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PubMed1975

Stereospecific morphine adsorption to phosphatidyl serine and other membranous components of brain.

In the course of investigating various membranous components for morphine binding, it was found that the major substance responsible was phosphatidyl serine. Other acidic lipids, such as phosphatidic acid and phosphoinositides bind to a considerably lesser extent, while neutral lipids, glycolipids and other phosphatides bind slightly or not at all. Total lipid extracts from a number of regions of rat brain exhibited different degrees of binding to (-)-morphine, such regions as the cerebral cortex and thalamus being the greatest. From an examination of the pH curve for binding and the effect of ionic strength, it was concluded that the binging was largely electrostatic. The method employed was the radioactive measurement of 14C-morphine adsorption to surface films of phosphatidyl serine. When the phosphatide was dispersed in a nonionic detergent near the critical micelle concentration, adsorption was maximal, attaining a value of 1 molecule of morphine adsorbed per molecule of phosphatidyl serine in the surface micelle. The relation between binding affinity and biological potency was not consistent. Morphine adsorption occurred with films prepared from a dispersion of the phosphatide and a hydrophobic protein from synaptic membranes. With the use of levorphanol and dextrorphan it could be shown that binding of morphine was stereospecific.

Adsorption↗
PubMed1978

Naloxone as a GABA antagonist: evidence from iontophoretic, receptor binding and convulsant studies.

From the following three lines of evidence, it is proposed that at least part of the convulsant activity of naloxone is a result of GABA receptor blockade. Firstly, iontophoretic naloxone reversibly antagonized GABA-evoked depression of firing rate in 21 of 27 neurons tested in the rat olfactory tubercle-nucleus accumbens region, without blocking inhibition evoked in the same cells by glycine (15 cells) or morphine (6 cells). Secondly, i.p. naloxone in high doses caused convulsions in mice, and potentiated the convulsant activity of bicuculline, but not that of strychnine. Diazepam, which protected mice against convulsions elicited by bicuculline, but not by strychnine, also protected mice against naloxone. Thirdly, naloxone, morphine, levorphanol and its non-analgesic enantiomer dextrorphan displaced 3H-GABA from GABA receptor sites in homogenates of human cerebellum, all with comparable low potencies (IC50 = 250--400 micron). There was no correlation with affinities at the stereospecific receptor sites that mediate opiate-induced analgesia, since the potent opiates etorphine and diprenorphine were relatively inactive (IC50 greater than 3 mM). In addition naloxone displaced 3H-GABA from receptor sites in rate forebrain and cerebellum, with similar low potency.

Action Potentials↗
PubMed1982

Morphine may mimic the apomorphine cue by inhibiting dopaminergic autoinhibition.

Rats were trained to discriminate the cue produced by 0.25 mg/kg apomorphine from that produced by saline, using a two-lever, drug discrimination task. This cue was blocked by haloperidol but not by DPI, ergometrine, bromocriptine, sulpiride, naloxone or naltrexone; none of these agents substituted for (mimicked) apomorphine. Morphine and levorphanol did, however, mimic apomorphine, whereas dextrorphan did not; pentazocine induced responding unlike either apomorphine or saline. The substitution of morphine for apomorphine was blocked by naltrexone or bromocriptone, and was partially antagonized by a low of ergometrine, but was unaffected by haloperidol or sulpiride. To explain these results, it was proposed that morphine mimics apomorphine by inhibiting dopaminergic autoregulation involving D2-receptors.

Animals↗
PubMed1986

Stereotyped behavior correlates better than ataxia with phencyclidine-receptor interactions.

