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Biomedical subjects

A E Takemori

Publications and source records attributed to A E Takemori.

At least 145 records · Page 8Linked to original sources
PubMed1983

Determination of the relative involvement of mu-opioid receptors in opioid-induced depression of respiratory rate by use of beta-funaltrexamine.

Using a simple method to measure respiratory rate, it was clearly shown that the depression of respiratory rate caused by morphine, ethylketazocine or [D-Ala2,D-Leu5]enkephalin was not altered by the highly selective, irreversible mu-antagonists, beta-funaltrexamine (beta-FNA) at a dose which produced marked antagonism of morphine antinociception. These results indicated that antinociception and depression of respiratory rate are mediated by different receptor interactions. However using a different method to measure respiratory rate (body plythesmograph), beta-FNA caused substantial antagonism of morphine-induced respiratory depression indicating that the degree to which mu-receptor interactions contribute to the depression of respiratory rate depends on the methodology. Possible explanations for this difference are discussed. It is concluded that careful consideration of the methodology must be given when one measures respiratory rate and caution must be exercised if measurement of rate alone is used to assess opioid-induced respiratory depression.

Analgesics↗
PubMed1983

In vivo binding of naloxone to opioid receptors in morphine-dependent mice.

In vivo binding assay of opioid receptors for naloxone was tested in morphine-dependent mice. The content of naloxone in the brain (whole brain minus cerebellum) and cerebellum was determined as the total binding and non-specific binding, respectively, 20 min after the intravenous injection of [3H]-naloxone. Acute treatment with 8 mg/kg of morphine sulfate markedly enhanced the non-specific binding of naloxone. In contrast, withdrawal for 6 hr after 72 hr of implantation of morphine decreased the non-specific binding of naloxone. The Scatchard analysis of the specific binding revealed two binding sites. The apparent low affinity Kd values of both morphine-tolerant and morphine-withdrawn mice were significantly decreased when compared to their respective controls. The apparent high affinity Kd and the high and low Bmax values were not altered by the morphine dependent-tolerant state.

Animals↗
PubMed1983

Alkylation of opioid receptor subtypes by alpha-chlornaltrexamine produces concurrent irreversible agonistic and irreversible antagonistic activities.

alpha-Chlornaltrexamine (1a, alpha-CNA), the C-6 epimer of the opioid receptor affinity label beta-CNA (1b), has been synthesized and tested in vitro and in vivo. In vitro, alpha-CNA appears to alkylate opioid receptor subtypes (mu, kappa, and delta) and is similar to beta-CNA in its ability to produce irreversible antagonism at all three subtypes. However, 1a differs from 1b in that it exhibits additionally an irreversible agonist activity in the guinea pig ileum preparation but not in the mouse vas deferens preparation. This latter activity is discussed in terms of an irreversible mixed agonism-antagonism at kappa receptors, or, alternatively, it may reflect differences between mu receptors in the two in vitro preparations.

Alkylation↗
PubMed1983

Importance of C-6 chirality in conferring irreversible opioid antagonism to naltrexone-derived affinity labels.

A series of five epimeric pairs of naltrexone derivatives that contain an electrophilic substituent at the 6 alpha- or 6 beta-position was synthesized and tested on the guinea pig ileal longitudinal muscle (GPI) and mouse vas deferens (MVD) preparations in order to determine if the orientation of the electrophile is important for covalent bonding to opioid receptors. In the GPI all compounds were pharmacologically active as reversible agonists, but only the 6 beta-isomers of the fumaramate ester 2b (beta-FNA) and isothiocyanate 6b exhibited covalent reactivity, involving a selective irreversible antagonism of the mu agonist, morphine, without affecting kappa agonists. The 6 alpha-isomer 2a (alpha-FNA) was itself nonalkylating but was able to protect the GPI against alkylation by its epimer, beta-FNA, indicating that the two epimers bind to the same receptor. These results suggest that the proper orientation of the electrophilic substituent is required for covalent bonding with a proximal nucleophile in the case of mu receptor blockade. Moreover, the lack of covalent bonding to kappa receptors by these or other ligands in this series indicates the possible absence of sufficiently reactive nucleophiles on this recognition site. In the MVD, 2b, but not 2a, irreversibly antagonized morphine (as in GPI), whereas neither epimer exhibited irreversible antagonism toward the delta agonist, [D-Ala2,D-Leu5]enkephalin (DADLE). In contrast, both of the isothiocyanate epimers (6a,b) irreversibly blocked mu and delta receptors. Evidence suggesting differences between mu receptors in the MVD and GPI was obtained with the beta-iodoacetamide 5b, which was an irreversible blocker of morphine only in the MVD. When analyzed together with those of previous studies with the nitrogen mustard analogues, alpha- and beta-chlornaltrexamine, the data suggest that the receptor-alkylating ability of each isomer in an epimeric pair differs most when the electrophile possesses a narrow spectrum of reactivity.

