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Biomedical subjects

A E Takemori

Publications and source records attributed to A E Takemori.

At least 127 records · Page 7Linked to original sources
PubMed1985

Increased sensitivity to dopamine agonists following a single dose of morphine or levorphanol in mice.

Acute administration of an opiate has been suggested to result in the development of supersensitive dopamine receptors. This hypothesis was tested in mice by determining the effect of a single administration of morphine or levorphanol on dopamine agonist-induced stereotypic behaviors and [3H]spiroperidol binding. Administration of morphine (1.0 mg/kg s.c.), which itself had no significant effect on spontaneous locomotor activity 3 h following administration, significantly potentiated locomotor activity induced by 1.5 or 4.5 mg/kg of apomorphine (i.p.) administered 3 h later. Morphine (10 mg/kg, s.c.) or levorphanol (0.2 and 2.0 mg/kg, s.c.), but not dextrorphan (up to 20 mg/kg, s.c.), enhanced climbing behavior induced by apomorphine (i.p.) or (-)-N-n-propylnorapomorphine (i.p.; NPA) administered 3 h later. An increase in whole brain and striatal [3H]spiroperidol binding sites was found 3 h after administration of 10 mg/kg of morphine. Concurrent administration of 5 mEq/kg of LiCl (i.p.) or 5 mg/kg of naloxone (i.p.; administered twice) attenuated both the potentiation of the climbing behavior induced by the two dopamine agonists and the increase in [3H]spiroperidol binding sites. These results suggest that a single administration of an opiate can induce the development of supersensitive dopamine receptors that is mediated by an interaction at opioid receptors.

Animals↗
PubMed1985

beta-Funaltrexamine (beta-FNA) and neural tumor response in mice.

The effects of beta-FNA, a highly selective and irreversible mu opioid receptor antagonist, in altering tumor response in A/Jax mice inoculated with S20Y cells were determined. Inoculation of neuroblastoma cells in control subjects resulted in 100% tumor incidence within 16 days, and mean and median survival times of 36 and 35 days, respectively, following tumor inoculation. Tumor incidence and survival times were comparable to controls for mice given chronic injections of 2 mg/kg and 10 mg/kg beta-FNA every 48 h beginning 2 days after tumor inoculation. Tumor growth was subnormal in the 10 mg/kg beta-FNA group. Both dosages of beta-FNA were found to block morphine-induced analgesia for 48 h. These results suggest that, in and by themselves, mu receptors selectively antagonized by beta-FNA do not play an important role in neuro-oncogenic events.

Animals↗
PubMed1985

Effects of (-)-N6-(R-phenylisopropyl)-adenosine (PIA) and caffeine on nociception and morphine-induced analgesia, tolerance and dependence in mice.

(-)-N6-(R-phenylisopropyl)-adenosine (PIA) was shown to possess analgesic activity in both the tail flick and acetic acid writhing assays. The analgesic actions of PIA were antagonized by caffeine in a dose-dependent manner. An apparent pA2 analysis in vivo suggested that the antagonism by caffeine was not competitive. Subanalgesic doses of PIA potentiated morphine-induced analgesia, tolerance and dependence. Caffeine antagonized these effects of morphine. PIA attenuated while caffeine exacerbated opiate withdrawal. While a low dose of caffeine antagonized PIA effects on withdrawal, a low dose of PIA did not antagonize the effects of caffeine. These results indicate that PIA can facilitate, and caffeine can antagonize the actions of morphine and that caffeine may be exerting some of its actions independent of adenosine receptor antagonism.

Adenosine↗
PubMed1985

TENA, a selective kappa opioid receptor antagonist.

