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PubMed1989

Neocortical epileptogenesis in vitro: studies with N-methyl-D-aspartate, phencyclidine, sigma and dextromethorphan receptor ligands.

Slices of rat neocortex have been used to study the role of N-methyl-D-aspartate (NMDA) receptors in the induction of epileptiform activity. The NMDA antagonist potency of a range of compounds with putative anticonvulsant activity has been compared with their ability to reduce epileptiform activity in this tissue. Epileptiform activity was induced by the omission of magnesium from the bathing medium. Competitive and noncompetitive phencyclidine-like NMDA antagonists reduced such spontaneous and stimulus-evoked epileptiform bursts and after potentials. Similar epileptiform activity induced by the addition of proconvulsant drugs, e.g. gamma-aminobutyric acidA antagonists, potassium channel blockers or carbachol was reduced by ketamine and/or D-2-amino-5-phosphonovaleric acid. In magnesium-free medium, the frequency of spontaneous bursts and the number of afterpotentials per burst were reduced in parallel. There was a good correlation (r greater than 0.9) between their potencies against NMDA depolarizations and against epileptiform bursts (MK-801 [(+)-5-methyl-10,11- dihydro-5H-dibenzvo[a,d]cyclohepten-5,10-imine] greater than thienylcyclohexylpiperidine phencyclidine greater than 3-(2-carboxypiperazine-4-yl)propyl-1-phosphonic acid greater than cyclazocine greater than D-2-amino-5-phosphonovaleric acid greater than dextrorphan greater than SKF10,047 (N-allylnormetazocine) greater than ketamine greater than dextromethorphan = or greater than pentazocine). Sigma and dextromethorphan receptor ligands (e.g. ditolyguanidine, carbetapentane and phenytoin), whereas inactive as NMDA antagonists, reduced epileptiform activity by decreasing the number of afterpotentials per burst with less effect on the burst frequency. The quisqualate/kainate antagonist, FG9041 (6,7-dinitro-quinoxaline-2,3-dione), only reduced spontaneous bursts at doses which also reduced NMDA. Our results imply a central role for NMDA receptors in epileptogenesis in neocortical slices.

Animals↗
PubMed1989

Tricyclic antidepressants and dextromethorphan bind with higher affinity to the phencyclidine receptor in the absence of magnesium and L-glutamate.

Recent studies from our laboratory have provided evidence that multiple states of the phencyclidine (PCP) receptor exist. In addition, several compounds such as PCP and the novel anticonvulsant MK-801 were found to inhibit binding more potently in the presence of Mg2+ and L-glutamate (L-GLU) than when these agents were excluded from the binding assay. In the present study, a number of pharmacological compounds that have been suggested to interact within the N-methyl-D-aspartate (NMDA) receptor complex, including tricyclic antidepressants (TCAs), were examined for their ability to inhibit the binding of [3H]1-[1-(2-thienyl)cyclohexyl]piperidine [( 3H]TCP) in the absence or presence of Mg2+ and L-GLU. The TCAs imipramine, amitriptyline, and opipramol produced shallow inhibition curves in the absence of Mg2+ and L-GLU. Computer analysis of the binding data indicated that a two-component binding model described the data significantly better than a one-component model. In the presence of Mg2+ and L-GLU, the inhibition curves became steeper and were shifted to the right, and computer analysis of the binding data indicated that a one-component model adequately described the binding data. A series of other centrally active compounds, including several antipsychotics and antihistamines, the antiparkinsonian anticholinergic trihexyphenidyl and the antitussive dextromethorphan, were also found to be affected similarly by the inclusion of Mg2+ and L-GLU in the binding assay. Dextrorphan, in contrast to dextromethorphan, inhibited [3H]TCP binding more potently in the presence of Mg2+ and L-GLU. The present results suggest that the compounds that inhibit binding more potently in the absence of Mg2+ and L-GLU are interacting with the PCP receptor in a different manner from that of PCP and MK-801, because these open-channel blockers inhibit [3H]TCP binding more potently in the presence of Mg2+ and L-GLU. The data support previous findings that TCAs interact with the NMDA receptor complex and suggest that the compounds trihexyphenidyl and dextromethorphan, which have been shown to block NMDA-mediated neurotoxicity, may produce their effects through an interaction with the PCP receptor, albeit by a different mechanism from that of open-channel blockers.

