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Biomedical subjects

A E Takemori

Publications and source records attributed to A E Takemori.

At least 109 records · Page 6Linked to original sources
PubMed1987

Kappa-selective opiate antagonist nor-binaltorphimine improves outcome after traumatic spinal cord injury in rats.

Nor-binaltorphimine (nor-BNI) is a recently developed opiate antagonist that has a high degree of selectivity for kappa-opiate receptors. Because of the proposed role of kappa-opiate receptors in mediating secondary damage after spinal trauma, the effect of nor-BNI was studied in a well-characterized model of traumatic spinal cord injury in rats. Nor-BNI, at a dose of 10 mg/kg administered intravenously at 15 min following impact trauma to T-9, significantly improved neurological recovery, measured both in terms of Tarlov motor scores and ability to maintain position on an inclined plane. Given intrathecally, at doses that were ineffective systemically (0.1 mg/kg), nor-BNI also significantly improved neurological recovery after trauma. These data are consistent with the hypothesis that endogenous opioids, through actions at kappa-opiate receptors within the spinal cord, contribute to the pathophysiological changes after spinal trauma that lead to irreversible tissue damage, and indicate that kappa-receptor antagonists may be beneficial for the treatment of acute spinal cord injury.

Animals↗
PubMed1987

Evidence for the interaction of morphine with kappa and delta opioid receptors to induce analgesia in beta-funaltrexamine-treated mice.

Mice were treated with increasing doses of beta-funaltrexamine (beta-FNA) ranging from 0.15 to 9.6 nmol i.c.v. in an attempt to substantially reduce the population of mu opioid receptors. Two hours later, the analgesic effect of morphine was assessed by the acetic acid writhing assay. ED50 of morphine [0.97 (0.58-1.60) nmol] was increased 2- and 8.5-fold at the lowest and highest dose of beta-FNA, respectively. When the highest dose was injected twice 24 hr apart and the mice were tested 24 hr after the second dose, the ED50 of morphine had increased 30.5-fold when compared with the control value. The latter beta-FNA-treated mice exhibited an apparent pA2 value of 6.19 (6.10-6.28) for morphine-naloxone compared with the control value of 7.39 (7.05-7.73), suggesting that morphine was interacting with receptors other than mu. Selective kappa (binaltorphimine) and delta (ICI 154129 and ICI 174864) antagonists were used to see whether these other receptors might be involved in mediating morphine analgesia in beta-FNA-treated animals. Because both the kappa and delta antagonists inhibited significantly the analgesic effect of morphine in beta-FNA-treated mice at doses that had no effect on morphine analgesia in control mice, these data suggest that morphine interacts with both kappa and delta receptors to produce analgesia when the population of functional mu receptors is drastically reduced by alkylation with beta-FNA.

Analgesia↗
PubMed1987

Modification of the development of acute opiate tolerance by increased dopamine receptor sensitivity.

Earlier studies have suggested that the acute administration of an opiate can result in the development of supersensitive dopamine receptors. The present study was undertaken to determine whether the supersensitive dopamine receptors can modify the development of opiate tolerance and dependence. Administration of morphine (100 mg/kg s.c.) 6 or 24 hr before apomorphine (i.p.) potentiated apomorphine-induced climbing behavior in mice. Administration of levorphanol (12 mg/kg s.c.) 3 or 6 hr, but not 24 hr, before apomorphine also potentiated apomorphine-induced climbing behavior. Coadministration of 5 mEq/kg of LiCl with morphine or levorphanol attenuated the increased sensitivity developed to apomorphine after either opiate. Acute tolerance and dependence was induced by administration of 100 mg/kg of morphine or 12 mg/kg of levorphanol. Lithium enhanced the development of acute tolerance when coadministered with morphine 3, 6 or 24 hr before test doses of morphine, or with levorphanol 3 hr before test doses of levorphanol. Administration of apomorphine 5 min before naloxone significantly decreased the naloxone ED50 for inducing withdrawal jumping in mice that had been pretreated with morphine or levorphanol. Although coadministration of lithium with morphine or levorphanol had no significant effect on naloxone-induced withdrawal jumping, it attenuated the ability of apomorphine to decrease naloxone ED50. Morphine (100 mg/kg s.c.) increased the number of whole brain [3H]spiroperidol binding sites 3 and 6 hr after administration of morphine. This increase was no longer present 24 hr after morphine administration. Levorphanol (12 mg/kg s.c.) also increased the number of binding sites 3 hr after administration. Coadministration of lithium with morphine attenuated the increase in [3H]spiroperidol binding sites.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

