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At least 919 records · Page 51Linked to original sources
PubMed1983

Cardiovascular and respiratory effects of mu-, delta- and kappa-opiate agonists microinjected into the anterior hypothalamic brain area of awake rats.

Relatively selective mu-, delta- and kappa-opiate agonists were microinjected into anterior hypothalamic and septal brain regions of the unanesthetized rat in order to investigate the potential role of specific opiate receptors in central cardiovascular regulation. Low doses (0.2-3 nmol) of both [D-Ala2,MePhe4,Gly-(ol)5] enkephalin (DAGO, mu-agonist) and [D-Ala2,D-Leu5]enkephalin (DADL, delta-agonist) caused dose-dependent increases in blood pressure and heart rate which were naloxone reversible. Higher doses (7.5-30 nmol) of DAGO and DADL produced pressor responses but had little effect on heart rate. The kappa-agonist MR 2034 had no effect on cardiovascular parameters at these doses. DAGO but not MR 2034 also depressed respiration at the higher doses resulting in hypoxia, hypercapnia and acidosis while DADL only slightly depressed respiration. DAGO was approximately 10-fold more potent than DADL in eliciting cardiovascular and respiratory responses. These findings implicate mu-receptors in mediating the cardiovascular and respiratory effects of opiates at anterior hypothalamic sites.

Animals↗
PubMed1983

The influence of the kappa-agonist bremazocine on ingestive behaviour in mice and rats.

The effects of bremazocine on drinking and eating behaviour were studied in non-deprived mice and 12 hr food and water deprived rats. In both species, bremazocine (1-8 mg/kg) produced substantial increase in fluid intake (dose-dependent in rats). The concomitant alterations of food intake were less pronounced and opposite: increase in mice, decrease in rats. Morphine (1.25-10.0 mg/kg) invariably inhibited eating and drinking behaviour in mice. The afore-said effects of the kappa-receptor agonist bremazocine are not affected by naloxone which attenuates the effects of the mu-receptor agonist morphine.

Analgesics↗
PubMed1983

Solubilization and preliminary characterization of mu and kappa opiate receptor subtypes from rat brain.

The opiate agonists [3H]dihydromorphine (DHM, mu-selective ligand), [3H]bremazocine (potent kappa ligand), and [3H]etorphine bound stereospecifically, with high affinity, and reversibly to partially purified 3-(3-cholamidopropyl)dimethylammonio-1-propanesulfonate (CHAPS)-solubilized extract from rat brain membranes. Recoveries of the three binding activities were as follows: [3H]DHM, 47%; [3H]bremazocine, 55%; and [3H]etorphine, 17%. Each ligand exhibited (by Scatchard analysis) binding to a class of high-affinity sites (Kd = 0.8-2 nM). Hill analyses revealed Hill coefficients of n = 1.1-1.3. Many of the properties of solubilized brain opiate receptors are similar to those of membrane-associated opiate receptors. Opiate binding in soluble fractions was inhibited by a variety of protein-modifying agents, including trypsin, proteinase K, and N-ethylmaleimide as well as by heat treatment (60 degrees, 15 min). The relative potencies of a series of opiate narcotic agonists and antagonists in displacing 2 nM [3H]etorphine binding to the CHAPS-solubilized extract was similar to that determined for rat brain homogenates. In contrast, D-Ala2, D-Leu5-enkephalin (DADLE, putative delta-selective ligand) exhibited a much lower affinity for solubilized brain opiate receptors than for the membrane-bound receptors unless assayed in the presence of manganese chloride, sodium chloride, and GTP. Mu agonist binding to solubilized receptors was inhibited relatively selectively by sodium and guanyl nucleotides. These findings lend support to the pharmacological relevance of the solubilized opiate-binding component(s). The pI of the solubilized brain opiate receptor(s) was estimated by liquid isoelectrofocusing to be pH 4. The sizes of the solubilized, prelabeled [3H]etorphine-receptor complex of the solubilized mu and kappa receptor subtypes, as assayed by stereospecific binding of [3H]DHM and [3H]bremazocine binding, respectively, were estimated by molecular exclusion chromatography. The [3H]etorphine-receptor complex migrated as a broad radioactive peak at a position corresponding to a protein of Stoke radius 63 A. A secondary peak of radioactivity was observed at the salt peak. Mu receptor activity chromatographed as two major peaks. The first of these eluted just behind, but significantly separated from, the protein void peak and corresponded to a Stokes radius of 70 A; the second eluted just ahead of the salt peak and corresponded to a radius of less than 20 A. Kappa receptor activity eluted at positions corresponding to macromolecules of 50 A and less than or equal to 20 A. Together, these findings indicate that selective mu and kappa ligands interact with high molecular weight species of somewhat different sizes as well as a lower molecular weight species, which may represent a common subunit that can bind both ligands.