Animals↗
PubMed1989

Delayed rescue of N-methyl-D-aspartate receptor-mediated neuronal injury in cortical culture.

The present study explored the neuroprotective efficacy of delayed manipulations performed after completion of an excitotoxic insult. Many cultured murine cortical neurons that would otherwise die after exposure to 500 microM N-methyl-D-aspartate (NMDA) or glutamate could be rescued by the late addition of NMDA antagonists to the bathing medium. D-2-Amino-5-phosphonovalerate (D-APV), MK-801 (5-methyl-10, 11-dihydro-5H-dibenzo[a,d]cyclohepten-5, 10-imine maleate) and dextrorphan all produced concentration-dependent neuroprotection, with EC50 about 10, 0.3 and 3 microM, respectively, and similar efficacy. The fraction of the doomed neuronal population that could be rescued depended on the time interval between washout of NMDA and antagonist addition, starting at a maximum of 40 to 80% with immediate addition, and decaying to zero after 30 min. D-APV only needed to be present for 30 min for near maximal protection. The ability of NMDA antagonists to rescue doomed neurons was not mimicked by several other drugs: 1 mM gamma-D-glutamyl-aminomethyl sulfonate, 1 mM L-glutamate diethyl ester, 10 microM 6-nitro-7-cyano-quinoxaline-2,3-dione, 1 mM secobarbital, 100 microM diphenylhydantoin, 10 microM nifedipine or 3 microM tetrodotoxin. The broad spectrum glutamate antagonist kynurenate had a protective action similar to that of D-APV, but when added to D-APV did not improve neuroprotection. Neurons could also be rescued by the delayed removal of extracellular calcium for 30 min after exposure to NMDA. In contrast, replacement of sodium with choline actually enhanced resultant neuronal damage.(ABSTRACT TRUNCATED AT 250 WORDS)

2-Amino-5-phosphonovalerate↗
PubMed1987

Covalent labeling of mu opioid binding site by [3H]beta-funaltrexamine.

[3H]beta-funaltrexamine ([3H]beta-FNA) bound irreversibly to bovine striatal membranes. Naloxone inhibited the irreversible binding of 5 nM [3H]beta-FNA in a dose-dependent manner and maximally inhibited this binding at approximately 1 microM. Thus, the specific irreversible binding of [3H]beta-FNA to opioid receptors was defined as that which could be inhibited by 1 microM naloxone. This specific irreversible binding of [3H]beta-FNA was characterized. Exclusion of Na+ from the incubation medium reduced the specific binding of [3H]beta-FNA, and Na+ could be substituted by Li+ but not by K+, Cs+, Mg2+, or guanylylimidodiphosphate. The specific irreversible binding was saturable, time- and temperature-dependent, and was linearly related to tissue mass. Several drugs were used to characterize this specific binding. Levorphanol was 1000 times more potent as an inhibitor than dextrorphan. mu Opioid ligands (sufentanil and morphine) were much better inhibitors than delta (ICI174,864) or kappa (U50,488H) ligands. The potency of [D-Ala2, D-Leu5]enkephalin (DADLE) was between those of sufentanil and ICI174,864. These results demonstrated that under appropriate conditions [3H]beta-FNA specifically and irreversibly bound to the mu opioid binding site. Membrane preparations labeled with [3H]beta-FNA in the presence or absence of 1 microM naloxone or beta-FNA were subjected to polyacrylamide gel electrophoresis under denaturing and reducing conditions. Fluorograms showed that [3H]beta-FNA specifically bound to a protein (most likely the mu opioid binding site) that migrated as a band with a molecular weight range of 68,000-97,000. Such electrophoretic behavior indicates that it is likely to be a glycoprotein. The glycoprotein nature was confirmed by its adsorption onto a wheat germ lectin-Sepharose column after solubilization and subsequent elution by N-acetyl-D-glucosamine. In this lectin column eluate, the mu opioid receptor was the only protein band labeled by [3H]beta-FNA in the total binding preparation, and no labeled protein was observed in the nonspecific binding preparation. When the wheat germ lectin column eluate of the total binding was treated with peptide:N-glycosidase F, the broad labeled band of Mr 68,000-97,000 became a sharp band of Mr 57,000 with high radioactivity and a faintly labeled band of Mr 49,000.

