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At least 289 records · Page 16Linked to original sources
PubMed1983

Opiate binding sites spectrum on bovine adrenal medullas and six human pheochromocytomas.

Opiate binding sites have been characterized on membranes from bovine adrenal medullas and six human pheochromocytomas. In human tumors, large variations in site distribution were observed. Kappa and benzomorphan sites represented the majority of the sites detected. The heterogeneity of the opiate sites on these tissues could explain the observed differences in the pharmacological responses to opiates of cultured cells from these tissues. Furthermore, adrenal medullas could be a good model for the study of the kappa site action at the cellular level.

Adrenal Gland Neoplasms↗
PubMed1983

Changes in alpha2 adrenoreceptors in various areas of the rat brain after long-term administration of "mu" and "kappa" opiate agonists.

Clonidine, an alpha 2 adrenoreceptor agonist, is used to treat opiate dependent individuals who are experiencing the signs and symptoms of withdrawal. Changes in the apparent number of alpha 2 adrenoreceptors in specific areas of the rat brain have been observed after chronic morphine administration. In the present study, the effects of chronically administered morphine sulfate upon alpha 2 adrenoreceptors were compared to those of UM-1072, (+/-)-5,9-alpha-dimethyl-2-hydroxy-2-tetrahydro-furfuryl-6, 7-benzomorphan HCl, a "kappa" agonist which does not produce typical morphine-like dependence. The maximum number of specific binding sites (Bmax) and dissociation constants (KD's) for 3H-clonidine were measured with neural membranes isolated from saline or drug-treated rats. Rats were injected with saline, morphine or UM-1072, i.p., every 8 hr for 14 days. Doses of morphine ranged from 10 mg/kg, t.i.d., on the first three days to 100 mg/kg, t.i.d., on the last two days. Doses of UM-1072 covered a similar range. In control experiments, the Bmax's for specific binding of 3H-clonidine were (in fmoles/mg protein): hypothalamus, 142 +/- 7; amygdala, 141 +/- 3; brainstem, 70 +/- 2; parietal cortex, 130 +/- 4; hippocampus, 94 +/- 2; and caudate nucleus, 62 +/- 3. After chronic morphine treatment, the Bmax's were decreased significantly in all areas except the hippocampus. After chronic UM-1072 treatment, the Bmax's were decreased significantly in all areas studied. Neither treatment altered appreciably the KD's for 3H- clonidine. This study suggests that "mu" and "kappa" agonists might have similar actions upon noradrenergic systems in the brain.

Animals↗
PubMed1984

Phencyclidine-induced inhibition of striatal acetylcholine release: comparisons with mu, kappa, and sigma opiate agonists.

The effects of phencyclidine (PCP) on ACh release were compared to those of morphine, ethylketocyclazocine (EKC), and N-allylnormetazocine (SKF10047) in a superfused striatal slice preparation. The (+)-isomer of the prototypic sigma opiate agonist, SKF10047, and the prototypic kappa opiate agonist, EKC, had essentially the same pharmacological profile as did PCP. That is, they each inhibited ACh release in a concentration dependent manner (with EKC being the most potent) and this effect was antagonized by 0.1 microM naloxone. Since morphine was without effect on ACh release, it is unlikely that these drugs inhibit ACh release by acting at mu receptors. In addition, we observed that the inhibitory effect of PCP, (+) SKF10047, and EKC on ACh release was reversed by 0.1 microM haloperidol. Given that PCP has been shown to stimulate basal DA release in this preparation, it is possible that PCP, EKC and (+) SKF10047 inhibit ACh release indirectly by stimulating DA release. The naloxone-induced blockade of the effect of PCP and these benzomorphans is discussed in relation to the effects of naloxone on other systems known to influence ACh release.

Acetylcholine↗
PubMed1986

Evidence for a supraspinal analgesic effect with cyclazocine and pentazocine.