The interaction of phencyclidine, dexoxadrol, their analogs and stereoisomers with phencyclidine receptors was compared to their ability to induce stereotyped behavior and ataxia after i.c.v. administration to rats. The order of potency for binding to phencyclidine receptors revealed that among the stereoisomers of phencyclidine derivatives, the (+) isomer was more potent than the (-) isomer. A similar order of potency of phencyclidine derivatives and degree of stereoselectivity was seen in the assays for stereotyped behavior and phencyclidine receptor interactions, which resulted in a good correlation between the relative potencies for binding to phencyclidine receptors and inducing stereotyped behavior. However, the order of potency for induction of ataxia and the stereoselectivity was different than that seen in the assays for phencyclidine receptor interactions and stereotyped behavior. A comparison of relative potencies for binding to phencyclidine receptors to induction of ataxia still resulted in a good fit to a straight line, but the line did not intersect the origin, indicating that a non-phencyclidine receptor component is also involved in mediating ataxia. Dextrorphan and 2-methyl-3,3-diphenyl-3-propylamine were equipotent as phencyclidine in phencyclidine receptor and behavioral assays. The order of potency for interacting with phencyclidine receptors and inducing phencyclidine-like behavior by the isomers of cyclazocine were opposite to that of other phencyclidine analogs. Also, the order of potency for induction of ataxia by the isomers of N-allylnormetazocine was opposite to that for phencyclidine receptor interactions. Ethylketocyclazocine did not induce any stereotyped behavior or ataxia, indicating that it is unlikely that a kappa opioid receptor interaction plays a role in mediating ataxia. Furthermore, stereotyped behavior and ataxia were not due to interactions with mu, kappa or delta opioid receptors as naloxone did not antagonize the behavioral effects of phencyclidine, (-)cyclazocine or (-)N-allylnormetazocine. These results indicate that stereotyped behavior is mediated by phencyclidine receptors, whereas ataxia is mediated by more than just phencyclidine receptors.

Animals↗
PubMed1988

Dextromethorphan inhibits NMDA-induced convulsions.

Dextromethorphan, its metabolite dextrorphan, phencyclidine, ketamine, MK-801, 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid and DL-2-amino-7-phosphonoheptanoic acid were evaluated for potency to antagonize N-methyl-D-aspartate-induced convulsions following intraperitoneal administration using male CF-1 mice. Whereas reference anticonvulsants (e.g., phenytoin) were ineffective in this model, dextromethorphan and all competitive and noncompetitive N-methyl-D-aspartate antagonists blocked seizures. The results are consistent with the interpretation that dextromethorphan elicits some of its pharmacological responses via an interaction with receptors for excitatory amino acids.

Animals↗
PubMed1988

Solubilization and characterization of the kappa-opioid receptor type from guinea-pig cerebellum.

The kappa-opioid receptor (kappa Op) from guinea-pig cerebellum membranes has been solubilized in an active form and in good yield (30-40%) with digitonin in 10 mM Tes-KOH buffer, pH 7.4. [3H]Bremazocine (KD = 1.1 nM in the soluble extract) was used to monitor the binding and hydrodynamic characteristics of the digitonin-solubilized receptor, s-kappa Op. Opioid agonists and antagonists bind s-kappa Op with a generally lower (yet still high) apparent affinity than they do its membrane-bound counterpart, m-kappa Op, but with the same rank order of potency. In particular, U50488, a kappa selective agonist, binds s-kappa Op with a considerably higher apparent affinity than do [D-Ala2, MePhe4, Glyol5]enkephalin, a mu selective agonist, and [D-Thr2,Leu5]enkephalyl-Thr, a delta selective agonist. s-kappa Op has also retained substantial stereospecificity since levorphanol was nearly 200-fold as potent as dextrorphan in competing with binding of [3H]bremazocine in the soluble extract. However, s-kappa Op appeared to be desensitized to regulation by Na+ ions: the selective inhibition by the allosteric effector of binding of agonists at the m-kappa Op was no longer observed in digitonin extracts from guinea-pig cerebellum membranes. The s-kappa Op behaved as a unique macromolecular entity both in molecular exclusion chromatography (appr. rs = 6.7 nm) and in sedimentation on linear density gradients (app. S20,w = 11.8 S).

Analgesics↗
PubMed1996

Pharmacology of N-methyl-D-aspartate-evoked [3H]noradrenaline release in adult rat spinal cord.

N-Methyl-D-aspartate (NMDA) produced a concentration-related increase in [3H]noradrenaline release from adult rat cervical spinal cord slices. Its potency was relatively low and the response concentrated in dorsal spinal regions although also observed in ventral slices. NMDA did not increase the release of radiolabelled glutamate, aspartate, gamma-aminobutyric acid (GABA), acetylcholine or serotonin. In comparison with previously characterised NMDA responses in the striatum, (release of dopamine, GABA, acetylcholine or spermidine) the spinal response was particularly sensitive to MK-801 and magnesium and to L-689,560 but not to other glycine receptor antagonists (7-chlorokynurenate, CNQX (6-cyano-7-nitroquinoxaline-2,3-dione), DNQX (6,7-dichloroquinoxaline-2,3-dione), (+)-HA966). Dextrorphan and dextromethorphan produced partial or biphasic inhibition curves suggesting a subdivision of NMDA receptors. NMDA-evoked [3H]noradrenaline release was moderately sensitive to CPP and CGP37849 but insensitive to arcaine. These characteristics distinguish the native spinal NMDA receptor subtype(s) from those so far characterised in the striatum suggesting a unique spinal NMDA receptor subtype.