Animals↗
PubMed1978

The effects of several narcotic analgesics on brain levels of 3-methoxy-4-hydroxyphenylethylene glycol sulfate in the rat.

The acute administration of levorphanol, morphine, anileridine, methadone, cyclazocine and pentazocine was found to increase brain levels of 3-methoxy-4-hydroxyphenylethylene glycol sulfate (MOPEG-SO4) in rats. Drug-induced increases in brain levels of this norepinephrine metabolite were dose-dependent and peak drug effects generally occurred 1 hr after intraperitoneal injection. Six to 8 hr after opiate agonist or partial agonist administration, MOEG-SO4 levels returned to control values or below. The narcotic effect appeared to be stereospecific, since high doses of d-methadone and dextrorphan produced either no change or only minimal increases in brain MOPEG-SO4 levels when compared with saline-treated controls. The relative potency of the analgesics tested in producing increases in brain MOPEG-SO4 levels appeared to correlate reasonably well with the ability of these drugs to produce other characteristic pharmacological effects. The drug-induced increases in brain MOPEG-SO4 levels were antagonized by naloxone. The rate of disappearance of MOPEG-SO4 from the brains of animals treated with pargyline was not decreased by the opiate agonists or partial agonists tested indicating that these drugs did not inhibit the acid transport process. These results indicate that the production of an increase in brain norepinephrine turnover is a specific component of the pharmacological actions of narcotic analgesics.

Analgesics, Opioid↗
PubMed1988

Pharmacology of the allodynia in rats evoked by high dose intrathecal morphine.

Morphine sulfate in doses of 90 to 150 micrograms/3 microliters evoke a prominent behavioral syndrome characterized by 1) periodic bouts of spontaneous agitation during which the rat scratches and bites at the skin of the caudal dermatomes and 2) vigorous agitation, vocalization and coordinated efforts to bite and escape evoked by a light tactile stimulus applied to the flank, suggestive of a pain state (allodynia). The phenomenon is not reversed by naltrexone or is it subject to tolerance. The ordering of activity of an opioid alkaloid related agent in producing this touch-evoked agitation is: noroxymorphone-3-glucuronide, morphine-3-glucuronide, morphine-3-ethereal sulfate, dihydromorphine, noroxymorphone dihydrate, hydromorphone, dihydrocodeine tartrate, morphine sulfate, dihydroisomorphine, morphine-HCl, 6-acetylmorphine, N-normorphine-HCl and (+)-morphine. The following agents were essentially without effect at the highest doses examined: 3,6-diacetylmorphine, N-normeperidine-HCl, nalorphine-HCl, alfentanil, sufentanil, naloxone, naltrexone, methadone, dextrorphan tartrate, meperidine-HCl, oxycodone, levorphanol, oxymorphone, codeine phosphate, thebaine, nalbuphine and naltrexone-3-glucuronide. The observations that the sulfated and conjugated metabolites are 10 to 50 times more potent than their unmetabolized precursor suggest the possibility that, in high concentrations certain phenanthrene opioid alkaloids with a free 3-OH position, an ether bridge and no N-methyl extension will be subject to conjugation and this metabolite will alter the processing of otherwise innocuous tactile stimuli. The fact that the phenomenon appeared at least partially stereospecific may reflect upon the fact that other laboratories have shown that glucuronyl transferase may preferentially convert (-)-morphine to the 3-glucuronide and (+)-morphine to the 6-glucuronide which may be less active.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesia↗
PubMed1986

Effect of dextromethorphan on guinea pig ileal contractility in vitro: comparison with levomethorphan, loperamide and codeine.

Dextromethorphan (DM) was tested for its effect on the contractility of the guinea pig ileum in vitro. Comparisons were made with levomethorphan, levorphanol, codeine and loperamide. DM and codeine inhibited the contractions of the electrically stimulated ileum, with IC50 values of 15 and 8 microM, respectively. The inhibitory effect of DM, in contrast to codeine, was not blocked by the opiate antagonist naloxone. Pretreatment (8, 50 and 100 microM) with DM and its I-isomer levomethorphan reduced in a dose-dependent fashion both phasic and tonic contractions produced by maximally effective concentrations of carbachol and 80 mM KCl. Pretreatment (8, 50 and 100 microM) with codeine, dextrorphan or levorphanol, unlike DM, did not reduce carbachol or KCl-induced contractions. The concentration-response curves to calcium in K+ depolarized ileum were shifted to the right in a parallel manner suggesting competitive antagonism for DM (pA2 5.3), levomethorphan (pA2 5.3) and loperamide (pA2 6.6). Codeine and levorphanol (8, 50 and 100 microM) did not antagonize calcium-induced contractions. In two assays of calmodulin-dependent processes DM was inactive (IC50 greater than 1 mM), whereas trifluoperazine and calmidazolium (standard calmodulin antagonists) were active in the micromolar range. In summary, these data suggest that DM, through a nonopiate mechanism, antagonizes gut contractility possibly by "stabilizing" neuronal and/or muscle cell membranes.