The antinociceptive effect of the benzomorphan class of opioid analgesics have been difficult to measure utilizing some of the standard animal pain models. This may be due, in part, to the sedative and/or motor effects associated with these drugs. In addition, it has been proposed that the major site of action for drugs with agonist activity at the kappa opiate receptor is exclusively at the spinal level opposed to both spinal and supraspinal as with the mu receptor agonists such as morphine. The present study examines the antinociceptive effect of the mixed agonist-antagonists cyclazocine and pentazocine utilizing electrical stimulation of the midbrain reticular formation (MRF) as the aversive stimulus in the rat. Animals were trained to escape MRF stimulation by turning a cylindrical manipulandum. An escape threshold was determined by varying the current intensity according to a modification of the psychophysical method of limits. In addition to the determination of the escape threshold the response latency and strength of response was also measured. Both cyclazocine (0.25-1.0 mg/kg) and pentazocine (2.5-12.5 mg/kg) raised the escape threshold in a dose-dependent manner without any concomitant change in the response latency or strength of response. These data suggest that the observed threshold elevation is due to a specific antinociceptive effect. Since the aversive stimulation was delivered supraspinally, the data also suggest that there are supraspinal mechanisms mediated by kappa receptors responsible for this analgesic effect.

Analgesia↗
PubMed1988

Pharmacological specificity of some psychotomimetic and antipsychotic agents for the sigma and PCP binding sites.

The pharmacological specificity of representative psychotomimetic agents such as phencyclidine (PCP) analogs, opiate benzomorphans and several antipsychotic agents was assessed for the sigma and PCP binding sites. In a series of binding experiments, in rat brain membranes, sigma and PCP binding sites were labeled with [3H]-1-[1-(3-hydroxyphenyl)cyclohexyl]piperidine [( 3H]PCP-3-OH), (+) [3H]-N-allylnormetazocine [(+) [3H]SKF 10047] and (+) [3H]-3-[3-hydroxy-phenyl]-N-(1-propyl)piperidine [(+) [3H]-3-PPP]. PCP analogs inhibit potently high affinity [3H]PCP-3-OH binding and (+) [3H]SKF 10047 binding, moderately the low affinity binding component of [3H]PCP-3-OH and very weakly (+) [3H]-3-PPP binding. (+)SKF 10047 and cyclazocine are potent to moderate inhibitors of (+) [3H]SKF 10047, high affinity [3H]PCP-3-OH and (+) [3H]-3-PPP binding, but extremely weak inhibitors of low affinity [3H]PCP-3-OH binding. The antipsychotic agents display high affinity for (+) [3H]-3-PPP binding sites, moderate affinity for (+) [3H]SKF 10047 sites and have no effect on either the high or low affinity [3H]PCP-3-OH binding. The present data further support the existence of multiple sigma and PCP binding sites.

Animals↗
PubMed1990

Affinity of the enantiomers of alpha- and beta-cyclazocine for binding to the phencyclidine and mu opioid receptors.

The enantiomers in the alpha and beta series of cyclazocine were evaluated for their ability to bind to phencyclidine (PCP) and mu-opioid receptors in order to determine their receptor selectivity. The affinity of (-)-beta-cyclazocine for the PCP receptor was 1.5 greater than PCP itself. In contrast, (-)-alpha-cyclazocine, (+)-alpha-cyclazocine, and (+)-beta-cyclazocine were 3-, 5- and 138-fold less potent than PCP, respectively. Scatchard analysis of saturable binding of [3H]Tyr-D-Ala-Gly-N-MePhe-Gly-ol (DAMGO) also exhibited a homogeneous population of binding sites with an apparent KD of 1.9 nM and an estimated Bmax of 117 pM. [3H]Tyr-D-Ala-Gly-N-MePhe-Gly-ol (DAMGO) binding studies revealed that (-)-alpha-cyclazocine (KD = 0.48 nM) was 31-, 1020- and 12,600-fold more potent than (-)-beta-cyclazocine, (+)-alpha-cyclazocine and (+)-beta-cyclazocine, respectively, for binding to the mu-opioid receptor. These data show that, although (-)-beta-cyclazocine is a potent PCP receptor ligand consistent with its potent PCP-like discriminative stimulus effects, it shows little selectivity for PCP receptors since it also potently displaces mu-opioid binding. However, these cyclazocine isomers, due to their extraordinary degree of stereoselectivity, may be useful in characterizing the structural requirements for benzomorphans having activity at the PCP receptor.

Animals↗
PubMed1992

Species differences in the stereoselectivity of kappa opioid binding sites for [3H]U-69593 and [3H]ethylketocyclazocine.

