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At least 883 records · Page 49Linked to original sources
PubMed1988

Effects of levorphanol and several kappa-selective opioids on respiration and behavior in rhesus monkeys.

The effects of the mu-selective opioid, levorphanol (0.03-1.0 mg/kg), and the kappa-selective opioids, U-50,488 (0.03-1.0 mg/kg), tifluadom (0.01-0.3 mg/kg), bremazocine (0.0003-0.01 mg/kg) and MR 2034 (0.001-0.03 mg/kg), on ventilation and on schedule-controlled behavior were studied in rhesus monkeys. In seated, unanesthetized monkeys prepared with a head plethysmograph, ventilation during exposure to 5% CO2 mixed in air was measured after cumulative doses of each drug. In other monkeys, effects on behavior were studied by administering cumulative doses preceding sequential periods of fixed-ratio responding. Levorphanol, tifluadom, bremazocine and MR 2034 produced dose-related decreases in minute volume, tidal volume and respiratory frequency. In contrast, U-50,488 had only minimal effects on ventilation over the range of doses studied. All drugs decreased fixed-ratio rates in a dose-related manner. Comparisons between their effects in behavioral and respiratory experiments differentiated levorphanol and MR 2034 from U-50,488, bremazocine and tifluadom. Doses of levorphanol or MR 2034 that decreased minute volume markedly had little effect on behavior. In contrast, bremazocine, tifluadom and U-50,488 had less pronounced effects on minute volume at doses that suppressed behavior markedly. Naltrexone (0.03-1.0 mg/kg) antagonized decreases in minute volume produced by levorphanol, MR 2034, bremazocine and tifluadom, and apparent pA2 values were similar for each naltrexone-agonist pair. When the effects of levorphanol (0.03-0.3 mg/kg) were determined in the presence of U-50,488 (0.3 mg/kg), tifluadom (0.1 mg/kg) or bremazocine (0.003 mg/kg), the levorphanol dose-effect curve was shifted approximately 3-fold to the left, suggesting that the effects of the drugs were additive.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMedDate not supplied

[Lateralization of opioid receptors and their putative ligands in the visual cortex of the turtle].

Opioid mu-agonist morphine, delta-agonist D-Ala2,D-Leu5-enkephalin (DADL) and kappa-agonist bremazocine locally applied to the surface of turtle visual cortex inhibited the orthodromic evoked potential (EP; fast negative component N1). The lack of cross-desensitization to the inhibitory action of opioids upon EP indicates that the drugs exert their effects via different opioid receptors. Morphine and bremazocine predominantly inhibited the left cortex EP, whereas DADL was a potent inhibitor of the right cortex EP. Thus opioid receptors which modulate evoked electrical activity of the left visual cortex (LVC) apparently belong mostly to mu- and kappa-type while delta-receptors were predominantly responsible for the modulation of electrical activity in the right visual cortex (RVC). Application of LVC- and RVC-extracts to the cortex surface led to EP inhibition, which was partially (60-80%) prevented by antagonist naloxone. LVC-extract proved to be a more potent inhibitor of the left cortex EP, whereas RVC-extract was found to be more effective when applied to the right cortex. It is suggested that not only opioid receptors, but also their endogenous ligands are lateralized in turtle visual cortex.

Animals↗
PubMed1988

Antagonism of the analgesic effects of mu and kappa opioid agonists in the squirrel monkey.

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)

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1988

Antagonist-induced opioid receptor up-regulation. II. Regionally specific modulation of mu, delta and kappa binding sites in rat brain revealed by quantitative autoradiography.

The neurochemical basis for the supersensitivity to mu or kappa opiate agonists observed after chronic naloxone infusion (reported in the preceding paper) has been investigated using the technique of quantitative in vitro autoradiography. The binding of [3H]-D-Ala2MePhe4Glyol enkephalin (3H-DAGO) to mu opioid sites was increased in many brain regions after chronic administration (7 days) of a low dose of naloxone (0.5 mg/kg/hr). The greatest increases were seen in the hippocampal strata moleculare and lucidum. The binding of [3H]-D-Ala2-D-Leu5 enkephalin (3H-DADL) to delta sites and of [3H]-bremazocine to kappa sites were not significantly affected in any region. In contrast, after administration of a higher dose of naloxone (3.0 mg/kg/hr), the binding to mu, delta and kappa sites was increased in many brain areas, suggesting that up-regulation is observed only when a sufficient proportion of the receptors in vivo are occupied by the antagonist. However, a different regional pattern of up-regulation was seen for each class of opiate binding site. The greatest increases in kappa binding in the brain were seen in the periaqueductal gray and the hippocampal molecular and pyramidal cell layers. The substantia nigra showed up-regulation of kappa but not of mu sites. Differences in the pattern of mu and kappa binding site up-regulation were also noted in the spinal cord. This regionally specific modulation of opiate binding sites suggests that, for each receptor type, the level of tonic activation varies between individual brain areas. In addition, the data demonstrate that all three types of opiate receptor can undergo up-regulation "in vivo."

