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PubMed1997

Differential agonist regulation of the human kappa-opioid receptor.

Opiates are potent analgesics used clinically in the treatment of pain. A significant drawback to the chronic use and clinical effectiveness of opiates is the development of tolerance. To investigate the cellular mechanisms of tolerance, the cloned human kappa-opioid receptor was stably expressed in human embryonic kidney (HEK 293) cells, and the effects of opioid agonist treatment were examined. The receptor-expressing cells showed specific high-affinity membrane binding for a kappa-selective opioid, 3H-labeled (+)-(5alpha,7alpha,8beta)-N-methyl-N-[7-(1-pyrrolidiny l)-1-oxaspiro [4,5] dec-8-yl] benzeneacetamide ([3H]U69,593), and a nonselective opioid antagonist, [3H]diprenorphine. Pretreatment with pertussis toxin or guanosine 5'-O-(3-thiotriphosphate) reduced [3H]69,593 binding, indicating that the human K receptor coupled to G proteins of the Gi or Go families in HEK 293 cells. The receptor-mediated inhibition of adenylyl cyclase was abolished by pertussis toxin pretreatment and was blocked by a kappa-selective antagonist, norbinaltorphimine. A 3-h pretreatment with a kappa-selective agonist, (+/-)-trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl] benzeneacetamide (U50,488), caused receptor down-regulation, whereas no receptor down-regulation was found after levorphanol pretreatment. U50,488 or dynorphin A(1-17) pretreatments (3 h) desensitized the ability of U50,488 or dynorphin A(1-17) to inhibit cyclic AMP accumulation, as evidenced by a decrease in functional potency. Also, U50,488 pretreatment desensitized the ability of levorphanol to inhibit forskolin-stimulated cyclic AMP accumulation. In contrast, pretreatment of cells with either levorphanol or a potent nonselective opioid, etorphine, resulted in no apparent receptor desensitization. Taken together, these results demonstrate that the human kappa receptor is differentially regulated by selective and nonselective opioid agonists, with selective agonists able to desensitize the receptor.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed2003

Oral opioid therapy for chronic peripheral and central neuropathic pain.

BACKGROUND: Although opioids are commonly used to treat chronic neuropathic pain, there are limited data to guide their use. Few controlled trials have been performed, and many types of neuropathic pain remain unstudied. METHODS: Adults with neuropathic pain that was refractory to treatment were randomly assigned to receive either high-strength (0.75-mg) or low-strength (0.15-mg) capsules of the potent mu-opioid agonist levorphanol for eight weeks under double-blind conditions. Intake was titrated by the patient to a maximum of 21 capsules of either strength per day. Outcome measures included the intensity of pain as recorded in a diary, the degree of pain relief, quality of life, psychological and cognitive function, the number of capsules taken daily, and blood levorphanol levels. RESULTS: Among the 81 patients exposed to the study drug, high-strength levorphanol capsules reduced pain by 36 percent, as compared with a 21 percent reduction in pain in the low-strength group (P=0.02). On average, patients in the high-strength group took 11.9 capsules per day (8.9 mg per day) and patients in the low-strength group took close to the 21 allowed (18.3 capsules per day; 2.7 mg per day). Affective distress and interference with functioning were reduced, and sleep was improved, but there were no differences between the high-strength group and the low-strength group in terms of these variables. Noncompletion of the study was primarily due to side effects of the opioid. Patients with central pain after stroke were the least likely to report benefit. CONCLUSIONS: The reduction in the intensity of neuropathic pain was significantly greater during treatment with higher doses of opioids than with lower doses. Higher doses produced more side effects without significant additional benefit in terms of other outcome measures.

Adult↗
PubMed1992

Nonopioid effect of morphine on electrically evoked acetylcholine release from Torpedo electromotor neurons.

The release of acetylcholine from Torpedo electric organ slices following their electrical stimulation was modulated by morphine, by the muscarinic antagonist atropine, and by the nicotinic antagonist tubocurarine. Addition of either atropine or tubocurarine in the presence of the acetylcholinesterase inhibitor phospholine iodide enhanced acetylcholine release. The effects of the two antagonists were additive, a result suggesting that the secreted acetylcholine regulates its own release by activating both muscarinic and nicotinic cholinergic receptors and that these receptors inhibit acetylcholine release by different mechanisms. The effects of opiates on acetylcholine release were examined under conditions in which the cholinergic modulation of release is blocked, i.e., in the presence of atropine and tubocurarine. These experiments revealed that electrically evoked release of acetylcholine is blocked by the opiate agonists morphine and levorphanol. However, the inhibitory effect of morphine on acetylcholine release was not reversed by the opioid antagonist naloxone. Furthermore, dextrorphan, the nonopioid stereoisomer of levorphanol, had the same inhibitory effect as its opioid counterpart. These findings suggest that the effects of opiates on electrically evoked release of acetylcholine are not mediated by opioid receptors. The possible mechanisms underlying these nonopioid effects of morphine and levorphanol are discussed.