Affinity Labels↗
PubMed1983

Relative involvement of mu, kappa and delta receptor mechanisms in opiate-mediated antinociception in mice.

The antinociceptive properties of morphine (mu), ethylketazocine (kappa), nalorphine (kappa), [D-Ala2, D-Leu5]enkephalin (delta) and [D-Ala2, Met5]enkephalinamide (mu, delta) were assessed using the radiant heat tail-flick and acetic acid-induced writhing assays in mice. The apparent pA2 values for the interaction of naloxone with morphine were the same regardless of the nociceptive stimulus employed or the route of administration of morphine. The apparent pA2 values for the interactions of naloxone with ethylketazocine and nalorphine in the writhing test differed significantly from that for the interaction of morphine and naloxone. Nalorphine did not produce a consistent antinociceptive effect on the tail-flick test. The apparent pA2 values for the interaction of ethylketazocine (s.c. or i.c.v.) with naloxone were similar to those for morphine-naloxone interactions on the tail-flick assay. The apparent pA2 values for the interactions of naloxone with [D-Ala2, D-Leu5] enkephalin differed from those for morphine-naloxone interactions on the writhing test. The highly selective mu antagonist beta-funaltrexamine antagonized the agonist actions of morphine and [D-Ala2, D-Leu5]enkephalin, and, in a previous study, beta-funaltrexamine antagonized the antinociceptive actions of [D-Ala2, Met5]enkephalinamide, but not those of nalorphine. It was concluded that agonist interaction with mu or kappa receptors can result in antinociceptive effects in the acetic acid-induced writhing test, and that an agonist interaction with mu, but not kappa, receptors results in antinociceptive action on the radiant heat tail-flick test, and furthermore, that a possible combination of mu and delta receptor interaction can result in antinociceptive activity in both tests.

Acetates↗
PubMed1982

Improved assays for the assessment of kappa- and delta-properties of opioid ligands.

The highly selective non-equilibrium mu-antagonist beta-funaltrexamine (beta-FNA) produced a maximal 20-fold shift in the IC50 for the mu-agonist morphine on the guinea-pig ileum preparation, whilst producing no significant change in the IC50 for the kappa-agonist ethylketazocine. On preparations pretreated with beta-FNA, the pA2 values for the interaction of morphine and ethylketazocine with naloxone were similar. These values were similar to the pA2 value for the interaction of ethylketazocine and naloxone determined on control tissues, but significantly different from the pA2 value for morphine-naloxone on control tissues, indicating that the agonist actions of morphine on preparations pretreated with high concentrations of beta-FNA are mediated by kappa-, rather than mu-receptor interaction. On the mouse vas deferens preparation, co-incubation with the highly selective delta-agonist Tyr-D-Ser-Gly-Phe-Leu-Thr (DSLET) and the non-selective non-equilibrium opiate antagonist beta-chlornaltrexamine (beta-CNA) resulted in marked inhibition of the agonist actions of morphine but had no effect upon the agonist actions of the delta-agonist leucine-enkephalin. The pA2 values for the interactions of naloxone with leucine-enkephalin and etorphine were unaltered by pretreatment with beta-CNA and DSLET. In similarly pretreated tissues, the agonist actions of ethylketazocine were markedly inhibited. It is concluded that manipulation of the guinea-pig ileum and mouse vas deferens preparations in the described manner results in assay systems that possess a largely homogeneous receptor population, and as such are valuable tools with which to evaluate opioid activity.