Animals↗
PubMed1983

Discriminative stimulus properties of nalorphine in the rhesus monkeys.

The discriminative stimulus properties of nalorphine were studied in rhesus monkeys trained to discriminate i.m. injections of nalorphine (1 mg/kg) from saline. During training, a two-lever paradigm was employed where a single, 3-min extinction schedule was followed by fixed-ratio-20 schedules of food presentation. During the fixed-rate schedules, responses on one of the two levers produced food when nalorphine had been administered and responses on the other lever produced food when saline had been administered. During stimulus generalization tests, responses on either lever produced food under the fixed-ratio schedule. The discriminative stimulus effects of nalorphine were antagonized by naloxone which, by itself, did not generalize to nalorphine. The kappa opiate agonists, ethylketocyclazocine, U-50,488, bremazocine, tifluadom, as well as two mixed kappa-sigma agonists, dl-cyclazocine and dl-N-allylnormetazocine (SKF-10047), generalized to nalorphine with the following potency ranking order: bremazocine greater than ethylketocyclazocine greater than tifluadom greater than cyclazocine greater than U-50,488 greater than N-allylnormetazocine greater than nalorphine. The levo-isomers of cyclazocine, N-allylnormetazocine or U-50,488 generalized to nalorphine whereas the dextroisomers did not. Generalization to nalorphine did not occur with the mu opiate agonists, morphine, methadone and meperidine, or the nonopiate compounds, phencyclidine, ketamine and chlorpromazine. The results suggest that a kappa opiate receptor mechanism mediates the discriminative effects of nalorphine in the rhesus monkey, which may also be involved with the naloxone-sensitive, sedative and dysphoric effects of nalorphine in humans.

Animals↗
PubMedDate not supplied

[Modulation of the process of habituation by single-component solutions of agonists of opiate mu-, delta-, kappa- and sigma-receptors].

The modulating influence of such specific agonists of opiate mu-, delta-, kappa- and sigma-receptors as morphine, D-Ala2, D-Ley5-enkephaline (DADL), bremazocine, and SKF 10,047 as well as that of naloxone, their specific blockator, on habituation of orthodromic evoked potential in the visual cortical area was studied in turtles. In spite of equal degree of suppression of evoked potentials by the agonists used, their ability to modify habituation was different. Morphine, bremazocine and SKF 10,047 were of high effectivity while DADL was of low one.

Animals↗
PubMedDate not supplied

[Interaction of various types of opiate receptors of cortical neurons in the turtle during activation by specific agonists].

The influence of polycomponent solutions of agonists of opiate mu-, delta, chi- and sigma-receptors (morphine, D-Ala2, D- Ley5 -enkephalin, bremazocine, SKF 10,047) and of met-enkephalin on the habituation of orthodromic evoked potential in the visual cortical area was studied in turtles. Interaction between the different types of opiate receptors was observed at their combined activation. The interaction resulted in an enhancement or attenuation of modulation of separate phases of evoked potential habituation which differed from simple sum of effects during isolated activation of each type of receptors.

Animals↗
PubMed1984

Plasma levels of opioid analgesics determined by radioreceptor assay.

Plasma levels of opioid drugs, Mr 1268 MS (3-(2-methyl-3-furylmethyl)-1,2,3,4,5,6-hexahydro-6 alpha,11 alpha-dimetyl-2,6-methano-3-benzazocin-8-ol methane sulfonate), Mr 2033 CL ( [2 alpha, 3(S*), 6 alpha, 11 R*]-(+/-)-1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-[(tetrahydro-2-furanyl) methyl]-2,6-methano-3-benzazocin-8-ol hydrochloride), MRZ 2549 BR ( (2-methoxypropyl)-1,2,3,4,5,6-hexahydro-6 alpha, 11 alpha-dimethyl-2,6-methano-3-benzazocin-8-ol hydrobromide), and pentazocine, have been determined by a radioreceptor assay after enteral and parenteral administration to human volunteers as well as to laboratory animals (monkeys and dogs), using [3H]dihydromorphine as radioligand and freshly prepared membrane homogenates of rat brains. The concentration of parent compound drug has been evaluated after a specific extraction from plasma. The method described presents a universal possibility for the determination of opioid drugs of different structures in plasma and other body fluids.

Analgesics↗
PubMed1984

Meptazinol activity on morphine-naive and morphine-dependent guinea-pig ileum: correlation with in vivo studies.