Animals↗
PubMed1982

Identification of a Mr 58 000 glycoprotein subunit of the opiate receptor.

A Mr 58 000 subunit of the opiate receptor has been identified using tritiated fentanyl isothiocyanate, a potent opiate alkylating reagent with specificity for the delta-opiate receptor subclass. The subunit is alkylated in the presence of dextrorphan but not levorphanol. The specifically labelled protein was retained on columns of immobilized wheat germ agglutinin and is therefore presumably a glycoprotein. Partial purification of the Mr 58 000 opiate receptor subunit from neuroblastoma X glioma NG108-15 hybrid cell membranes is described.

Animals↗
PubMedDate not supplied

Receptor-related interactions of opiates with PGE-induced adenylate cyclase in brain.

The inhibition by opiates of the PGE2-induced formation of cAMP in slices from rat brain striatum was investigated. A maximal, 3.5-fold increase over the basal level of cAMP was obtained with an EC50 for PGE2 of 3 microM. Opiate agonists of both mu and kappa type were inhibitory. The IC50 values for morphine, levorphanol and ethylketocyclazocine (EKC) were 110 nM, 80 nM and 25 nM, respectively. These values were similar to the potencies of the compounds in displacing stereospecifically bound 3H-etorphine in rat brain membranes. As evidenced by the inactivity of dextrorphan, the inhibition of PGE2-dependent cAMP formation was stereospecific. Also ineffective were the opiate antagonists naloxone, naltrexone and MR 2266. These compounds did, however, reverse the inhibition by agonists, displaying thereby selectivity toward the putative mu and kappa opiates. Thus, the inhibition by morphine was antagonized to a greater degree by naloxone than by MR 2266, and the action of EKC was blocked more effectively by MR 2266 relative to naloxone.

Adenylyl Cyclases↗
PubMed1982

Stereospecific binding of 3H-phencyclidine in brain membranes.

Phencyclidine (PCP) displaceable binding of 3H-PCP to glass-fiber filters was eliminated and total binding markedly reduced by initial treatment of the discs with 0.05% polyethyleneimine. Assessed with treated filters, unlabeled PCP displaced 3H-PCP in both rat and pigeon brain membranes with an EC50 of 1 microM. Of similar high inhibitory potency were dextrorphan, levorphanol, SKF 10047 and ketamine, while morphine, naloxone and etorphine had EC50 values higher then 1 mM. Using the dissociative anesthetic dexoxadrol and its inactive isomer levoxadrol as displacing agents, stereospecific binding of 3H-PCP was obtained in rat and pigeon brain membranes. The markedly higher potency of dexoxadrol, relative to levoxadrol, in displacing bound 3H-PCP is compatible with behavioral data for these enantiomers. However, they were equipotent in displacing 3H-PCP bound to glass-fiber filters in the absence of tissue. Heat denaturation, but not freezing, abolished stereospecific binding of 3H-PCP, which was also absent in rat liver membranes. The stereospecific binding component in brain displayed biphasic saturability at 60-70 nM and 300-400 nM, respectively.

Animals↗
PubMed1983

Opiate tolerance and dependence is associated with a decreased activity of GTPase in rat striatal membranes.

In vitro addition of opiates to rat striatal membranes significantly stimulated a low Km GTPase activity. The opioid peptide (D-Ala2, Met5) enkephalinamide was ten folds more active than morphine to elicit the effect while the kappa agonist ethylketocyclazocine was almost inactive. Opiate stimulation was antagonized by naloxone, indicating that specific opiate receptors were involved. Moreover, the effect was stereospecific since levorphanol significantly increased the GTPase activity while its enantiomer dextrorphan was completely inactive, even at concentrations as high as 100 microM. On the other hand, opiates have been reported to inhibit striatal adenylate cyclase whose activity is dependent on GTP. Our data suggest therefore that stimulation of GTPase can be the mechanism by which opiates lower adenylate cyclase activity. This view is supported by the finding that in striatal membranes of rats made tolerant-dependent to morphine, GTPase activity was significantly decreased. Narcotic tolerance and dependence is in fact associated to hyperactivity of adenylate cyclase. It is concluded that GTPase could be the primary site on which opiates act to produce the acute or chronic effects on adenylate cyclase activity.