A number of opioid antagonists (TENA, naloxone, Mr 2266, WIN 44441) were evaluated for their selectivity in antagonizing the effect of mu, kappa, and delta agonists in the guinea pig ileum (GPI) and mouse vas deferens (MVD) preparations. Among these four antagonists, TENA was the most potent and the only ligand which was selective for kappa receptors. In this regard TENA was approximately 27-times more effective in antagonizing the kappa agonist, U-50488H, relative to the mu agonist, morphine, and it was about 5-times more effective against ethylketazocine (EK) relative to morphine. At the same concentration (20 nM) TENA did not significantly antagonize the delta agonist, [D-Ala2,D-Ala5]enkephalin (DADLE), in the MVD. Also, TENA was more effective than naloxone, EK, or U-50488H in protecting kappa receptors from irreversible blockage by beta-CNA. The results of this study indicate that TENA is the most selective kappa antagonist yet reported.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1985

Opioid receptor binding characteristics of the non-equilibrium mu antagonist, beta-funaltrexamine (beta-FNA).

beta-Funaltrexamine (beta-FNA) bound to mouse brain membranes in a reversible and an irreversible (not removed by washing of the membrane) manner, and a portion of each type of binding was opioid-specific. Addition of 100 mM NaCl to the incubating medium enhanced the binding of beta-FNA to membranes. Using membranes preincubated with beta-FNA (1 microM) and then washed three times, the maximum number of binding sites available to [3H]morphine was markedly diminished whereas the affinity of morphine for binding sites was not significantly altered. The binding of [3H]naltrexone was also reduced markedly by beta-FNA pretreatment. In similarly pretreated membranes, the binding of [3H]methionine enkephalin [3H][D-Ala2,D-Leu5]enkephalin (DADLE) or [3H]ethylketazocine was reduced to a smaller extent. Using brain membranes from mice pretreated with a single subcutaneous injection of beta-FNA (100 mg/kg) 48 h prior to use, the binding of [3H]methionine enkephalin was unaffected whereas the number of binding sites available to [3H]morphine was significantly reduced. The inhibition by various ligands of the reversible binding of [3H] beta-FNA resembled the relative ability of the same ligands to inhibit the binding of [3H]ethylketazocine. It was concluded that the irreversible portion of the binding of beta-FNA demonstrates a selectivity for mu over delta binding sites, and that the reversible portion of the binding of beta-FNA demonstrates a selectivity for kappa binding sites over mu or delta binding sites. As such, the binding characteristics of beta-FNA are consistent with its profile in vivo and in isolated tissue studies in vitro.

Animals↗
PubMed1985

Receptors for opioid peptides in the guinea-pig ileum.

Cryptic receptor sites in the guinea-pig ileum preparation have been uncovered by the treatment of the preparation with the highly selective, irreversible mu opioid receptor antagonist, beta-funaltrexamine. These beta-funaltrexamine-insensitive sites appear to interact only with opioid peptides ([D-Ala2, D-Leu5]enkephalin, [D-Ala2, Met5]enkephalinamide, Tyr-D-Ser-Gly-Phe-Leu-Thr and [D-Ala2, MePhe4, Gly-ol5]enkephalin) but not with nonpeptide agonists. These new sites could not be protected by either mu-selective (morphiceptin and [D-Ala2, MePhe4, Gly-ol5]enkephalin) or delta-selective ([D-Ala2, D-Leu5]enkephalin, Tyr-D-Ser-Gly-Phe-Leu-Thr, (Allyl)2-Tyr-Gly-Gly-psi-(CH2S)-Phe-Leu, and (Allyl)2-Tyr-Aib-Aib-Phe-Leu) peptides against beta-chlornaltrexamine alkylation. However, naloxone afforded full protection of these sites against beta-chlornaltrexamine alkylation. The delta-selective antagonist, (Allyl)2-Tyr-Aib-Aib-Phe-Leu, had no activity at these cryptic sites at concentrations that effectively blocked delta receptors in the mouse vas deferens. The cryptic sites do not appear to be typical mu or delta receptors. The new receptors were termed mu', a mu subtype, and a receptor model that is consonant with our data is presented.

Alkylation↗
PubMed1984

Comparative antagonism by naltrexone and naloxone of mu, kappa, and delta agonists.

In the guinea pig ileum preparation, naltrexone was 3.5 to 5 times more potent than naloxone in antagonizing morphine but the antagonists were equipotent in antagonizing ethylketazocine. In the mouse vas deferens preparation, naltrexone and naloxone were equipotent in antagonizing both morphine and [D-Ala2-D-Leu5]enkephalin. The data provide evidence that the naltrexone-reversible mu population of receptors in the guinea pig ileum are different from those in the mouse vas deferens. These findings also point out the uniqueness of the mu receptor system in the guinea pig ileum which is reflected by the potency differences between naltrexone and naloxone.