The mu, kappa and delta properties of various opioid agonists.

Using the delta-enriched mouse vas deferens and the kappa-enriched guinea-pig ileal longitudinal muscle preparations, a large variety of so-called 'mu, kappa, delta and sigma' opioid agonists were tested for their mu, kappa and delta properties. Buprenorphine and U50,488H appeared to be the most highly selective agonists for mu and kappa opioid receptors, respectively. Most ligands identified as specific agonists are in fact only selective and appear to interact at more than one receptor type.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1986

Effects of beta-funaltrexamine (beta-FNA) on morphine dependence in rats and monkeys.

The opioid mu receptor antagonist beta-funaltrexamine (beta-FNA) blocked the development of physical dependence in rats when infused simultaneously with morphine for 6 days. In addition, beta-FNA given s.c. 24 h prior to the initiation and on day 3 of a 6 day period of morphine infusion in rats reduced the development of physical dependence in a dose-dependent manner. In morphine-dependent rhesus monkeys, beta-FNA precipitated a prompt and long-lasting withdrawal, which was not reversed within 30 h by subsequent injections of morphine. In contrast, naloxone-induced withdrawal lasted approximately 90 min. These results provide further evidence that beta-FNA is a long-acting antagonist of the opioid mu receptor, and that this receptor has a major role in the development of morphine-induced physical dependence.

Animals↗
PubMed1986

Chronically administered morphine increases dopamine receptor sensitivity in mice.

Chronic morphine treatment has been suggested to cause the development of supersensitive dopamine receptors. This increase in sensitivity was detected as a hypersensitivity in direct-acting dopamine agonists and as an increase in the affinity of dopamine receptors. However, these binding studies were performed in animals which had been withdrawn from morphine for a period of 24-48 h prior to killing. In the present study mice were implanted with pellets containing 75 mg of morphine free base. The pellets were left in situ in all experiments. One group of mice exhibited an increased sensitivity to apomorphine 72 h following pellet implantation as evidenced by a decrease in the ED50 of apomorphine for inducing cage climbing behavior. A second matched group of mice was found to have a significant increase in whole brain [3H]spiroperidol binding sites. These results suggest that chronic morphine treatment can cause the development of central supersensitive dopamine receptors. Lithium administered concurrently with the morphine attenuated the increased sensitivity to apomorphine and the increase in the number of [3H]spiroperidol binding sites. Concurrent lithium treatment also facilitated the degree of analgesic tolerance, and naloxone-induced withdrawal hypothermia. The ability of lithium to enhance analgesic tolerance while simultaneously attenuating the increase in dopamine receptors suggests that alterations in dopamine receptors might modify the degree of analgesic tolerance which develops to chronic morphine administration, or might modify the animal's response to thermal stimuli. The mechanism by which lithium enhanced naloxone-induced hypothermia is presently unknown.

Analgesia↗
PubMed1986

Cross-tolerance studies between caffeine and (-)-N6-(phenylisopropyl)-adenosine (PIA) in mice.