Acetylcholine↗
PubMed1978

Genetic control of opiate-induced locomotor activity in mice.

Swiss-Webster stock male and female mice were tested for running activity after a 20 mg/kg dose of levorphanol. The best runners and worst runners were then bred. Within each litter, brother-sister pairs with the highest and lowest running activity after a test dose of levorphanol (20 mg/kg) were segregated and bred. This procedure was followed to the F4 generation. Running activity, analgesia and brain catecholamines were studied. The results showed that the "non-running" (NR) trait segregated at the F1 generation, while the "running" (R) trait diverged more slowly. However, by the third generation, the R mice differed significantly from the F0 stock mice. NR mice also did not show locomotor activity when tested with amphetamine. While the NR mice showed reduced running response to levorphanol they were significantly more sensitive than the F0 stock to the analgesic effect. Measurement of brain catecholamines showed no difference between R and NR mice in dopamine or serotonin, but did show a significant increase in norepinephrine in the NR strain.

Analgesics↗
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↗
PubMedDate not supplied

Effects of limited paternal exposure to xenobiotic agents on the development of progeny.

This report represents a series of investigations of the postnatal functional sequelae of paternal exposure to opioids and other xenobiotic agents. In separate studies, young adult male mice were exposed to (1) morphine; (2) levorphanol or its nonanalgesic isomer dextrorphan; or (3) 80% nitrous oxide/20% oxygen. Males (5-8/group) were injected twice daily for 5 1/2 or 8 1/2 days with opioids or saline, or received a single 4 hour inhalation exposure to nitrous oxide/oxygen or compressed air. At 6-8 1/2 days post-treatment, each male was housed with 3 drug-naive nulliparous females. With the exception of birth weights of litters, no alterations in reproductive indices were observed. Changes in reproductive endocrine parameters included marked attenuation of serum luteinizing hormone response to castration in both young adult (8 week) and older (18 week) F1 morphine offspring, when compared with saline-derived groups. The morphine progeny showed decrements in body weight and delayed onset of maturational indices through four generations of selective inbreeding. Similar developmental delays occurred in F1 offspring originating from paternal levorphanol, dextrorphan and nitrous oxide groups, when compared with their respective controls. Behavioral study of F1 offspring revealed alterations in: water maze performance and learning, if preceded by unavoidable footshock, in morphine offspring at 8 and 18 weeks; aberrant swim patterns in both levorphanol and dextrorphan progeny at 6 1/2 and 8 1/2 weeks. Nitrous oxide progeny showed a blunting of hypothermic response to pharmacologic challenge at 16 weeks, in comparison to compressed air controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1979

Effect of narcotics on monoamine oxidase activity of mouse brain.

The effect of morphine, levorphanol and methadone on the monoamine oxidase (MAO) activity of mouse brain was studied. Both methadone and levorphanol produced a concentration-dependent inhibition of whole brain mitochondrial MAO in vitro with an IC50 of approximately 7.4 x 10(-4) for levorphanol and 2.5 x 10(-6)M for methadone. Methadone also produced a 60% inhibition of the MAO activity of the hippocampus, a 32% inhibition of the striatal and hypothalamic enzyme, a 30% inhibition of liver, and a 20 and 23% inhibition of the cerebral cortex and cerebellum, respectively. Naloxone did not antagonize this effect of methadone. In contrast, morphine had little effect in vitro except at very high concentrations where it was inhibitory. This was not linear with concentration and no IC50 could be estimated. This would imply that the inhibition by morphine is non-specific. When acutely administered to mice, morphine and methadone, again differed. Methadone produced a slight but significant inhibition of whole brain MAO and a 34% inhibition of the striatal enzyme. Morphine, on the other hand, produced a marked enhancement in the activity of the striatal enzyme. Since this action could not be demonstrated in vitro, it would suggest that the in vivo effect of morphine is indirect resulting from an alteration of some other modulating system.

Animals↗
PubMed1995

Human granulocytes contain an opiate alkaloid-selective receptor mediating inhibition of cytokine-induced activation and chemotaxis.