Actins↗
PubMed1985

Characterization of specific binding sites for [3H](d)-N-allylnormetazocine in rat brain membranes.

Binding of [3H](d)-N-allylnormetazocine ([3H](d)-NANM) to rat brain membranes is stereospecific, reversible, and saturable (Bmax = 260 fmol/mg of protein) and manifests moderately high affinity (Kd = 20 nM). The rank order of potency among opioidbenzomorphans and phencyclidine (PCP) analogs for competition for [3H](d)-NANM-binding sites is as follows: (d)-NANM = PCP-3-OH greater than (d)-cyclazocine greater than N-ethylphenylcyclohexylamine greater than PCP greater than (l)-cyclazocine = dextrorphan greater than (d/l)-ethylketocyclazocine greater than (d/l)-bremazocine greater than (1)-NANM greater than 1-phenylcyclohexylamine greater than levorphanol. Other opioid ligands, relatively selective for each of the types of opioid binding sites other than sigma, such as morphine (mu), H-Tyr-D-Ala(Me)Phe-NH-CH2-OH (mu), D-Ala2-D-Leu5-enkephalin (delta), tifluadom (kappa), and U 50488 (kappa) as well as etorphine and naloxone were all unable to compete with [3H](d)-NANM for specific binding even at a concentration of 1 microM. Regional distribution studies of [3H](d)-NANM-binding sites show high density in the hippocampus, thalamus, hypothalamus, and amygdala and low density in cerebellum and nonfrontal neocortex membranes of the rat brain. These binding sites are very sensitive to protein-modifying enzymes and reagents such as trypsin and N-ethylmaleimide and to heat denaturation. These results provide direct biochemical evidence for the existence of distinct (d)-NANM-binding sites in rat brain. In addition, this study supports the view that PCP and several of its analogues and the dextrorotatory isomers of psychotomimetic benzomorphans may act at a common recognition site in rat central nervous system.

Animals↗
PubMed1985

Opiate agonist-antagonist interactions: application of a three-key drug discrimination procedure.

Pigeons were trained to discriminate among i.m. injections of morphine (5.6 mg/kg), saline and naltrexone (10.0 mg/kg) in a three-key operant procedure with food reinforcement. Animals acquired the discrimination; each training condition occasioned responding on the injection-appropriate key, and the effects of morphine and naltrexone were dose-dependent. The opiate agonists ethylketazocine, buprenorphine and pentazocine substituted completely for morphine, and the opiate antagonist naloxone substituted completely for naltrexone. Meperidine, dextrorphan, beta-funaltrexamine, diprenorphine and nalorphine produced responding predominantly on the saline key, indicating that these compounds do not share completely discriminative properties with naltrexone or morphine in the pigeon. Small doses of naltrexone (0.01 and 0.1 mg/kg) shifted the morphine discrimination dose-effect curve in parallel to the right, without producing naltrexone-appropriate responding. Larger doses of naltrexone (1.0-10.0 mg/kg) prevented the discriminative effect of morphine and generated dose-dependent naltrexone-appropriate responding. The prior administration of small doses of morphine (0.1 and 1.0 mg/kg) enhanced the discriminative effects of naltrexone. Some dose combinations of naltrexone and morphine produced responding on all three keys, up to doses that suppressed behavior. The study of agonist-antagonist interactions may be aided by the use of these procedures, as descriptions of insurmountable antagonism may be complemented by the identification of stimulus conditions associated with the antagonist, as well as those conditions that represent novel stimulus states.

Animals↗
PubMed1979

Methadone binding at nonopiate receptor binding sites.