Chronic administration of caffeine to mice (1 mg/ml in drinking water X 14 d) led to a downward shift in the dose-response curve for the locomotor effects of caffeine. Caffeine was also less effective as an antagonist against (-)-(N6-phenylisopropyl)-adenosine (PIA)-induced analgesia in the tail flick assay in these animals. The dose-response curves of PIA for both analgesia and locomotor depression were shifted to the left in animals chronically administered caffeine. In mice chronically administered PIA (1 mg/kg/d X 14 d), the dose-response curves of PIA for both analgesia and locomotor depression were shifted to the right. The dose-response curve for the locomotor effects of caffeine was shifted to the left, and caffeine exhibited greater antagonist activity against the analgesic action of PIA in these animals. There was no change in the Kd or Bmax values of either 3H-PIA or 3H-diethylphenylxanthine (DPX, a potent adenosine receptor antagonist) in mice chronically administered PIA. The Bmax values for both 3H-PIA and 3H-DPX were significantly increased, while the Kd values were not changed in mice chronically administered caffeine. There was no detectable change in the brain levels of either PIA or caffeine in animals chronically treated with either drug. The results demonstrate that chronic administration of caffeine increases the sensitivity of mice to the actions of PIA and vice versa, providing supportive evidence for the interaction of these drugs at the same receptor, which is probably an adenosine receptor.

Adenosine↗
PubMed1986

The effect of chronic administration of caffeine on morphine-induced analgesia, tolerance and dependence in mice.

Morphine-induced analgesia, and the development of morphine-induced tolerance and dependence was determined in mice which had drunk caffeinated water (1 mg/ml) for 14 days or in mice which had received (-)-N6-(phenylisopropyl)-adenosine (PIA) 1 mg/kg i.p. for 14 days. Analgesia was assessed by the tail flick assay. The development of dependence was assessed by determining the ED50 of naloxone to precipitate withdrawal jumping (3 h after 100 mg/kg morphine pretreatment or 72 h after s.c. implantation of a morphine 75 mg pellet) and by determining the extent of naloxone-precipitated hypothermia in morphine-implanted animals. In mice chronically administered caffeine, the ED50 for morphine-induced analgesia was significantly decreased while the naloxone ED50 for withdrawal jumping increased by 2-fold after both types of morphine pretreatment. In control animals (tap water for 14 days), doses of 1 and 10 mg/kg of naloxone caused significant hypothermia in morphine-implanted animals. Doses of naloxone up to 100 mg/kg did not cause significant hypothermia in morphine-implanted animals which had received chronic caffeine. The development of tolerance was determined by computing the morphine potency ratio for the tail flick assay (tolerant ED50/control ED50). In mice chronically administered caffeine, the potency ratio was decreased significantly in morphine-implanted animals when compared to control. Morphine-induced analgesia, tolerance and dependence was not changed significantly in animals chronically administered PIA. Neither the distribution of morphine to the brain nor the opioid receptor binding parameters for [3H]etorphine and [3H]naltrexone were altered in mice chronically administered caffeine or PIA.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesia↗
PubMed1986

Investigation of the structural requirements for the kappa-selective opioid receptor antagonist, 6 beta,6 beta'-[ethylenebis(oxyethyleneimino)]bis[17-(cyclopropylmethyl)- 4,5 alpha-epoxymorphinan-3,14-diol] (TENA).

In an effort to determine whether or not the basic nitrogens in the spacer of the bivalent ligand 6 beta,6 beta'-[ethylenebis(oxyethyleneimino)]bis[17-(cyclopropylmethyl)4,5 alpha-epoxymorphinan-3,14-diol] (TENA, 1) is responsible for its selective kappa opioid antagonist activity, we have synthesized monovalent analogues 2-4 that contain a C-6 side chain with basic nitrogens. Analogue 2 behaved as a potent opioid agonist in the guinea pig ileum preparation (GPI) and possessed no significant kappa opioid antagonist activity (IC50 ratio = 1) relative to TENA (IC50 ratio = 20). The agonist activity of 3 and 4 interfered with the opioid antagonist assay and therefore did not permit evaluation of antagonist activity in a concentration range where TENA is effective. Although the results obtained with 2 are consistent with the requirement of a second opiate pharmacophore (rather than a second basic nitrogen in the spacer) for the kappa antagonist activity of TENA, the potent agonism associated with these monomers do not allow a firm conclusion in this regard.