Human peripheral blood granulocytes previously were found to contain opioid delta 2-receptors mediating stimulation by opioid peptides of chemotaxis. Studies presented in this work indicate that granulocytes also contain opiate alkaloid-selective, opioid peptide-insensitive receptors mediating inhibition by morphine and other opiates of cytokine-induced activation and chemotaxis. Binding studies with [3H]morphine and [3H]diprenorphine ([3H]DPN) indicated the presence of receptor sites, at considerable density with affinities and selectivity for opiates comparable with those of the mu 3-receptor of human peripheral blood monocytes (macrophages). The influence of the guanosine 5'-triphosphate (GTP) analogue GppNHp on binding indicated that the granulocyte receptor was linked to a G protein. Morphine but not opioid peptides interfered with activation and/or chemotaxis of the granulocytes induced by TNF-alpha, IL-1 alpha, IL-8, and FMLP (chemotactic peptide). These effects of morphine were blocked by the antagonist naloxone. Levorphanol inhibited TNF-alpha-induced activation, and also potentiated the inhibition by morphine. Furthermore, in binding assays, levorphanol enhanced the affinity of the receptor for morphine. Dextrorphan had no effect on activation or chemotaxis, and it also had no effect on binding, indicative of stereoselectivity for the effect of levorphanol. It is concluded that human granulocytes contain opiate alkaloid-selective mu 3-receptors that mediate inhibitory effects of morphine on cellular activation by cytokines.

Adult↗
PubMed1981

Changes in the activity of nigral neurones induced by morphine and other opiates in rats with an intact brain and after prenigral decerebration.

The effect of morphine and related opiates on the spontaneous activity of nigral neurones was studied in unanaesthetized rats with an intact brain or after prenigral decerebration. Less than 50% of the neurones were influenced by the opiates. In the intact brain, intravenous (i.v.) injection of morphine 2 mg/kg, dextrorphan 1 mg/kg and tilidine 5 mg/kg increased the discharge rate, whereas levorphanol 1 mg/kg, pethidine 20 mg/kg and codeine 10 mg/kg reduced it. Naloxone 0.2 mg/kg i.v. abolished the effects of morphine, levorphanol and codeine; it reduced the effect of pethidine and was ineffective against dextrorphan and tilidine. Intracaudate injections of morphine 10 microgram and pethidine 50 microgram increased the spontaneous activity of some neurones in the ipsilateral substantia nigra and reduced that of others; the increase in activity after morphine was more pronounced than the depression. The effects of intracaudate injections of morphine or pethidine were reduced by i.v. naloxone. After prenigral decerebration, i.v. injections of morphine depressed, and i.v. injections of levorphanol increased the activity of nigral neurones; pethidine i.v. either increased or reduced the spontaneous activity. These effects were reduced or abolished by naloxone. It is concluded that opiates including morphine affect the activity of nigral neurones not only by an action on opiate receptors in the striatum but also by an action on opiate receptors outside the striatum (e.g. in the substantia nigra and, perhaps, by an action unrelated to opiate receptors.

Animals↗
PubMed1988

Modulation of adenylate cyclase activity of mouse spinal cord-ganglion explants by opioids, serotonin and pertussis toxin.

Organotypic cultures of fetal mouse spinal cord-ganglion explants (2-4 weeks in vitro) contain forskolin-stimulated adenylate cyclase (AC) activity that is inhibited by levorphanol and other opioid agonists in a dose-dependent manner. Inhibition by levorphanol no longer occurs if sodium is omitted from the incubation and the levorphanol inhibition is blocked by the opioid antagonist, naloxone. These findings together with the ineffectiveness of dextrorphan indicate that the opioid inhibition of forskolin-stimulated AC is receptor mediated. Both the delta- and kappa-receptor subtypes appear to be involved since the selective delta-opioid agonist, [D-Pen2, D-Pen5]enkephalin, and the selective kappa-opioid agonist, t-3,4-dichloro-N-methyl-N[2-(1-pyrrolidinyl)cyclohexyl]-benzene acetamide (U-50,488H) are both effective at nanomolar concentrations. In contrast, the selective mu-opioid agonist, Tyr-D-Ala-Gly-N-MePhe-Gly-ol, has no significant effect even at micromolar concentrations. Both cord and ganglion components of the explants contain opioid-sensitive AC. Forskolin-stimulated AC of the explants is also inhibited by serotonin and carbachol. The serotonin effect appears to be mediated by 5-HT1A receptors, based on relative agonist and antagonist selectivity. Chronic exposure of cultures to morphine results in enhanced basal and forskolin-stimulated AC as well as attenuation of opioid-inhibition of AC assayed in the presence of forskolin; treatment of explants with pertussis toxin causes similar changes in the AC system. The inhibitory effect of serotonin is also attenuated by the pertussis toxin treatment. Basal AC activity of the explants (assayed without forskolin present) is stimulated to a small but significant extent by opioids and by serotonin. The opioid stimulatory effect is markedly enhanced following either morphine or pertussis toxin treatment of the explants. The attenuation of opioid- and serotonin-inhibition of AC produced by chronic exposure to pertussis toxin and the attenuation of opioid inhibition produced by exposure to morphine are consonant with the attenuation of opioid and monoaminergic depression of sensory evoked dorsal horn network responses after similar chronic treatments. It is proposed that the inhibitory effects of opioids and serotonin on these neurons are mediated by receptors that are negatively coupled via a pertussis toxin sensitive Gi protein to AC. Furthermore, alterations of AC with chronic morphine treatment may be involved in the development of physiologic tolerance to opioids.

