding once on a second response lever. In one component of this schedule, an external discriminative stimulus signalled the completion of the response requirement on the first lever, whereas no stimulus change was programmed in the other. Morphine, l-methadone, U50488, ketocyclazocine, phencyclidine, and (+/-)N-allylnormetazocine decreased the percent of reinforced response runs (accuracy) under the FCN schedule without the external discriminative stimulus, but had no effect under the FCN schedule with the external discriminative stimulus. Naloxone and bremazocine, in contrast, had no effect on the accuracy of the discrimination under either FCN schedule. With the exception of bremazocine and U50488, which increased rates of responding at low doses, all drugs produced comparable decreases in rates of responding under both FCN schedules. During tests of antagonism, a 0.1 mg/kg dose of naloxone reversed completely the accuracy-decreasing effects produced by U50488 and morphine. The rate-decreasing effects of morphine and U50488 were reversed completely by a 0.01 and 1.0 mg/kg dose of naloxone, respectively. These results suggest that the addition of an external discriminative stimulus can modulate the disruptive effects of opioids, and that mu, sigma and some kappa agonists produce similar effects when evaluated under the FCN schedules.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Benzomorphans; Conditioning, Operant; Cyclazocine; Discrimination Learning; Ethylketocyclazocine; Male; Methadone; Morphine; Naloxone; Narcotics; Phenazocine; Pyrrolidines; Rats; Reinforcement Schedule

Administration of the prototypical mu opiate agonist, morphine sulphate, 1-10 mg/kg, produced over three hours a significant dose-dependent increase in the ingestive responses of free-feeding slugs, Limax maximus, although lower doses, 0.10 mg/kg, attenuated feeding. The mixed mu and kappa opiate agonist, ketocyclazocine hydrochloride, in the dose range 1.0-10 mg/kg, also induced significant increases in food consumption. With both of these opiates there was a latency of about 0.5 hr before initiation of feeding. The more specific kappa opioid agonist, U-50,488H, given over the dose range 0.10-1.0 mg/kg, produced a more potent increase in three hour food consumption by Limax, whereas a dose of 10 mg/kg produced a significant increase in ingestive responses for 3-4 hr after a 1-2 hr period of inactivity. The prototypic mu opiate antagonist, naloxone hydrochloride (1.0 mg/kg) blocked the feeding effects of morphine and ketocyclazocine and reduced the effects of U-50,488H. The delta antagonist, ICI 154,129, in a dose of 10 mg/kg, reduced the effects of morphine as well as decreasing food intake of free-feeding slugs. These results indicate that activation of differential opiate receptors in invertebrates has similar effects on feeding behavior as occur in mammals, suggesting early evolutionary development of opioid involvement in the control of feeding.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Cyclazocine; Ethylketocyclazocine; Feeding Behavior; Mollusca; Morphine; Narcotic Antagonists; Narcotics; Pyrrolidines; Receptors, Opioid; Receptors, Opioid, kappa; Receptors, Opioid, mu; Time Factors

The feeding behavior of the deer mouse, Peromyscus maniculatus, includes food hoarding as well as ingestion. Administration of the prototypical mu opiate agonist, morphine sulfate, 1-20 mg/kg, produced over three hours a significant dose-dependent stimulation of hoarding by free feeding deer mice. The specific kappa opiate agonist, U-50,488H, 0.10-10 mg/kg, markedly increased ingestion without having any augmentatory effects on hoarding. The mixed mu and kappa opiate agonist, ketocyclazocine hydrochloride, 1-10 mg/kg, as well as various combinations of morphine sulfate and U-50,488H, augmented both hoarding and ingestion. Food restriction for 24 hr caused a significant, naloxone (1.0 mg/kg) reversible, increase in food intake. Food deprivation also modified the hoarding and ingestion responses of the deer mice to the mu and kappa opiate agonists, reducing the relative amounts of food that were hoarded. These results indicate that mu and kappa opioid systems are differentially involved in the mediation of various aspects of feeding. This also suggests that environmental factors, such as food restriction, can modify the relative roles of mu and kappa opioid systems in the expression of feeding behavior.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Cyclazocine; Endorphins; Ethylketocyclazocine; Feeding Behavior; Food Deprivation; Male; Morphine; Peromyscus; Pyrrolidines; Receptors, Opioid; Receptors, Opioid, kappa; Receptors, Opioid, mu

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

Several 'so-called' kappa-opiate receptor agonists e.g., ketocyclazocine (Kc), ethylketocyclazocine (Ekc), bremazocine, MR-2034 and U-50488H, were tested on basilar and middle cerebral arteries of the dog in vitro for relaxant or contractile activities. Ekc, Kc and bremazocine were found to produce concentration-dependent reductions in basal tone and to relax cerebral arteries contracted with prostaglandin F2 alpha (PGF2 alpha). All three agonists appear to act on benzomorphan-kappa opiate receptors which subserve relaxation in cerebral blood vessels. MR-2034 and U-50488H were found to induce contraction in the cerebral arteries. These opiate agonists appear to act on phencyclidine (PCP) or sigma-opiate receptors which subserve contraction. A variety of pharmacological antagonists (phentolamine, propranolol, methysergide, atropine, diphenhydramine, cimetidine, naloxone) did not modify any of the cerebral vascular effects produced by the opiates. These results suggest: (1) specific benzomorphan-kappa opiate receptors which subserve relaxation exist in cerebral blood vessels; (2) some kappa agonists appear to produce, primarily, contraction in cerebral vessels via PCP or sigma-opiate receptors: and cerebral vascular muscle may provide a useful tool to analyse the molecular constitution of these two distinct and opposite-acting opiate receptors.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Benzomorphans; Cerebral Arteries; Cyclazocine; Dinoprost; Dogs; Drug Interactions; Ethylketocyclazocine; Female; In Vitro Techniques; Male; Muscle Relaxation; Muscle, Smooth, Vascular; Phencyclidine; Prostaglandins F; Pyrrolidines; Receptors, Opioid; Receptors, Opioid, kappa

The effects of various opioid agonists and antagonists on urination were studied in the normally hydrated rat. Two kappa agonists, U-50,488H and proxorphan, markedly increased urination. The increased urination produced by U-50,488H was antagonized by opioid antagonists in a potency order which indicated that the effects were due to an action at kappa opioid receptors. Mu agonists decreased urination and were blocked by low doses (0.01 and 0.1 mg/kg) of naloxone, whereas kappa agonists increased urination and were only blocked by a high dose (10 mg/kg) of naloxone. The diuretic effects of U-50,488H and ketazocine, but not proxorphan and bremazocine, were reduced by morphine, consistent with the idea that proxorphan and bremazocine have morphine antagonist activity. Water deprivation produced a shift to the right for the dose-effect curve for bremazocine-induced diuresis. Kappa agonists were ineffective in increasing urination in Brattleboro rats that were homozygous for diabetes insipidus, whereas mu agonists were still effective in decreasing urination. The data are consistent with the hypothesis that kappa agonists inhibit release of vasopressin from the neurohypophysis and this decrease in vasopressin release leads to increased urination. The effects of opioids on urination in the normally hydrated rat can be extremely useful in classifying the activities of opioid on mu and kappa receptors in vivo.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Benzomorphans; Cyclazocine; Diuresis; Ethylketocyclazocine; Male; Morphinans; Naloxone; Narcotic Antagonists; Narcotics; Piperidines; Pyrrolidines; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, kappa; Receptors, Opioid, mu; Urination