Animals↗
PubMed1984

Effect of prolyl-leucyl-glycinamide and alpha-melanocyte-stimulating hormone on levorphanol-induced analgesia, tolerance and dependence.

Prolyl-leucyl-glycinamide (PLG) at a low dose (10 ng/mouse) administered by an intracerebroventricular (i.c.v.) injection did not affect levorphanol analgesia, but PLG at higher doses (10 and 100 micrograms/mouse) and alpha-melanocyte-stimulating hormone (alpha-MSH) (10 ng/mouse) antagonized levorphanol analgesia. Development of levorphanol tolerance was facilitated by 10 ng/mouse of PLG, unaffected by 10 micrograms/mouse of PLG, but antagonized by 100 micrograms/mouse of PLG and 10 ng/mouse of alpha-MSH. The effect of PLG on levorphanol dependence was assessed by changes in body weight and temperature during naloxone-induced withdrawal. PLG (10 ng/mouse) facilitated the development of levorphanol dependence, but 10 micrograms/mouse of PLG had no effect. PLG (100 micrograms/mouse) antagonized development of levorphanol dependence. PLG at doses of 10 and 100 micrograms/mouse precipitated withdrawal in levorphanol-dependent mice. alpha-MSH (10 ng/mouse) antagonized development of levorphanol dependence as evidenced by an increase in the ED50 of naloxone required to induce withdrawal jumping. These results indicate that PLG and alpha-MSH affected levorphanol-induced analgesia, tolerance and dependence in a qualitatively similar manner to their effect on morphine-induced analgesia, tolerance and dependence.

Analgesia↗
PubMed1984

Dose-dependent effects of prolyl-leucyl-glycinamide on morphine-induced analgesia, tolerance and dependence.

Prolyl-leucyl-glycinamide (PLG) at a low dose (10 ng/mouse) administered intracerebroventricularly (i.c.v.) did not affect morphine analgesia, but produced a greater increase in the ED50 of morphine-pretreated (100 mg/kg of morphine sulfate) mice as compared to control mice. PLG at doses of 10 and 100 micrograms/mouse antagonized morphine analgesia. Development of morphine tolerance was unaffected by 10 micrograms/mouse but antagonized by 100 micrograms/mouse of PLG. Development of morphine dependence was assessed by changes in body weight and temperature during naloxone-induced withdrawal. PLG (10 ng/mouse) potentiated, 10 micrograms/mouse had no effect and 100 micrograms/mouse antagonized development of morphine dependence. PLG at doses of 10 and 100 micrograms/mouse precipitated withdrawal in morphine-dependent mice. When mice were pretreated with 1.0 mg/kg naloxone i.p. 15 min before PLG, all doses of PLG had no effect on morphine analgesia, but potentiated the development of morphine tolerance and dependence. None of the doses of PLG altered whole brain levels of morphine. PLG did not alter the affinity of opioid receptors for etorphine or the maximal number of binding sites but PLG did exhibit a very weak affinity for opioid receptors. These results indicate that PLG potentiated development of morphine tolerance and dependence through a mechanism not involving opioid receptors. However, at very high doses it was a weak opioid receptor antagonist.

Analgesia↗
PubMed1984

Design and synthesis of naltrexone-derived affinity labels with nonequilibrium opioid agonist and antagonist activities. Evidence for the existence of different mu receptor subtypes in different tissues.

A series of beta-funaltrexamine (2, beta-FNA) analogues (3-14) were synthesized that contain a variety of electrophilic groups attached at the 6 beta-position of the opiate. The opioid agonist and antagonist activities of these ligands were evaluated in the guinea pig ileum (GPI) and mouse vas deferens (MVD) in vitro assays. Several of the compounds behaved like beta-FNA in that they exhibited reversible agonist activity at kappa opioid receptors and irreversible antagonist activity at mu opioid receptors. The rank order of irreversible antagonism for a series of related Michael acceptors did not parallel their intrinsic chemical reactivity, confirming that the degree of covalent binding is in part dependent on the spatial disposition of the electrophilic center relative to the receptor nucleophile (secondary recognition). The maleimidoacetamide 8 behaved very differently from beta-FNA in that it exhibited considerably greater irreversible mu antagonism in MVD relative to the mu blockage in the GPI. This suggests that different proportions of mu receptor subtypes exist in the two tissues. Several of the agents tested, including some nonreactive control compounds, displayed an unusual type of persistent kappa agonist activity in the GPI. This activity, which was reversed by addition of naloxone, reappeared upon washing. Receptor models have been presented to explain this effect. A few of the reactive ligands displayed a true nonreversible kappa agonist activity, suggesting a covalent association with the receptor. Of note in this regard was the propiolamide 6, which appeared to be an irreversible mixed agonist-antagonist at kappa and mu receptors.