The effects of meptazinol and some opioid agonists and antagonists were studied on opioid-naive guinea-pig ileum (GPIN) and ileum taken from morphine-dependent guinea-pigs (GPID). Meptazinol produced a biphasic effect in GPIN and GPID with a depression of the electrically induced twitch response at lower concentrations and contractural potentiation at higher concentrations. The effects of meptazinol in both GPIN and GPID were similar, thus distinguishing it from the other opioid agonists and antagonists which produced differential effects on these tissues. In morphine-pelletted rats, meptazinol (5 mg/kg i.p.) did not produce notable withdrawal as measured by behavioural observation. However, meptazinol (30 mg/kg i.p.) enhanced the signs associated with cholinergic activation. It is suggested that meptazinol possesses a cholinergic component and that the morphine-withdrawal signs observed to the higher meptazinol dose were more probably attributable to cholinergic stimulation rather than any underlying opioid-precipitated withdrawal.

Animals↗
PubMed1981

Historical perspective on the chemistry and development of naltrexone.

The first clinically useful narcotic antagonist was nalorphine. This compound was relatively weak, short-acting, and produced a number of side effects, the most prominent of which were psychotomimetic in nature. For these reasons nalorphine did not qualify as a possible modality for the treatment of heroin addiction. Cyclazocine is a totally synthetic narcotic antagonist which is much more potent and longer acting than nalorphine. It was the first compound used by Martin in clinical trials in postaddicts. However, its dysphoric effects necessitated long induction periods and these CNS effects precluded its use in long-acting delivery systems. Naloxone was a "pure" antagonist which did not produce the psychotomimetic effects of either nalorphine or cyclazocine. Although it is a potent antagonist when given parenterally, it is shorter acting than cyclazocine. Replacement of the N-allyl substituent of naloxone with the cyclopropylmethyl radical of cyclazocine led to naltrexone, which is even more potent than either naloxone or cyclazocine and has a longer duration than naloxone. Because of this favorable combination of properties naltrexone proved to be the drug of choice for inclusion in long-acting delivery systems.

Animals↗
PubMed1983

Pharmacological evaluation of N-allynormetazocine (SKF 10,047) on the basis of its discriminative stimulus properties in the rat.

The purpose of the present experiments was to evaluate the pharmacological properties of the discriminative stimulus effects of the prototypic sigma receptor agonist N-allylnormetazocine (NANM, SKF 10,047). Rats were trained to discriminate between saline and 3.0 or 5.6 mg/kg of NANM in a two-choice, shock-avoidance procedure. NANM-like stimulus control of behavior was produced by the opiates, in order of relative molar potency, cyclazocine greater than NANM greater than N-propylnormetazocine HCI greater than levallorphan greater than dextrorphan greater than pentazocine. Metazocine produced NANM-like discriminative effects but only when tested concomitantly with naloxone. Seven other opiate derivatives, including levorphanol, ethylketazocine and nalorphine, failed to produce NANM-like discriminative stimuli. Among enantiomeric pairs tested in the lower training dose group, d-NANM and l-NANM as well as levallorphan and dextrallorphan were equipotent, but the levo isomers of cyclazocine and pentazocine were more potent than their dextro counterparts, whereas dextrorphan but not levorphanol produced NANM-like discriminative stimuli. In the lower training dose group, the opioid antagonist naloxone failed to antagonize the NANM-like discriminative effects of NANM, l-cyclazocine and levallorphan, although naloxone did produce a parallel shift to the right of the dose-effect curve for pentazocine, and "unmasked" NANM-like effects of higher doses of metazocine. The nonopiate psychoactive drugs phencyclidine and dexoxadrol, but not its enantiomer levoxadrol produced NANM-like discriminative stimuli. Propranolol also occasioned an appreciable percentage of NANM-appropriate responding in the lower training dose group but not the higher dose group. Diazepam, d-amphetamine, d-lysergic acid diethylamide tartrate, imipramine, clonidine and haloperidol also failed to produce NANM-like discriminative stimuli in the lower training dose group. The present results demonstrate that the discriminative stimulus properties of NANM are distinguishable from those of morphine and ethylketazocine but similar to those of dissociative anesthetics such as phencyclidine and lend additional support to the hypothesis that sigma receptors mediate the common actions of NANM and phencyclidine.

Animals↗
PubMed1980

Synthesis and pharmacological evaluation of some 2-N-alkyl-and -aralkyl-3,4:6,7-dibenzomorphans.

2-N-Alkyl or 2-aralkyl-5,9-dimethyl-3,4:6,7-dibenzomorphans 3a-c were synthesized by condensing 1-alkyl or aralkyl-3,4-dimethylquinolinium iodides 1a-c with benzyl magnesium chloride followed by subsequent cyclization of 2-benzyl-1-alkyl or aralkyl-3,4-dimethylquinolines 2a-c. Their structures were established through elemental and spectral studies. The preliminary pharmacological screening of 3a-c and other 3,4:6,7-dibenzomorphans [16] on mice showed that these compounds have a depressant action on CNS.