Animals↗
PubMed1982

Pharmacological profiles of beta-funaltrexamine (beta-FNA) and beta-chlornaltrexamine (beta-CNA) on the mouse vas deferens preparation.

The profiles of action of beta-funaltrexamine (beta-FNA) and beta-chlornaltrexamine (beta-CNA) have been assessed in the mouse vas deferens preparation. beta-FNA, but not beta-CNA, demonstrated a reversible agonist action that appeared to be mediated via kappa-receptor interaction. beta-CNA produced an irreversible antagonism of mu-, kappa- and delta-mediated agonist actions, whereas beta-FNA irreversibly antagonized mu-mediated agonist effects only. This selective action of beta-FNA could also be seen following administration in vivo. beta-CNA and particularly beta-FNA should prove valuable in the elucidation of multiple opioid receptors.

Animals↗
PubMed1982

Stereospecific accumulation of dihydromorphine and naltrexone by corpus striatal slices of morphine-dependent mice.

Stereospecific accumulation of [3H]dihydromorphine and [3H]naltrexone by striatal slices from morphine-dependent mice was examined in Krebs-Ringer bicarbonate medium. Striatal slices showed a saturable and stereospecific accumulation of both [3H]ligands. The accumulation constant of naltrexone, determined by Wilkinson's analysis, was significantly decreased in both morphine-dependent mice and dependent mice abruptly withdrawn for 6 hr. The maximal accumulation of naltrexone was not changed in withdrawn mice, but decreased in dependent mice. This could be due to the high concentration of residual morphine in the slices. There were no significant differences in the accumulation constant or maximal accumulation of dihydromorphine among the striatal slices from control, dependent and withdrawn mice. These data indicate that in morphine-dependent mice, there is an increased affinity of the opioid receptors for the narcotic antagonist, naltrexone but not for the agonist, dihydromorphine.

Animals↗
PubMed1982

Antagonism of morphine-induced behavioral suppression by opiate receptor alkylators.

Experiments were conducted to test the in vivo opiate specificity and long-lasting effects of two non-equilibrium opiate antagonists: beta-chlornaltrexamine (beta-CNA) and the beta-fumarate methyl ester derivative of naltrexone (beta-FNA). beta-CNA (2.5 or 5.0 micrograms, ICV) partially antagonized suppression of conditioned autoshaped behavior by morphine, when morphine was administered 48-72 hr after beta-CNA. beta-CNA had no effect on amphetamine-induced suppression of autoshaped responding, nor did it antagonize the suppression in rearing activity induced by either morphine or amphetamine. Similarly, beta-FNA (5 mg/kg, IP) antagonized the suppression of conditioned behavior by morphine, for up to 48 hr, while having no effect on amphetamine-induced suppression of autoshaped responding, or on the suppression of rearing activity induced by morphine or amphetamine. Further peripherally administered beta-FNA acts in the brain, since it antagonized analgesia following ICV morphine administration.

Amphetamine↗
PubMed1982

Narcotic antagonistic potency of bivalent ligands which contain beta-naltrexamine. Evidence for bridging between proximal recognition sites.