Animals↗
PubMedDate not supplied

The effect of morphine dependence and abstinence on opioid receptors in the cerebral cortex and spinal cord of the rat.

The characteristics of cerebral cortical and spinal cord opiate mu, delta and kappa receptors were investigated by measuring of the specific binding of [3H]naloxone, [3H]DADLE and [3H]bremazocine in drug-free rats and in rats rendered tolerant to morphine and in those in which morphine abstinence syndrome was precipitated with naloxone. The opiate receptors in the spinal cord were less dense than those in the cortex; the difference was most pronounced in the case of delta receptors. The characteristics of the investigated opioid receptors did not change in the state of tolerance or abstinence.

Animals↗
PubMed1988

Opposite effects of mu and kappa opiate agonists on dopamine release in the nucleus accumbens and in the dorsal caudate of freely moving rats.

We studied the effect of opiates acting preferentially on mu receptors, like morphine, methadone and fentanyl (mu agonists) and on kappa receptors, like U50,488, bremazocine and tifluadom (kappa agonists) on the release of dopamine (DA) and of its metabolites, dihydroxyphenylacetic acid and homovanillic acid, from the nucleus accumbens and from the dorsal caudate of freely moving rats using brain dialysis coupled to high-performance liquid chromatography with electrochemical detection. Spontaneous behavior was videotaped and analyzed by estimating the percentage of time spent by the animals in performing certain specific behavioral items. Mu agonists stimulated DA-release and metabolism in the accumbens at lower doses than in the caudate. Maximal stimulation of DA release did not exceed 100% except after high doses of methadone (10 mg/kg) which stimulated DA release in the accumbens by more than 300%, possibly as a result of hypoxia. Stimulation of DA release was associated to stimulation of behavior at low doses and to a biphasic inhibitory-stimulatory syndrome after higher doses of the opiates. Pretreatment with low doses of naloxone (0.1 mg/kg s.c.) or with the irreversible mu antagonist beta-funaltrexamine (10 nmol i.c.v.) increased the ED50 for the stimulation of DA release by the three opiates. In contrast with mu agonists, agonists of kappa receptors like U50,488, bremazocine and tifluadom decreased DA release in the accumbens and in the caudate and reduced motor activity. These effects were antagonized only by rather high doses of naloxone (2.5 mg/kg s.c.) and were not affected by pretreatment with beta-funaltrexamine (10 nmol i.c.v.).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Effects of kappa-opioid receptor agonists on locomotor activity and memory processes in mice.

The effects of the kappa-opioid receptor agonists tifluadom, bremazocine and U-50,488 on locomotor activity (test: toggle-floor box) and memory (test: passive avoidance) were assessed in C57BL/6 (C57) and DB/2 (DBA) mice. The drugs administration resulted in activity depression in both strains, the effect was higher in DBA mice and was enhanced by pretreatment with haloperidol and with muscimol. Memory impairment was observed in DBA mice following posttraining administration of all drugs. This effect was enhanced by immobilization stress and decreased by familiarization with the apparatus. Memory improvement was evident in C57 mice (U-50,488 experiments). In a research carried out with CD1 mice, amygdaloid lesions decreased the memory impairing effect of U-50,488. The results are compared with those previously obtained with mu agonists and, as concerns memory, are discussed in terms of the involvement of emotional factors in mice responses to kappa agonists administration.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1985

Antagonism of N-methyl-D-aspartate-induced transmitter release in the rat striatum by phencyclidine-like drugs and its relationship to turning behavior.

Representatives from several chemical classes known to share behavioral properties with phencyclidine [(1-phenylcyclohexyl)piperidine] (PCP) have been shown to antagonize the excitatory effects of N-methylaspartate on spinal neurons selectively. This study compared the abilities of several of these PCP-like drugs to inhibit N-methyl-D-aspartate (NMDA)-stimulated efflux of acetylcholine in rat striatum. PCP completely inhibited this parameter with an IC50 value of 68 nM. The IC50 values (nanomolar) found for the other drugs tested were as follows: etoxadrol (98), (-)-cyclazocine (120), N-allylnormetazocine (or SKF 10047) (940), ketamine (1600) and ethylketocyclazocine (8300). Morphine had no effect at concentrations as high as 30,000 nM. In addition, 100 nM dexoxadrol, 1-[1-(napthyl)cyclohexyl]piperidine HCl (m-amino PCP) and (-)-cyclazocine inhibited NMDA-induced acetylcholine release by about 50%, whereas the same concentration of their enantiomers (or a structural analog in the case of m-amino-PCP) produced no significant effect. It was also found that 10 mg/kg of dexoxadrol, m-amino-PCP and (-)-cyclazocine induced significant ipsilateral turning in rats with unilateral destruction of the substantia nigra, whereas 10 mg/kg of levoxadrol, 1-[1-(m-nitrophenyl)cyclohexyl]piperidine HCL (m-nitro-PCP) and (+)-cyclazocine produced no such similar effect. In spite of the ability of several dopaminergic antagonists to block turning produced by (+/-)-cyclazocine, we concluded, based on our previously reported studies of the dopaminergic properties of these drugs, that turning is the result of nondopaminergic properties of the PCP-like drugs.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1986

Flumezapine, an antagonist of central dopamine and serotonin receptors.