Animals↗
PubMed1983

Hypersensitivity of the opioid-tolerant guinea pig ileum to electrical stimulation after abrupt agonist removal.

Studies were initiated on the myenteric plexus of the guinea pig ileum to ascertain whether a supersensitive response by abrupt withdrawal could be elicited after tolerance development to opioids. After an optimal twitch response to a given electrical stimulus was established and its height measured, the mean concentration of an opioid to inhibit half maximally the response (IC50) was determined. Subsequently, the tissues were rendered tolerant by incubating with 1x to 5x the IC50 of the agonist for two hours. The agonist was then removed by thorough washing with Ringer solution and the twitch height to the same electrical stimulation was remeasured. The increase in twitch height after washing over that before incubation provided an index of the degree of hypersensitivity of the tolerant-dependent tissue. The degree of hypersensitivity was found to increase in relation to the concentration of morphine. Stereo-specificity of agonist action was evinced by a hypersensitive response to levorphanol and not to dextrorphan. The development of hypersensitivity was blocked by naloxone and by chloramphenicol. Ethylketocyclazocine, a k ligand, did not show a hypersensitivity response. It is concluded that physical dependence on u-opioids can be developed in vitro and that it can be quantified by a super-sensitivity response.

Animals↗
PubMed1988

Opioid binding site in EL-4 thymoma cell line.

Using EL-4 thymoma cell-line we found a binding site similar to the k opioid receptor of the nervous system. The Scatchard analysis of the binding of [3H] bremazocine indicated a single site with a KD = 60 +/- 17 nM and Bmax = 2.7 +/- 0.8 pmols/10(6) cells (51 pmols/mg total cell proteins). To characterize this binding site, competition studies were performed using selective compounds for the various opioid receptors. The k agonist U-50,488H was the most potent displacer of [3H] bremazocine with an IC50 value = 0.57 microM. The two stereoisomers levorphanol and dextrorphan showed the same affinity for this site (IC50 = 2.9 microM and 1.9 microM respectively). While morphine, [D-Pen2, D-Pen5] enkephalin and beta-endorphin failed to displace, except at very high concentrations, codeine demonstrated a IC50 = 60 microM, that was similar to naloxone (IC50 = 69 microM).

Analgesics↗
PubMed1992

The effect of opiate agonists and antagonists on Na(+)-Ca2+ exchange in cardiac sarcolemma vesicles.

Opiate agonists and antagonists inhibit Na(+)-Ca2+ exchange in the isolated cardiac sarcolemma vesicles. Non-opioid stereoisomers (dextrorphan, Mr 1542MS, WIN 44,441-3) display effects similar to their opioid isomers (levorphanol, Mr 1543MS, WIN 44,441-2) suggesting that inhibition is not mediated by opiate receptors. Naloxone (permeable) and methylnaloxone (impermeable) inhibit the Na(+)-Ca2+ exchange similarly, suggesting an extravesicular location of inhibitory site. The inhibitory potency of naloxone is pH-independent in the range of 7.4-9.1, suggesting that the charge-carrying properties of drug-protein interactions are not altered under the tested conditions. Opiates display similar dose-response relationships for Na(+)-Ca2+ exchange and its partial reaction, the Ca(2+)-Ca2+ exchange. The opiate-induced inhibition is complete and noncompetitive in regard to extravesicular calcium. These data suggest that opiates do not bind to the Ca(2+)-binding domain (A-site), but they may interest either with the Na(+)-binding site (B-site) or with a putative opiate-binding site, presumably located outside of the ion-binding vicinity. Further studies on structure-activity relationship might lead to the discovery of potent and more specific inhibitors of cardiac Na(+)-Ca2+ exchanger. A possible relevance of these findings to some non-opioid pharmacological effects of naloxone on the cardiac muscle is suggested.

Animals↗
PubMed1983

Characteristics of [3H]fentanyl binding to the opiate receptor.