Two-bivalent ligands (P-X-P) containing the beta-naltrexamine pharmacophore (P) and a connecting oligoethylene glycol spanner (X) were synthesized and evaluated for narcotic antagonistic activity in the guinea pig ileum (GPI) and mouse vas deferens (MVD). The bivalent ligand 2 whose spanner contains three ethylene units possessed 10-fold greater antagonistic potency than its monovalent analogue (4) in antagonizing the effects of ethylketazocine (EK) on the GPI, while no differential antagonism of morphine was observed among the compounds. In the MVD, 2 was not substantially more potent than 4 as an antagonist against [D-Ala2,D-Leu5]enkephalin (DADLE). The bivalent ligand 3, whose spanner contains six ethylene units, exhibited 15 times greater potency in antagonizing the agonist effects of DADLE on the MVD than its monovalent ligand 4. No marked increase in the ability of 3 to antagonize the effects of morphine or EK on the GPI was observed. The data indicate that mu, kappa, and delta opioid receptors exhibit different selectivity toward bivalent ligands whose spanner lengths differ. The enhanced potency associated with different receptor interactions is consistent with simultaneous occupation of proximal recognition sites. Whether such proximal recognition sites are identical or different remains to be clarified. The distance between proximal sites appears to depend on the opioid receptor subtype involved.

Animals↗
PubMed1982

Pharmacological characterization in vivo of the novel opiate, beta-funaltrexamine.

The profile of action of beta-funaltrexamine (beta-FNA), the fumaramate methyl ester derivative of naltrexone, on antinociceptive tests in vivo was investigated. Beta-FNA demonstrated antinociceptive actions that were of short duration and that appeared to be mediated by kappa receptor interaction. In contrast, the antagonist actions of beta-FNA were of remarkably long duration and were selective toward nu agonist interactions. This profile of action is consistent with the profile of action of beta-FNA in vitro. The selective long-lasting antagonism of mu-mediated effects by beta-FNA may be of great value in the elucidation of multiple opioid receptor function.

Acetates↗
PubMed1981

Facilitation of morphine-induced tolerance and physical dependence by prolyl-leucyl-glycinamide.

The pretreatment of mice with 30 mg/kg morphine s.c. did not alter the analgesic effect of morphine in mice pretreated with saline but decreased the analgesic effect of morphine in mice pretreated with prolyl-leucyl-glycinamide (PLG). Tolerance was evaluated by the effect of PLG on morphine-induced enhancement of naloxone potency which is a measure of the capacity of naloxone to antagonize morphine-induced analgesia and is postulated to be an indicator of tolerance development. The naloxone potency of PLG-treated mice was 2-fold greater than that of control mice. PLG did not alter the whole brain levels of morphine, nor did it alter the naloxone potency in mice which were not pretreated with 30 mg/kg morphine. In mice treated with 100 mg/kg morphine or implanted with 50 mg morphine pellets for 24 or 72 h, the amount of naloxone required to induce jumping was not altered by PLG. However, PLG treatment did increase the hypothermia and body weight loss seen after naloxone-induced withdrawal. Administration of PLG to morphine-dependent mice 1 h prior to naloxone did not modify the resultant hypothermia or body weight loss. These results indicate that PLG facilitated the development of morphine tolerance and dependence.

Analgesia↗
PubMed1981

The irreversible narcotic antagonistic and reversible agonistic properties of the fumaramate methyl ester derivative of naltrexone.

The fumaramate methyl ester derivatives of naltrexone (beta-FNA) and oxymorphone (beta-FOA) were both found to be reversible agonists on the guinea pig ileal longitudinal muscle preparation. In addition, beta-FNA possessed on irreversible antagonistic effect against morphine whereas beta-FOA had no such capacity. Analysis by pA2 values revealed that beta-FOA resembled pure agonists like morphine and enkephalin while beta-FNA resembled the mixed agonist-antagonists like nalorphine and pentazocine. The antagonism by beta-FNA was very selective in that it antagonized pure agonists but had little or no effect on the effects of either mixed agonist-antagonists, ethylketocyclazocine or other non-opiate-type agonists like norepinephrine.

Affinity Labels↗
PubMed1981

Antagonism by chlornaltrexamine of some effects of delta 9-tetrahydrocannabinol in rats.

Chlornaltrexamine (beta-CNA) a selective, long-acting irreversible opiate antagonist inhibited the analgesia, hypothermia, hypothermia tolerance and physical dependence produced by delta 9-tetrahydrocannabinol (THC) in rats. The results suggest that there are some common features between cannabis and opiates and some actions of THC may be mediated by opioid related mechanisms in the central nervous system.

Analgesia↗