Flumezapine, 7-fluoro-2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3- b] [1,5]benzodiazepine, antagonized the increases in serum corticosterone concentration caused by a serotonin agonist, quipazine, and by a dopamine agonist, pergolide, in rats. Flumezapine did not alter the elevation of serum corticosterone by a kappa opioid agonist, bremazocine. Flumezapine resembled but was more potent than clozapine and zotepine in blocking these effects of quipazine and pergolide, differing from spiperone and fluphenazine which were selective antagonists of pergolide and from metergoline and mianserin which were selective antagonists of quipazine. All of the antagonists had high affinity for 5HT2 receptors as measured by radioligand-binding in vitro. Spiperone, fluphenazine, zotepine and flumezapine had high affinity for dopamine D2 receptors as measured by radioligand-binding in vitro. The potency of the compounds in antagonizing the pergolide-induced elevation of serum corticosterone concentration matched their affinity for D2 receptors in vitro. There was poor correlation between the potency of the compounds in antagonizing the quipazine-induced elevation of serum corticosterone concentration and their affinity for 5HT2 receptors in vitro, possibly indicating that the receptor mediating the effect of quipazine is not identical to or exclusively the 5HT2 receptor. The results suggest that flumezapine is a potent blocker of dopamine D2 and of some serotonin receptors.

Animals↗
PubMedDate not supplied

The difference in stress-induced analgesia in C57BL/6 and DBA/2 mice: a search for biochemical correlates.

The level of opioid peptides: beta-endorphin and dynorphin, binding to the mu and kappa opioid receptors and the analgesic response of those endogenous opioid systems to stress were investigated in two strains of mice: C57BL/6 (C57) and DBA/2 (DBA). The nociceptive threshold of DBA mice was higher than that of C57 mice. KD values for spinal mu receptors were lower in C57, while KD for cerebral kappa receptors were higher in this strain. DBA mice have significantly higher concentrations of dynorphin in the hypothalamus and neurointermediate lobe of the pituitary. Stress-induced analgesia was much greater in C57 than in DBA mice. In the hypothalamus both stress procedures depressed the concentrations of beta-endorphin in C57, and dynorphin in DBA mice. The level of beta-endorphin increased in the neurointermediate lobe in C57 and in anterior lobe of the pituitary in DBA mice. In the spinal cord both stress procedures depressed the dynorphin level. The above data indicate that C57 and DBA mice differ in the endogenous opioid peptide content, stress-induced alteration and opioid receptor affinity, the effects which might correlate with their different responses to environmental factors and pharmacological agents.

Analgesia↗
PubMed1985

Diuresis and suppression of vasopressin by kappa opioids: comparison with mu and delta opioids and clonidine.

The effects of agonists at kappa, mu and delta opioid receptors were determined on vasopressin levels in water-deprived rats. Bremazocine and U-50, 488 (kappa agonists) markedly suppressed vasopressin levels, whereas morphine and methadone (mu agonists) and metkephamid (a mixed mu and delta agonist) did not suppress vasopressin levels. Likewise, clonidine, a potent diuretic in normally hydrated rats, did not clearly suppress vasopressin levels. Metkephamid was shown to have a modest diuretic effect in normally hydrated rats but not in water-deprived rats. The diuretic effects of bremazocine were blocked completely by simultaneous treatment with desmopressin, a synthetic vasopressin-like analog. Desmopressin also blocked the diuretic effect of a waterload, but only partially attenuated the diuretic effect of clonidine. These results support the hypothesis that kappa opioid agonists produce a diuretic effect by suppressing plasma levels of vasopressin, and at higher doses produce a pattern of urination similar to animals lacking vasopressin. By comparison, mu and delta opioid agonists have little effect on vasopressin levels in water-deprived rats.

Animals↗
PubMed1986

Inhibition of mu and delta but not kappa opioid binding to membranes by Fab fragments from a monoclonal antibody directed against the opioid receptor.