The present study characterises the binding of the highly lipophilic opiate agonist [3H]fentanyl to homogenates of the rat central nervous system. At 25 degrees C, association of [3H]fentanyl with its binding site was rapid (t1/2 = 2.5 min). Dissociation from the binding site was biphasic (t1/2's = 4.0 and 100 min) suggesting the existence of high and low affinity binding sites. Scatchard plots of saturation isotherms were curvilinear, confirming the presence of high (KD = 0.46 nM) and low KD = 4.26 nM) affinity binding sites. Increasing temperature and the concentration of sodium ion decreased the [3H]fentanyl binding. Opiate agonists, antagonists and mixed agonist-antagonists were all potent (IC50's less than 20 nM) in displacing [3H]fentanyl and displacement by levorphanol and dextrorphan indicated that [3H]fentanyl binding was stereospecific. The mu and delta selective peptides, morphiceptin and [D-Ala2,D-Leu5]enkephalin, had IC50 values of 87 and 9.2 nM respectively. The regional distribution of [3H]fentanyl binding was in the rank order striatum approximately equal to midbrain greater than hypothalamus greater than cortex greater than hippocampus greater than brainstem greater than spinal cord greater than cerebellum. Comparison of [3H]fentanyl, [3H]naloxone and [3H-D-Ala2,D-Leu5]enkephalin binding in the hypothalamus-thalamus (mu-enriched) compared with the frontal cortex-striatum (delta-enriched) indicated that the pattern of [3H]fentanyl labelling was similar to that obtained with [3H]naloxone, but differed from that obtained with [3H-D-Ala2,D-Leu5]enkephalin. These characteristics suggest that [3H]fentanyl binds to the mu-opiate receptor. These findings are discussed in relation to the high lipid solubility of fentanyl as compared with morphine.

Animals↗
PubMed1979

Opiate modification of intracranial self-stimulation in the rat.

Studies were conducted to confirm the involvement of central opiate receptors in the expression of opiate modulation of intracranial self-stimulation (ICSS). Biphasic, dose-related changes in ICSS responding are described following IP administration of morphine sulfate (1-25 mg/kg) and levorphanol tartrate (LEV, 0.5-5 mg/kg). Similar patterns of response modification are reported following intraventricular (IVt) administration of LEV (0.01-0.2 muMoles) LEV's enantiomorph, dextrorphan, was not found to elicit comparable effects after either IP or IVt administration. Both the facilitatory and the depressant phases of LEV's action were antagonized by naltrexone (10 microgram, IVt), which had no apparent effect on ICSS by itself. Complete tolerance developed to the suppression of responding by 2.5 mg/kg LEV (IP) but not to the facilitatory effect of 0.5 mg/kg (IP), during a 5-day course of administration. The implications of these results for opiate reinforcement theory are discussed and possible mechanisms are advanced.

Animals↗
PubMed1982

Effects of chronic opiate administration of spontaneous activity of fetal rats.

No studies have been reported previously on fetal behavior after chronic morphine administration during the period of opiate receptor ontogenesis. In the present study, pregnant rats were injected with 20 mg/kg/day divided into either two or four daily doses. The injections were made from day 12 through the end of gestation. On days 18-20, the effect of morphine and naloxone on fetal activity in the pretreated animals was assessed by visual observation and quantification. Animals exposed twice daily to morphine showed a morphine-induced depression in spontaneous activity similar to animals pretreated with saline while animals injected four times daily developed tolerance to the depressant effect of the morphine. Animals injected with either morphine or levorphanol were hyperactive after challenge with naloxone. Animals injected with saline or dextrorphan or pair-fed were not hyperactive after exposure to naloxone. Even though behavioral changes were seen in utero after injection of morphine, 30-day neonates which had been treated identically prenatally did not show changes in the analgesic response to morphine.

Animals↗
PubMed1986

Opiate-induced turning in rats after injection into the ventral tegmental area.

Morphine and ethylketazocine caused ipsilateral circling when injected unilaterally into the ventral tegmental area (VTA) of rats. Systemic naloxone only slightly inhibited this effect while systemic diprenorphine completely prevented circling. Systemic haloperidol and alpha-methyl-p-tyrosine also blocked circling. Rats made tolerant to morphine still turned after morphine injection into the VTA. Levorphanol, dextrorphan, methadone, DADLE, dynorphin(1-13), SKF 10,047 and phencyclidine were inactive when injected unilaterally into the VTA of naive rats; naloxone and naltrexone alone also were inactive. The opiate-induced circling appears to involve a non-mu opiate receptor as well as a dopaminergic neuronal system.

Animals↗