Adenylate Cyclase Toxin↗
PubMed1981

Calcium ions, morphine tolerance and noradrenergic transmission in the mouse vas deferens.

The response of the isolated vas deferens of the mouse to electrical stimulation is inhibited by morphine and levorphanol via an opiate receptor, the inhibition decreasing with increasing stimulation frequency (0.2-16 Hz). Tolerance to the locomotor stimulant effect of morphine was induced over 48 h using a slow release preparation. Vasa from mice similarly treated with the slow release preparation showed a shift to the right of the morphine and levorphanol twitch inhibition curves. The reduction in the fractional release of [3H]noradrenaline by morphine and levorphanol was less in vasa from morphine-pretreated mice. Altering the Krebs solution by reducing the Ca2+ or Na+ or adding Mg2+ increased the effect of opiate agonists in vasa from naive and morphine-tolerant mice. Therefore, tolerance to morphine has not changed the ability of these ions to modulate opiate responses.

Animals↗
PubMed1994

Agonist and antagonist opioid activity of axial and equatorial conformations of S-methyl- and S-allyl-morphinans.

Resolved axial (beta) and equatorial (alpha) forms of S-methyl (beta-sulforphanol, alpha-sulforphanol) and S-allyl (beta-sulfallorphan, alpha-sulfallorphan) morphinans were tested for their ability to depress the electrically evoked contractions of the guinea pig ileum and of the mouse vas deferens, to compete with the binding of prototype ligands selective for mu-, delta-, and kappa-opioid receptors in membrane preparations of rat brain and guinea pig cerebellum and to produce analgesia in a rat thermal pain assay. beta-Sulforphanol was more potent than alpha-sulforphanol in the guinea pig ileum (relative potencies of 93% and 29% respectively, as compared with levorphanol). beta-Sulfallorphan and alpha-sulfallorphan were both inactive in the guinea pig ileum assay. In the mouse vas deferens preparation, beta-sulforphanol and alpha-sulforphanol had relative potencies of 2.1% and 1.2% as compared with levorphanol, respectively, while the S-allyl derivatives were inactive. All morphinan derivatives displayed marked binding selectivity for mu-opioid receptors but alpha-sulfallorphan also showed significant binding potency on delta-opioid receptors (12% as compared to levorphanol). The compounds were also tested for their ability to antagonize the biological activity of morphine. In the guinea pig ileum, alpha-sulfallorphan potently inhibited morphine with a Ke value of 41.7 nM. alpha-Sulforphanol also antagonized morphine but with a smaller potency (Ke = 350 nM). In the mouse vas deferens, no antagonist activity against morphine was observed with any morphinan derivative tested at 1 microM. In the rat thermal pain assay, beta-sulforphanol (intracisternally, i.c.) was more potent than alpha-sulforphanol in producing analgesia while the other morphinan derivatives were inactive.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

DSLET (D-ser2-leu5-enkephalin-Thr6) produces analgesia on the hot plate by mechanisms largely different from DAGO and morphine-like opioids.