Analgesics↗
PubMed1993

Spinal involvement of both dynorphin A and Met-enkephalin in the antinociception induced by intracerebroventricularly administered bremazocine but not morphine in the mouse.

Previous reports show the tail-flick inhibition induced by bremazocine given i.c.v. is mediated by supraspinal stimulation of both epsilon and kappa opioid receptors and the spinal activation of descending serotonergic and opioid systems. The present studies questioned what endogenous opioid peptides in the spinal cord were involved in i.c.v. bremazocine-induced antinociception in male ICR mice. beta-Endorphin, trans(+-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]- benzene-acetamide methane sulfonate (U50,488H) and morphine were used as reference compounds for epsilon, kappa and mu opioid receptor activity, respectively. Intrathecal pretreatment with antibody to Met-enkephalin dose-dependently attenuated the antinociception induced by i.c.v. bremazocine or beta-endorphin but not morphine or U50,488H; whereas intrathecal (i.t.) pretreatment with antibody to dynorphin A (1-13) dose-dependently blocked the antinociception induced by i.c.v. bremazocine or U50,488H but not beta-endorphin or morphine. Intrathecal Leu-enkephalin and beta-endorphin antibodies did not block i.c.v. bremazocine, beta-endorphin or morphine antinociception. Intrathecal Met-enkephalin or dynorphin A (1-17) increased the tail-flick latency at 1 to 2 min. Met-enkephalin given i.t. blocked the antinociception induced by i.c.v. DPDPE, bremazocine and beta-endorphin but not morphine or U50,488H whereas i.t. dynorphin A (1-17) pretreatment blocked the inhibition induced by i.c.v. U50,488H and bremazocine but not DPDPE, beta-endorphin or morphine. Bremazocine given i.c.v. did not exhibit antianalgesic activity in our studies. The dynorphin released by i.c.v. bremazocine for antinociception appears to be different from the dynorphin released by morphine for antianalgesia.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1994

Kappa agonist and antagonist properties of mixed action opioids in a pigeon drug discrimination procedure.

Previous investigations indicate that mixed action opioids (i.e., opioids with activity at a combination of opioid receptor sites or a combination of opioid and nonopioid sites) often possess kappa-like stimulus effects in the rat and monkey, but mu-like stimulus effects in pigeons. In the present investigation, the kappa agonist and antagonist actions of a series of mixed action opioids were examined in pigeons trained to discriminate a 0.017-mg/kg dose of the kappa agonist bremazocine from saline. The mixed-action opioids (-)-n-allylnormetazocine, (-)-cyclazocine, (-)-metazocine, levallorphan, buprenorphine, nalbuphine, butorphanol and nalorphine failed to substitute for the bremazocine stimulus. When administered in combination with the training dose of bremazocine, each of these opioids produced a dose-related antagonism of the bremazocine stimulus. With the exceptions of butorphanol and (-)-metazocine, the antagonist effects of these opioids were surmountable. Buprenorphine, (-)-n-allylnormetazocine and levallorphan produced their kappa antagonist effects at doses approximately 2 to 3 log units lower than those that decreased rates of responding when these opioids were administered alone, whereas approximately 1 log unit separated the kappa antagonist and rate-decreasing effects of nalorphine, nalbuphine and (-)-cyclazocine. In contrast, the kappa antagonist effects of butorphanol and (-)-metazocine were observed only at doses of markedly decreased response rates. A somewhat different profile was obtained with ethylketocyclazocine and ketocyclazocine in that these mixed action opioids produced partial substitution for and partial antagonism of the bremazocine stimulus.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

[The disparate modulation by mu- and kappa-agonists of the cholinoceptor plasticity of the RPa3 and LPa3 neurons in the snail].

The existence of modulatory opiate mu- and kappa-receptors on the somata of identified RPa3 and LPa3 Helix neurons was shown using double microelectrode voltage clamp techniques. Agonists of these receptors, morphine and bremazocine, inhibit activity of somatic electrogenic cholinoreceptors. The equal quantities of mu-receptors but not kappa-receptors were found on the somata of RPa3 and LPa3 neurons. There were more kappa-receptors on the soma of RPa3 neuron that on the soma of LPa3. Both opioids (50-100 microM) had a reversible influence on an extinction depth of the inward current evoked by a local acetylcholine application into the soma (ACh-current) directions of both opioids' effects being mutually opposite. Morphine deepened the extinction of Ach-current of RPa3 neuron. Bremazocine loosened the extinction of Ach-current of RPa3 neuron and did not influence cholinoreceptor plasticity of LPa3 neuron.

Animals↗