The binding of 3H-methadone to rabbit brain synaptosomes was studied. Binding was saturable at methadone concentrations below 10(-6)M and unsaturable above 10(-6)M. Except at high 3H-methadone concentrations, only a small fraction of the specific saturable binding of methadone was blocked by levorphanol, naloxone or morphine, suggesting that much of the saturable binding of methadone to rabbit synaptosomes is not binding at the opiate receptor. At low methadone concentrations, stereospecific methadone binding to the opiate receptor is essentially undetectable as determined by displacement with levorphanol and dextrorphan. Experiments with preparations from beef caudate, on the other hand, indicate that a larger percentage of the methadone bound to this preparation is bound to the opiate receptor but that some specific binding is also at other sites.

Animals↗
PubMed1984

Inhibition of urinary bladder contractions by a spinal action of morphine and other opioids.

Systemic morphine (1.0 mg/kg i.v. or s.c.) consistently inhibited spontaneous urinary bladder contractions recorded isometrically in the anesthetized rat. This effect was reversed by intrathecal (i.t.) naloxone (1-4 micrograms) at doses which were ineffective systemically. Intrathecal morphine was also inhibited bladder activity when administered into cervical, thoracic or lumbar regions but was faster acting and more effective when injected i.t. directly in the vicinity of the lumbo-sacral cord. The effect of morphine was dose-related and appeared to be a stereospecific opiate effect being observed with i.t. levorphanol but not with dextrorphan. Bladder inhibition by i.t. morphine at low doses could be overcome by increasing the intravesicular pressure. Intrathecal morphine was also reversed by i.t. (1-2 micrograms) or s.c. (0.5 mg/kg) naloxone but not by i.c.v. naloxone (1-2 micrograms). Intrathecal naloxone in naive animals increased bladder contraction frequency and intravesicular pressure only at high doses (10-20 micrograms i.t.). Bladder activity was consistently inhibited by [D-Ala2,MePhe4,Gly-(ol)5] enkephalin (mu agonist) and [D-Ala2-D-Leu5]enkephalin (delta agonist) but was unaffected by U-50, 488H i.t., (kappa agonist). The observations support the hypothesis that spinal opioid mechanisms are involved in the neurogenic control of bladder function and that systemically or i.t. administered opioid drugs mediate inhibition of bladder motility by spinal mechanisms involving mu and delta opioid receptors.

Animals↗
PubMed1984

Stereoisomers of [3H]-N-allylnormetazocine bind to different sites in mouse brain.

(+)- and (-)-[3H]-N-allylnormetazocine (NANM) were synthesized and evaluated for binding to mouse brain membranes. Scatchard analysis of the saturable binding of (-)-[3H]NANM suggested a single class of binding sites with an apparent KD of 2.1 nM and an estimated maximum binding of 197 fmol/mg of protein. Increasing the concentration of Na+, K+, Mn++ or Ca++ decreased (-)-[3H]NANM specific binding. (-)-[3H]NANM apparently binds to the mu opiate receptor in that (-)-isomers, but not the (+)-isomers, of N-cis-3-chloroallylnormetazocine, N-propynylnormetazocine, pentazocine, cyclazocine, naloxone, phenazocine and morphine competed for binding. (-)-Isomers of ethylketocyclazocine, ketocyclazocine and NIH 9101 also displaced (-)-[3H]NANM binding which suggested kappa activity in addition to mu activity. Phencyclidine and its analogs did not bind to the (-)-[3H]NANM site. Scatchard analysis of saturable binding of (+)-[3H]NANM also revealed a homogeneous population of binding sites with apparent KD of 12 nM and an estimated maximum binding of 360 fmol/mg of protein. This binding site was unaffected by increasing concentrations of Na+ and K+, but binding was decreased by high concentrations of Mn++ and Ca++. The (+)-isomers of the benzomorphans N-cis-3-chloroallylnormetazocine, phenazocine, pentazocine and cyclazocine effectively displaced (+)-[3H]NANM binding. In addition, the (+)-isomers of ketocyclazocine and ethylketocyclazocine, as well as dextrorphan, a (+)-morphinan, bind to the (+)-[3H]NANM site. The (-)-isomers of mu agonist/antagonists and kappa agonists competed poorly, or not at all, for the (+)-[3H]NANM site whereas phencyclidine and related compounds exhibited a low affinity for this site.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1980

Phencyclidine-like discriminative effects of opioids in the rat.