Animals↗
PubMed1986

Activity of N-methyl-alpha- and -beta-funaltrexamine at opioid receptors.

The N-methyl analogues (2a, 2b) of the nonequilibrium mu opioid receptor antagonist beta-funaltrexamine (1b) were synthesized and evaluated in the guinea pig ileum preparation (GPI). These analogues are highly potent, reversible opioid agonists and possess no nonequilibrium antagonist activity. The ineffectiveness of 2b in protecting against irreversible blockage of mu opioid receptors by 1b and the fivefold lower reactivity of 2b with cysteine suggest that N-methyl substitution adversely affects both the first and second recognition steps that are essential for effective covalent blockage of opioid receptors.

Animals↗
PubMed1986

Synthesis and opioid antagonist potencies of naltrexamine bivalent ligands with conformationally restricted spacers.

Bivalent ligands 1-4 with naltrexamine pharmacophores and spacers of different lengths containing a fumaryl moiety were synthesized and evaluated for mu and kappa opioid antagonist activity on the electrically stimulated guinea pig ileal longitudinal muscle (GPI). The fumaryl moiety was incorporated into the spacer in order to determine the effect of conformational restriction of the spacer on the relationship between spacer length and opioid antagonist potency. While it was found that the fumaryl and succinyl series (11) possessed a very similar structure-potency profile with respect to antagonism at mu opioid receptors, the interaction of these two series at kappa receptors differed substantially from one another. This difference was manifested by the longer spacer requirement for peak kappa antagonist potency in the fumaryl relative to the succinyl series. It is concluded that the conformational restriction imposed by the fumaryl group in a short spacer (n = 0) prevents effective interaction of both pharmacophores with vicinal recognition sites of the kappa receptor system; as the spacer is lengthened (n = 2) and becomes more flexible, the simultaneous occupation of vicinal recognition sites occurs with greater facility.

Animals↗
PubMed1986

Opioid agonist and antagonist bivalent ligands. The relationship between spacer length and selectivity at multiple opioid receptors.

Bivalent ligands containing the oxymorphamine or naltrexamine pharmacophores connected to spacers of varying length were synthesized and evaluated for their selectivity at mu, kappa, and delta opioid receptors. The oxymorphamine bivalent ligands (1-8) behaved as mu agonists on the electrically stimulated guinea pig ileum longitudinal muscle preparation (GPI). The spacer that conferred peak agonist activity in these series contains a total of four glycyl units (n = 2). Binding studies with guinea pig brain membranes showed a qualitatively similar profile at mu receptors as a function of spacer length. Also, delta receptor selectivity increased as the spacer was lengthened. The naltrexamine bivalent ligands (9-13) effectively antagonized the mu receptor agonist morphine in the GPI at the same optimal spacer length (n = 2) as in the agonist series. However, the peak antagonism of ethylketazocine, a kappa receptor agonist, occurred with the bivalent ligand 9 containing the shortest spacer (n = 0), and it was found that 9 is the most selective kappa antagonist in the series. While receptor binding roughly parallels that of kappa antagonist activity in the GPI, no correlation between binding and antagonist activity was observed at mu opioid receptors. The possible significance of these results is discussed.

Animals↗
PubMed1986

Synthesis and biological activity of analogues of beta-chlornaltrexamine and beta-funaltrexamine at opioid receptors.

beta-Chlornaltrexamine and beta-funaltrexamine analogues 4-7 with different length "arms" to which an electrophilic moiety is attached were synthesized in an effort to obtain affinity labels that would selectively and irreversibly block specific opioid receptor types and subtypes. One of the compounds, 4, was a potent, irreversible blocker of opioid receptors in the guinea pig ileum and mouse vas deferens preparations. The results of this study suggest that nucleophiles that are remote from the recognition locus are capable of alkylation by reactive electrophiles.