Stereoselectivity of the binding sites for the specific kappa-opioid agonist [3H]U-69593, a benzeneacetamido based ligand was investigated in membrane suspension prepared from frog and rat brain, as well as guinea pig cerebellum, using the pure chiral forms of different unlabelled opiates. The ligand binding sites showed stereospecificity with at least three orders of magnitude differences in the affinities (measured as Ki values) of the opioid stereoisomer pairs both in rat and guinea pig membrane fractions. However, in frog brain membranes there was no substantial difference in potencies of the (-) and (+) isomers competing for the [3H]U-69593 binding sites. Another type of the kappa-site preferring opioid ligand, [3H]ethylketocyclazocine, a benzomorphan derivative was able to discriminate between (-) and (+) forms of the same compounds even in frog brain membrane preparation. Our data concerning binding profile of [3H]U-69593 in frog brain membranes are consistent with the observation that kappa opioid binding sites in frog (Rana esculenta) brain differ from those kappa-sites found in mammalian brains.

Animals↗
PubMed1994

[3H]-(+)-pentazocine binding to sigma recognition sites in human cerebellum.

The binding characteristics of the sigma-1 selective benzomorphan [3H]-(+)-pentazocine were determined in human cerebellar membranes. Saturation binding analysis revealed two affinity sites with a KDH of 1.4 +/- 0.7 nM and a KDL of 33.6 +/- 11.9 nM. Kinetic studies performed at 25 degrees C demonstrated reversible binding with association and dissociation rate constants determined for two classes of sites. In saturation binding studies, the addition of (+)-SKF 10,047 occluded binding of [3H]-(+)-pentazocine to high affinity sigma binding sites. The affinity profile of ligands displacing [3H]-(+)-pentazocine was consistent with the labeling of sigma-1 recognition sites with haloperidol > (+)-pentazocine > (+)-SKF 10,047 > (+)-3-PPP > DTG > (-)-pentazocine > (-)-SKF 10,047. The potency of the putative D3 receptor-selective ligand (+)-7-OH-DPAT was close to that measured for (+)-pentazocine in displacement experiments. These data suggest that [3H]-(+)-pentazocine labels sigma-1 sites in human cerebellum under appropriate assay conditions.

Binding Sites↗
PubMed1996

Solubilization and characterization of binding sites for [3H]NE-100, a novel and potent sigma 1 ligand, from guinea pig brain.

The binding sites for [3H]NE-100, a newly defined sigma 1 ligand, was solubilized from guinea pig brain, using zwitterionic detergent 3-[(3-c holamidopropyl) dimethylamino]-1-propanesulfonate (CHAPS), and the properties of the solubilized binding sites were compared to those for [3H](+)-pentazocine, a selective sigma 1 ligand. The pharmacological selectivity of solubilized sites for both [3H]NE-100 and [3H](+)-pentazocine was identical to that obtained from membrane preparations. Stereoselectivity of benzomorphan such as pentazocine and SKF10,047 was preserved in displacing [3H]NE-100 binding in solubilized preparations as observed in membrane preparations. The inhibitory potencies of several sigma ligands on [3H]NE-100 binding were similar to those on [3H](+)-pentazocine binding, indicating that the pharmacological characteristics of the binding sites for [3H]NE-100 are retained after solubilization. Phenytoin augmented the binding of [3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl) piperidine hydrochloride (3-PPP) to solubilized sigma binding sites while it had no effect on the binding of [3H]NE-100. Furthermore, the inhibitory effect of putative sigma receptor agonists such as (+)-3-PPP and dextromethorphan were enhanced by phenytoin; the effects of haloperidol, a putative sigma receptor antagonist, were unaltered. Molecular weight of [3H]NE-100 binding protein was estimated to be 440KDa by Sepharose CL-6B gel filtration chromatography, and the value was identical to that of [3H](+)-pentazocine binding protein, a putative sigma 1 binding protein. These findings indicate that [3H]NE-100 binding sites are putative sigma 1 binding sites, and that NE-100 may act as an antagonist at sigma 1 binding sites.

Animals↗
PubMed1985

Binding characteristics of kappa opioids in rat brain. A comparison of in vitro binding paradigms.