Fifteen generations of selective breeding were used to produce lines (strains) of mice which differ markedly from one another in levorphanol-induced antinociception on the hot plate assay. These are the high antinociceptive response (HAR) and low antinociceptive response (LAR) selection lines, which now differ by over 5-fold in the i.p. dose of levorphanol doubling control (no drug or saline) latency scores. We sought to determine if these large genetically-mediated differences in antinociceptive sensitivity bred into these selection lines with i.p. levorphanol would generalize equally to a series of enkephalin analogues known to differ in their selectivity for mu and delta opioid receptors. DAGO (D-ala2, MePhe4, Gly-ol5 enkephalin), a highly mu selective agent, produced a 67-fold difference between HAR and LAR mice in the slopes of the dose-response curves on the hot plate assay, while DSLET (D-ser2, leu enkephalin Thr6), a delta selective agent, only produced a 5.4-fold difference via the i.c.v. route. DADLE (D-ala, D-ser enkephalin) a slightly delta preferring ligand, was found to be intermediate (17.4-fold difference). These findings demonstrate that selective breeding has been quite successful in altering those genes which control analgesia due to mu selective agents, while relatively little change has occurred in those genes which control analgesia due to delta agonists. Thus, analgesia mediated by the former has been genetically dissociated from analgesia mediated by the latter, implying that DAGO has mechanisms of action largely dependent of DSLET on the hot plate assay. These findings are consistent with the contention that the mu receptor mediates analgesia produced by DAGO, while a different receptor (presumably delta) mediates much of the analgesic effects of DSLET.

Analgesics↗
PubMed1981

Studies on the inhibitory action of opiate compounds in isolated bovine adrenal chromaffin cells: noninvolvement of stereospecific opiate binding sites.

In isolated bovine adrenal chromaffin cells, beta-endorphin, dynorphin, and levorphanol caused a dose-dependent inhibition of catecholamine (CA) secretion elicited by acetylcholine (ACh), with an ID50 of 50, 1.3, and 4.3 microM, respectively. The inhibition by the opiate compounds was specific for the release evoked by ACh and nicotinic drugs and was noncompetitive with ACh. Stereospecific binding sites for the opiate agonist [3H]etorphine were found in homogenates of bovine adrenal medulla (KD = 0.59 nM). beta-Endorphin, dynorphin, levorphanol, and naloxone were potent inhibitors of the binding of [3H]etorphine with an ID50 of 12, 0.4, 5.2, and 6.2 nM, respectively. However, [3,5-I2Tyr1]-beta-endorphin, [3,5-I2Tyr1]-dynorphin, and dextrorphan, three opiate compounds with no or little activity in the guinea pig ileum assay, were relatively ineffective in inhibiting the binding of [3H]etorphine (ID50 700, 600, and 10,000 nM, respectively). On the other hand, these three compounds were equipotent with beta-endorphin, dynorphin, and levorphanol, respectively, in inhibiting the ACh-evoked release of CA from the adrenal chromaffin cells (ID50 of 10, 1.5, and 6 microM, respectively). Inhibition of CA release was also obtained with naloxone (ID50 = 14) microM) and naltrexone (ID50 greater than 10(-4) M), two classical antagonists of opiate receptors, and this effect was additive to that of beta-endorphin. These data indicate that the opiate modulation of CA release from adrenal chromaffin cells is not related to the stimulation of the high affinity stereospecific opiate binding sites of the adrenal medulla. The physiological function of these sites remains to be determined.

Acetylcholine↗
PubMed1975

An analysis of the phenomenon of acute tolerance to morphine in the guinea-pig isolated ileum.

1 The observations which Paton (1957) interpreted as 'acute tolerance' and 'dependence' have been confirmed for coaxially stimulated segments of guinea-pig ileum and extended to the contractions evoked by field stimulation in the myenteric plexus-longitudinal muscle preparation. Evidence is adduced that the morphine receptors of the myenteric plexus are not involved in the two phenomena. 2 The contraction of the longitudinal muscle depressed by low concentrations of morphine, or levorphanol, can be restored to control level not only by high concentrations of morphine but also by levorphanol and equally well by its (+)-isomer, dextrorphan, which does not fulfil the stereospecific requirements of the morphine receptor. Acetylcholine output was not increased. 3 When, after restoration of the twitch by high concentrations of morphine, the drug is washed out, contractions become depressed. This effect cannot be due to 'dependence' because either morphine or its antagonist, naloxone, restore the twitch again. 4 In the concentrations used, morphine, levorphanol and dextrorphan inhibit the cholinesterase of homogenates of the myenteric plexus-longitudinal muscle preparation by 10-15%. Since a concentration of physostigmine which causes a similar inhibition also restores the twitch, it is concluded that the described phenomena are best explained by the anticholinesterase effects of the drugs.