Possible commonalities in the discriminative stimulus properties of phencyclidine (PCP) and opioids were investigated in rats trained to discriminate between i.p. injections of saline and 2.0 mg/kg of PCP in a two-choice discrete-trial avoidance paradigm. Behavior was considered to be under stimulus control when a rat reliably completed at least 18 trials of a 20-trial session on the appropriate choice lever after receiving PCP or saline. Tests of stimulus generalization were performed over an 8- to 32-fold range of doses with ketamine, a PCP analog, and eight opioids. Dose- and time-dependent stimulus control of behavior comparable to that produced by 2.0 mg/kg of PCP (defined by the number of trials completed on the PCP-appropriate choice lever) were produced by ketamine and the opioids cyclazocine, SKF 10,047 and dextrorphan. These drugs also produced orderly increases in responses during the interval between trials suggestive of a relationship between this effect and PCP-like stimulus control. In contrast, after ethylketocyclazocine, ketocyclazocine, pentazocine and dextromethorphan trials were completed primarily on the saline-appropriate lever and responding between trials produced did not change. Neither the PCP-like stimulus control of behavior nor the increased responding between trials produced by cyclazocine were prevented by pretreatment with naltrexone (1.0 mg/kg). These results provide further evidence that PCP and certain opioids share a common component of action that is probably mediated by neuronal substrates not usually associated with the activity of opioids.

Analgesics, Opioid↗
PubMed1978

Solid-phase radioimmunoassay for morphine, with use of an affinity-purified morphine antibody.

Morphine antibody purified by affinity chromatography was used to develop a solid-phase radioimmunoassay for morphine in polystyrene tubes. The tubes are coated with an appropriate concentration of the purified antibody, rinsed three times with buffered saline, and stored at -15 degrees C. Using tritiated dihydromorphine, we determined competitive morphine binding by difference when the radioactivity in the assay supernates was measured after incubation (1 h, 37 degrees C). Five standard curves, with use of serum equivalents of morphine ranging from 0 to 6 mug/liter, were linear and had a mean correlation coefficient of 0.98. Uncer conditions of the assay, levorphanol was comparable to morphine in its inhibitory effect on binding of labeled dihydromorphine, whereas dextrorphan was essentially inactive. Morphine-3-glucuronide, a major metabolite, is 55-fold less inhibitory in terms of its capacity to displace the radiolabel. We believe that the sensitivity of the technique, coupled with the simplicity of nonseparatory sampling, renders the system suitable for rapid determination of morphine and related compounds in biological fluids.

Antibodies↗
PubMed1982

Evidence for sigma opioid receptor: binding of [3H]SKF-10047 to etorphine-inaccessible sites in guinea-pig brain.

A portion of the specific binding of tritiated SKF-10047 to the guinea-pig brain suspension of the particulate fraction is not inhibited by the strong narcotic analgesic l-etorphine. The binding properties of these etorphine-inaccessible (EI) sites were examined. The specific binding of [3H]SKF-10047 to the EI sites is saturable. Scatchard analysis of the saturation curve revealed a single class of binding sites with apparent Kd of 252 nM and an estimated Bmax of 663 fmol/mg of protein. The EI binding was reduced by heat treatment, trypsin digestion and phospholipase C digestion. The presence of sodium ions slightly increased specific EI binding. Lithium ion increased the EI binding by about 38% at the optimal concentration of 1 mM. Divalent cations such as Mg++, Ca++ and Mn++ reduced EI binding. Morphine-like drugs such as morphine, levorphanol and naltrexone were poor inhibitors for the EI binding, whereas opioid derivatives such as pentazocine, dextrallorphan, cyclazocine, SKF-10047 and dextrorphan were potent inhibitors. Nonopioid drugs such as haloperidol, imipramine, pimozide and propranolol were also potent inhibitors of the EI binding. Distribution of the EI sites in brain was different from that of the mu receptor: highest concentration of EI sites was found in brainstem, midbrain and cerebellum, whereas lower concentrations were found in striatum and cortex. It is suggested that EI sites are not mu receptors but may represent sigma receptors in the central nervous system, mediating psychotomimetic effects of several opioids and other drugs.

Animals↗
PubMed1983

A rapid and simple method for the quantitative determination of tolerance development to opiates in the guinea-pig ileum in vitro.