Putative kappa binding was investigated in homogenates of the brain of the rat using [3H]ethylketocylazocine and [3H]diprenorphine under conditions where mu and delta sites were blocked. Under blocked conditions, the binding of [3H]ethylketocyclazocine labelled a single site, as defined by kinetic and equilibrium analysis, which showed high affinity for dynorphin 1-17, U50,488H, and benzomorphan compounds. However, blocked binding of [3H]diprenorphine showed a biphasic dissociation curve, and did not show high affinity for the specific kappa agonists dynorphin 1-17 or U50,488H. It is proposed that blocked [3H]ethylketocyclazocine is the more appropriate paradigm to study putative kappa binding, while blocked [3H]diprenorphine may label additional non-mu/non-delta sites.

Animals↗
PubMed1985

The opioid receptors in the hamster vas deferens are of the delta-type.

The motor responses of the isolated vas deferens of the hamster were unaffected by opioid-receptor agonists which are selective for the mu- or kappa-receptor, while agonists which show degrees of selectivity for the delta-opioid receptor caused dose-related inhibition of the stimulation-evoked contractions. The agonist action of the enkephalins and their congeners was only apparent when various inhibitors of tissue peptidases were present. Responses to opioid agonists were antagonised in a competitive manner by naloxone and by the selective delta-receptor antagonist, ICI 174864. It is noteworthy that the benzomorphans bremazocine, ethylketocyclazocine and Mr 2034, which are agonists at kappa-receptors in other tissues, are antagonists at the delta-receptor of the hamster vas deferens. Thus, the vas deferens of the hamster contains opioid receptors only of the delta-type and may therefore provide a simple and specific test for the assay of activity at the delta-opioid receptor.

Animals↗
PubMed1989

Haloperidol pretreatment unmasks the kappa opioid effects of U-50, 488H on cortical EEG and EEG power spectra in rats.

Adult female Sprague-Dawley rats were implanted with chronic cortical EEG electrodes and intravenous cannulae. U-50, 488H injection (5.0 mg/kg) produced initial EEG desynchrony and EEG spectral power that was mainly distributed over the zero to 10 Hz range, including a relatively small spectral peak in the 4-6 Hz band. In contrast, following haloperidol pretreatment (0.1 mg/kg), U-50, 488H injection produced high-voltage EEG bursts and a predominant EEG spectral peak in the 4-6 Hz band. These effects of U-50, 488H after haloperidol pretreatment were identical to those previously demonstrated with the benzomorphan kappa agonist ethylketocyclazocine. Thus, haloperidol pretreatment unmasked the kappa opioid effects of U-50, 488H.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1991

Kappa-opioid receptor-mediated thermonociceptive mechanisms in streptozotocin diabetes.

The effects of the benzomorphan kappa-opiate antagonist MR 2266 and its dextro enantiomer MR 2267 were assessed on thermonociception in male Swiss Webster mice. Experimental diabetes was induced by injecting streptozotocin (200 mg/kg IP, 7-8 days before). Animals with dextrose treatment (5 g/kg, IP, at the time of opiate injection) were used as acute hyperglycemic controls. Nociception was assessed by supraspinal nociceptive reflex (licking and jumping in hot plate test) indicative of higher cognitive process as well as a predominantly lower spinal monosynaptic reflex (tail immersion test). In normoglycemic, acute hyperglycemic and diabetic mice, MR 2266 decreased, while MR 2267 increased, the reaction latencies. The results indicate tonic stereospecific kappa-opiate receptor-mediated spinal and supraspinal thermonociceptive reactions are not modulated by experimental diabetes and thus are distinct from those of naloxone-sensitive mu-opiate receptor sites.

Animals↗
PubMed1981

Stereoselective effects of opiate agonists and antagonists on ingestive behavior in rats.

In male Sprague Dawley rats, the (-)-isomer of the opiate antagonist GPA 1843 (beta-9-methyl-5-phenyl-2-allyl-2'-hydroxy-6, 7-benzomorphan) produced dose-related decreases in nocturnal feeding and of hyperphagias induced by 2-deoxy-D-glucose (2-DG; 400 mg/kg) and 24 hr food deprivation (FD). The hyperphagia induced by insulin (10 U/kg) was not significantly decreased by GPA 1843. In contrast, comparable doses of the (+)-stereoisomer, GPA 1847, had no effect on nocturnal, 2-DG or FD hyperphagia. In addition, hyperphagia and hyperdipsia were observed following administration of the opiate agonist levorphanol, but not its stereoisomer, dextrorphan. Thus, the effects of these agents on consummatory behavior are mediated by a stereospecific interaction with opiate receptors, which further indicates that endogenous opiate peptides are involved in the expression of these opiate-related hyperphagias.