Acetylcholine↗
PubMed1997

Opioid regulation of the mouse delta-opioid receptor expressed in human embryonic kidney 293 cells.

Opioid analgesics are used extensively in the management of pain. Although the clinically effective opioids bind with high affinity to the mu-opioid receptor, studies have suggested that the delta-opioid agonists might represent more ideal analgesic agents, with fewer side effects. A limitation to opiate effectiveness is the development of tolerance, an event that has been linked to opioid receptor desensitization. To gain a better understanding of delta-receptor agonist regulation, the cloned mouse delta receptor was stably expressed in human embryonic kidney 293 cells, and the functional effects of agonist pretreatment were examined. With a 3-hr pretreatment protocol, the delta-selective agonists [D-Pen2,D-Pen5]enkephalin, [D-Ala2,D-Leu5]enkephalin, and [D-Ser2,Leu5]enkephalin-Thr and the nonselective opioids levorphanol, etorphine, and ethylketocyclazocine were found to desensitize delta receptors. [D-Pen2,D-Pen5]enkephalin, [D-Ser2,Leu5]enkephalin-Thr, [D-Ala2,D-Leu5]enkephalin, and etorphine treatments also caused a pronounced internalization of the epitope-tagged delta receptor, suggesting that the desensitization and internalization may be related. In contrast, levorphanol pretreatment did not internalize the receptor but still resulted in a 400-fold reduction in potency, suggesting that prolonged treatment with levorphanol only uncoupled the delta receptor from adenylyl cyclase. In contrast to the desensitization induced by peptide-selective delta agonists, pretreatment with the delta-selective nonpeptide agonist 7-spiroindanyloxymorphone and morphine sensitized the opioid inhibition of forskolin-stimulated cAMP accumulation. This differential regulation of the delta receptor may be due to variations in the ability of agonists to bind to the receptor. This hypothesis was supported by the finding that a point mutation that converted Asp128 to Asn128 (D128N) diminished the ability of delta-selective agonists to inhibit cAMP accumulation while increasing the potency of morphine to reduce cAMP accumulation. In particular, a lack of desensitization of the delta receptor by morphine may contribute to our understanding of the molecular basis of development of morphine-induced tolerance and dependence.

Adenylyl Cyclases↗
PubMed1964

INHIBITION OF BACTERIAL GROWTH BY DRUGS OF THE MORPHINE SERIES.

The growth of Escherichia coli is reversibly inhibited by drugs of the morphine series. The order of inhibitory effectiveness for the drugs tested was levallorphan > levorphanol > dextrorphan > nalorphine > morphine. The synthetic analgesic, levorphanol, was studied in greater detail. Its effectiveness was found to be strongly dependent on the pH of the medium. Raising the pH of the medium provides a higher concentration of the neutral free base which is thought to diffuse across cell membranes more readily. However, considerations other than the rate of entry of drug into the cells must be of importance since an already established growth inhibition is promptly reversed upon lowering the pH of the medium. Two mutants of Escherichia coli with altered sensitivity to levorphanol were isolated.

Analgesics↗
PubMed1977

The blockade of serotonin uptake into synaptosomes:relationship to an interaction with monoamine oxidase inhibitors.

To test the hypothesis that the hyperpyrexia produced by meperidine and detromethorphan in rabbits pretreated with a monoamine oxidase inhibitor is related to inhibition of neuronal uptake of serotonin (5-hydroxytryptamine (5-HT)), fluoxetine (Lilly 110140) was studied. This potent and specific 5-HT neuronal uptake blocker was administered to phenelzine-pretreated rabbits and found to produce a lethal hyperpyrexia in doses equal to or greater than 2.5 mg/kg. The order of potency in blocking 5-[14C]HT uptake into synaptosomes prepared from rabbits was: fluoxetine greater than meperidine = dextromethorphan = levorphanol greater than anileridine greater than alphaprodine greater than morphine. Since fluoxetine, meperidine, and dextromethorphan produce hyperpyrexia in phenelzine-pretreated rabbits, whereas anileridine, alphaprodine, and morphine do not, there appears to be some correlation between the hyperpyrexic response and inhibition of 5-HT uptake. The exception is levorphanol, which is not hyperpyrexic despite being equipotent with meperidine and dextromethorphan in inhibiting 5-HT uptake. The ineffectiveness of levorphanol in producing hyperpyrexia may be due to its marked depressant properties, since the addition of another depressant drug (pentobarbital) antagonized the hyperpyrexic effect of meperidine.

Analgesics, Opioid↗