Fab fragments from a monoclonal antibody, OR-689.2.4, directed against the opioid receptor, selectively inhibited opioid binding to rat and guinea pig neural membranes. In a titratable manner, the Fab fragments noncompetitively inhibited the binding of the mu selective peptide [D-Ala2,(Me)Phe4,Gly(OH)5][3H] enkephalin and the delta selective peptide [D-Pen2,D-Pen5] [3H]enkephalin (where Pen represents penicillamine) to neural membranes. In contrast, kappa opioid binding, as measured by the binding of [3H]bremazocine to rat neural membranes and guinea pig cerebellum in the presence of mu and delta blockers, was not significantly altered by the Fab fragments. In addition to blocking the binding of mu and delta ligands, the Fab fragments displaced bound opioids from the membranes. When mu sites were blocked with [D-Ala2,(Me)Phe4,Gly(OH)5]enkephalin, the Fab fragments suppressed the binding of [D-Pen2,D-Pen5][3H]enkephalin to the same degree as when the mu binding site was not blocked. The Fab fragments also inhibited binding to the mu site regardless of whether or not the delta site was blocked with [D-Pen2,D-Pen5]enkephalin. This monoclonal antibody is directed against a 35,000-dalton protein. Since the antibody is able to inhibit mu and delta binding but not kappa opioid binding, it appears that this 35,000-dalton protein is an integral component of mu and delta opioid receptors but not kappa receptors.

Animals↗
PubMed1987

[The role of various opiate receptors in the regulation of the nociceptive reaction of the arterial pressure].

The experiments on alert rats have shown that dissociation in opioid regulation of behavioural and hemodynamic pain manifestations is determined at a spinal opiate receptor level. Opiates and opioids suppress blood pressure nociceptive reactions to mu-opiate receptors, while sigma-opiate receptors are involved into the generation of autonomic activating effect in opiate analgesia.

Animals↗
PubMed1987

Autoradiographic differentiation of mu, delta, and kappa opioid receptors in the rat forebrain and midbrain.

While there is an abundance of pharmacological and biochemical evidence to suggest the existence of multiple opioid receptors, their precise localization within the brain is unclear. To help clarify this issue, the present study examined the distributions of the mu, delta, and kappa opioid receptor subtypes in the rat forebrain and midbrain using in vitro autoradiography. Mu and delta receptors were labeled with the selective ligands 3H-DAGO (Tyr- D-Ala-Gly-MePhe-Gly-ol), and 3H-DPDPE (D-Pen2, D-Pen5-enkephalin), respectively, while the kappa receptors were labeled with 3H-(-)bremazocine in the presence of unlabeled DAGO and DPDPE. Based on previous findings in our laboratory, the labeling conditions were such that each ligand selectively occupied approximately 75% of each of the opioid sites. The results demonstrated that all 3 opioid receptor subtypes were differentially distributed in the rat brain. Mu binding was dense in anterior cingulate cortex, neocortex, amygdala, hippocampus, ventral dentate gyrus, presubiculum, nucleus accumbens, caudate putamen, thalamus, habenula, interpeduncular nucleus, pars compacta of the substantia nigra, superior and inferior colliculi, and raphe nuclei. In contrast, delta binding was restricted to only a few brain areas, including anterior cingulate cortex, neocortex, amygdala, olfactory tubercle, nucleus accumbens, and caudate putamen. Kappa binding, while not as widespread as observed with mu binding, was densely distributed in the amygdala, olfactory tubercle, nucleus accumbens, caudate putamen, medial preoptic area, hypothalamus, median eminence, periventricular thalamus, and interpeduncular nucleus. While all 3 opioid receptor subtypes could sometimes be localized within the same brain area, their precise distribution within the region often varied widely. For example, in the caudate putamen, mu binding had a patchy distribution, while delta and kappa sites were diffusely distributed, with delta sites being particularly dense ventrolaterally and kappa sites being concentrated ventromedially. These results support the existence of at least 3 distinct opioid receptors with possibly separate functional roles.

Animals↗
PubMed1987

Kappa agonist-induced diuresis: evidence for stereoselectivity, strain differences, independence of hydration variables and a result of decreased plasma vasopressin levels.

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.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1987

[Effect of the opiate antagonist naloxone on the electrical activity of identified neurons in the edible snail].

The opiate antagonist naloxone modifies the electric activity of some identified neurons of the Helix lucorum which have not been preliminary exposed to the effect of exogenous opioids. Some neurons are excited while others are inhibited by naloxone, and in both cases the reaction may have both a short and long latent period. The reactions depend on naloxone dose and become less expressed or are blocked when naloxone is administered together with the agonists of opiate receptor (morphine, D-Ala2, D-Leu5-enkephalin, bremazocine and beta-endorphin). Opioids alone do not produce any effect on neurons. The effect of naloxone on neurons is assumed to be a result of the elimination by the opiate antagonist of the tonic effect of endogenous opioids by their replacing on opiate receptors which are constantly stimulated by endogenous ligands.

Animals↗