Naltrexone↗
PubMed1986

Irreversible blockage of opioid receptor types by ester homologues of beta-funaltrexamine.

A series of ester homologues 2-5 of the mu receptor nonequilibrium antagonist beta-funaltrexamine (1, beta-FNA) was synthesized. These ligands were of interest in our investigation of the relationship between the structure of the ester function and the ability to irreversibly block mu opioid receptors. While all of the ligands were potent reversible agonists in the guinea pig ileum (GPI) and mouse vas deferens (MVD) preparations, most appeared to behave as irreversible antagonists of morphine. The benzyl 5 and phenethyl 6 esters possessed irreversible mu antagonist potency that was of similar magnitude to that of beta-FNA in the GPI. In the MVD, all esters appeared to irreversibly block the agonist effect of morphine, but none of the compounds irreversibly antagonized [D-Ala2,D-Leu5]enkephalin to a significant degree. [3H]Dihydromorphine displacement studies revealed no relationship between the affinity of the esters 1-6 and the irreversible blockage of mu receptors in the GPI or MVD. Possible reasons for the observed structure-activity relationship are discussed.

Animals↗
PubMed1986

Effects of caffeine and 8-phenyltheophylline on the actions of purines and opiates in the guinea-pig ileum.

The antagonist effects of 8-phenyltheophylline (8-PT) and caffeine against the actions of adenosine, (-)-N6-(R-phenyl-isopropyl)-adenosine (PIA), morphine and nalorphine on the guinea pig ileum preparation were examined. Antagonism of both adenosine and PIA by caffeine and 8-PT was concentration dependent. The slopes of Schild plots for both alkylxanthines vs. adenosine were significantly less than -1 unless the adenosine reuptake blocker dipyridamole (0.1 microM) was include in the tissue bath. Under these conditions, the 95% confidence intervals of the Schild plot slopes embraced theoretical unity, suggesting competitive antagonism. The antagonism of PIA by the alkylxanthine was also competitive. Dipyridamole had no effect on the potency of PIA. The pA2 value for caffeine-adenosine was not different from that for caffeine-PIA, and the pA2 values of 8-PT-adenosine and 8-PT-PIA were similar, suggesting that these two agonists interacted with similar receptors. The pA2 values using 8-PT were approximately 1.5-fold higher than those employing caffeine, suggesting higher affinity for 8-PT at these receptors. Caffeine significantly antagonized morphine at all concentrations used (0.5-1.0 mM), but only antagonized nalorphine at the two highest concentrations. After treating ilea with the mu-specific irreversible antagonist beta-FNA (beta-funaltrexamine) (resulting in a preparation with relatively pure kappa receptor population), the antagonist effect of caffeine against morphine was reduced such that only a concentration of 1 mM resulted in significant antagonism, while the effects of caffeine against nalorphine were unchanged. 8-PT did not antagonize morphine or nalorphine.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗
PubMed1986

Changes in adenosine receptor sensitivity in morphine-tolerant and -dependent mice.

Treatment of mice with either a 75-mg morphine pellet (72 h) s.c. or 100 mg/kg of morphine s.c. (3.5 h) did not alter the ED50 of (-)-N6-(phenylisopropyl)adenosine (PIA) in the tail-flick assay. Under the same treatment conditions, caffeine became a more potent antagonist of PIA-induced analgesia, and the dose-response curve for the locomotor effects of caffeine was shifted to the left. There was no change from control in the distribution of caffeine to the brain in mice pretreated with morphine. Brain levels of PIA were decreased significantly at the two highest doses used to elicit analgesia in morphine-implanted mice when compared to control. Adenosine receptor binding assays, utilizing [3H]PIA and [3H]diethylphenylxanthine as agonist and antagonist ligands, respectively, revealed significant increases in the Bmax values for both ligands without changes in Kd in morphine-implanted mice when compared to control. These data suggest that there is an increase in sensitivity to drugs which interact with adenosine receptors in morphine-tolerant and -dependent mice.

Animals↗