The rate and degree of tolerance development of morphine, normorphine and methadone were assessed in vitro on the guinea-pig ileum. After the half-maximal concentration to inhibit electrically induced contractions (IC50) for each compound was determined, tolerance to a fixed concentration representing 0.5, 1 or 2 times its IC50 was induced by incubation at 37 degrees C for 1, 2 or 4 hr. The IC50 was then redetermined and the ratio of the IC50 after and before incubation provided a quantitative index of the degree of tolerance development to each agonist. For any given concentration or time, morphine induced the highest, whereas normorphine the intermediate and methadone the lowest degree of tolerance. Tolerance to opiates was associated with some degree of physical dependence as evidenced by the fact that the application of naloxone at the end of each experiment elicited a muscular contraction. Specificity of tolerance development to opiates was demonstrated by several experiments. Coincubation of morphine with naloxone under the same conditions resulted in an inhibition of tolerance development. The stereospecificity of the process was demonstrated by the fact that levorphanol and I-methadone induced a high degree of tolerance, whereas, under the same conditions the less active d-isomers, dextrorphan and d-methadone, did not. Moreover, subsensitivity to acetylcholine, norepinephrine and adenosine monophosphate did not develop in the presence of tolerance to morphine. The validity of this method for investigating mechanisms involved in tolerance and physical dependence was further demonstrated by obtaining data compatible with earlier experiments in vivo that cyclic AMP enhances tolerance development and cycloheximide inhibits this phenomenon. The present method should facilitate studies on the mechanisms involved in opiate tolerance and physical dependence development.

Animals↗
PubMed1983

Further characterization of the three-choice morphine, cyclazocine and saline discrimination paradigm: opioids with agonist and antagonist properties.

Rats were trained in a three-choice morphine (3.0 mg/kg), cyclazocine (0.3 mg/kg) and saline discrimination using a discrete-trials avoidance procedure. Behavior was considered to be under stimulus control when an animal reliably completed at least 18 trials of a 20-trial session on the correct lever after s.c. administration of either morphine, cyclazocine or saline. In tests of stimulus generalization, levorphanol produced a dose-related increase in trials completed on the morphine choice lever, whereas its optical enantiomer, dextrorphan, produced predominantly cyclazocine-appropriate responding, indicating that stimulus control of behavior was stereoselective. Ethylketocyclazocine, ketocyclazocine, levallorphan and SKF 10,047 engendered stimulus control of behavior that was unambiguously cyclazocine-like. In contrast, three other opioids with mixed agonist and antagonist properties occasioned responding on both the morphine- and cyclazocine-appropriate choice levers consistent with the mixture of morphine- and cyclazocine-like activity exhibited by these drugs in other procedures in animals and man. The stimulus effects of phencyclidine, a nonopioid compound, were not clearly interpretable within the present experimental context. This three-choice discrimination paradigm provides an approach for studying concurrently the morphine- and cyclazocine-like discriminative stimulus effects of opioids with multiple components of action and may lead to a more precise characterization of the stimulus properties of mixed-acting opioids than has been possible with conventional two-choice discrimination paradigms alone.

Animals↗
PubMed1983

High-affinity dextromethorphan binding sites in guinea pig brain. I. Initial characterization.

Tritiated dextromethorphan ([3H]DM) binds to two distinct sites in guinea pig brain, a high-affinity site (Kd = 13-20 nM) and a low-affinity site (Kd greater than 200 nM). Binding of [3H] DM to the high-affinity site is rapid, reversible, saturable, proportional to tissue concentration, and pH-dependent. The sites have a protein-like component, since preincubating brain homogenate in the presence of proteolytic enzymes and protein-modifying reagents significantly reduces binding. There is also a progressive loss of binding when brain homogenate is heated to temperatures in excess of 37 degrees. Millimolar concentrations of lithium, calcium, magnesium, and manganese decrease DM binding while sodium, in concentrations as high as 100 mM, has little effect; calcium in micromolar concentrations slightly enhances binding. The pons-medulla and cerebellum contain the highest density of sites. Subcellular localization studies have shown that high-affinity sites are confined almost exclusively to the microsomal fraction. Binding of DM to brain microsomes does not appear to be related to drug-metabolizing enzymes. The characteristics of DM binding suggest that DM sites are not a subclass of opiate receptors. Studies using tritiated dextrorphan as radioligand failed to reveal a high-affinity binding site for in brain.

Animals↗