Animals↗
PubMed1986

Reinforcing and phencyclidine-like stimulus properties of enantiomers of metazocine.

The positive reinforcing properties of the racemate and stereoisomers of the benzomorphan, metazocine, were tested in three rhesus monkeys trained to self-administer IV injections of cocaine. The (-)-isomer maintained responding above saline levels at the highest dose tested (30 micrograms/kg/injection) in two of the three monkeys. Likewise, (+)-metazocine maintained self-administration responding in two monkeys at a dose of 100 micrograms/kg/injection. Responding for (+-)-metazocine was maintained in all three monkeys at doses of 10-100 micrograms/kg/injection. The discriminative stimulus properties of the three forms of metazocine were tested in rats trained to discriminate phencyclidine (PCP; 3.0 mg/kg) from saline on a two-lever food-reinforced operant task. When metazocine was tested in these animals, only the (+)-isomer produced dose-related increases in responding on the PCP-lever. Both (+-)- and (-)-metazocine resulted in only saline-appropriate responding. Thus, the results of these two experiments demonstrate that both enantiomers of metazocine function as positive reinforcers in monkeys and further, the reinforcing properties of (+)-metazocine may be due to the PCP/sigma properties of this isomer.

Animals↗
PubMed1987

Animal models of intravenous phencyclinoid self-administration.

Phencyclidine (1-(1-phenylcyclohexyl)piperidine, PCP) self-administration has been demonstrated in rhesus monkeys, baboons, dogs and rats. Generally, an orderly inverted U-shaped dose-response curve for rates of self-injection has been observed. Total drug intake appears to increase slightly with increases in unit dose; however, this increase is much less than might be expected with other CNS depressants such as barbiturates or morphine. Additionally, several arylcyclohexylamine analogues of PCP and some members of the benzomorphan and dioxolane classes referred to collectively as "phencyclinoids" are self-administered by primates and dogs. New data are presented in this review profiling the self-administration of some of these drugs in rats, as well as a characterization of the self-administration of higher unit doses of PCP than previously reported. Also, preliminary results of the assessment of the reinforcing efficacy of some PCP analogues measured by the progressive ratio procedure are presented.

Animals↗
PubMed1988

Phencyclidine receptors and N-methyl-D-aspartate antagonism: electrophysiologic data correlates with known behaviours.

Using cortical wedges and isolated frog spinal cords, the potency of a series of psychoactive phencyclidine (PCP) and sigma receptor ligands as antagonists of N-methyl-D-aspartate (NMDA) has been compared with their potency in neurochemical and behavioural studies. Phencyclidine receptor, but not sigma or kappa, ligands were selective antagonists of NMDA on both preparations. Combination studies suggested that dissociative anaesthetics and sigma benzomorphans act at the same site. The relative potencies of the drugs as NMDA antagonists correlated well with their potency in PCP receptor binding studies in vitro and in PCP discrimination studies in vivo.

Anesthetics, Dissociative↗
PubMed1989

Tripelennamine interactions with the psychotomimetic sigma agonist N-allylnormetazocine.

The pharmacological effects of individual and combined intravenous doses of the antihistamine tripelennamine and the psychotomimetic sigma benzomorphan opioid derivative, N-allylnormetazocine (NANM), on nociceptive reflexes, autonomic parameters and behavior were assessed in the chronic spinal dog. NANM (1.65 mg/kg, IV) produced antinociception, mydriasis, tachycardia, hyperthermia and behavioral signs of canine delirium. Tripelennamine (1.25 mg/kg, IV) produced antinociception, mydriasis and tachycardia without affecting behavior. The combined effects of the two drugs were additive except for heart rate. However, tripelennamine did not antagonize any of the physiological effects or the signs of canine delirium produced by NANM. The findings are inconsistent with the hypothesis that tripelennamine antagonizes the psychotomimetic NANM-like effects of pentazocine to make pentazocine-tripelennamine combinations (T's and Blues) more desirable as a heroin substitute.

Animals↗