Affinity Labels↗
PubMed1984

Activities of morphinone and N-(cyclopropylmethyl)normorphinone at opioid receptors.

Morphinone (3) and N-(cyclopropylmethyl)normorphinone (4) were synthesized and tested on electrically stimulated smooth muscle preparations (guinea pig ileum and mouse vas deferens) and in mice. Compound 3 behaved as an agonist and 4 as an antagonist in vitro and in vivo. No pronounced nonequilibrium agonist or antagonist activity was observed with either compound.

Animals↗
PubMed1984

Role of spinal mu opioid receptors in the development of morphine tolerance and dependence.

We previously demonstrated that the spinal cord is a primary site for the development of morphine-induced tolerance and dependence. In the current investigation, we have determined the significance of mu opioid receptors in the spinal cord in tolerance and dependence induced by systemically administered morphine. Rats surgically implanted with intrathecal (i.t.) catheters were injected i.t. with various doses of beta-funaltrexamine (beta-FNA), a specific irreversible mu opioid receptor antagonist. beta-FNA (i.t.) dose-dependently antagonized morphine-induced analgesia (i.p.) with approximately one-half the potency of beta-chlornaltrexamine, a nonselective irreversible opioid receptor antagonist. Rats injected with saline i.t. 24 h before implanting morphine pellets developed a significant degree of tolerance and dependence 72 h after morphine administration. Tolerance did not develop in similarly treated animals that received i.t. injections of 4.5 nmol beta-FNA. Signs of naloxone-precipitated withdrawal were also significantly antagonized in all instances, except weight loss, in animals pretreated with beta-FNA (i.t.). We conclude that i.t. injections of beta-FNA significantly antagonized the development of tolerance and dependence induced by systemically administered morphine. Therefore, our results indicate that mu opioid receptors within the spinal cord, and probably throughout the central nervous system, play a primary role in morphine-induced tolerance and dependence.

Analgesia↗
PubMed1984

Antagonism of morphine-induced analgesia, tolerance and dependence by alpha-melanocyte-stimulating hormone.

The effect of alpha-melanocyte-stimulating hormone (alpha-MSH) on morphine-induced analgesia, tolerance and dependence was investigated by administering alpha-MSH by intracerebroventricular (i.c.v.) injection to mice 15 min before morphine administration. alpha-MSH antagonized morphine-induced analgesia at doses lower than that necessary to demonstrate hyperalgesia. Pretreatment of mice with 100 mg/kg of morphine sulfate s.c. did not increase the ED50 of morphine in alpha-MSH-treated mice to the same degree as that of control mice. Furthermore, the increase in naloxone potency due to morphine pretreatment, which was used as an indicator of tolerance development, was inhibited by alpha-MSH. The ED50 of naloxone needed to induce withdrawal jumping in dependent mice was increased by alpha-MSH administered 15 min before morphine, but not when alpha-MSH was administered 15 min before naloxone. alpha-MSH did not alter whole-brain levels of morphine. Naloxone (1.0 mg/kg), administered i.p. 15 min before alpha-MSH, did not alter the antagonism by alpha-MSH of morphine-induced analgesia, tolerance or dependence. Furthermore, alpha-MSH did not change the affinity of opioid receptors for etorphine or the maximal number of binding sites, but alpha-MSH did exhibit a very weak affinity for opioid receptors. These results indicate that alpha-MSH antagonized the actions of morphine but this antagonism did not appear to be mediated through an interaction with opioid receptors.

Analgesia↗
PubMed1983

Spinal antagonism of tolerance and dependence induced by systemically administered morphine.

We observed that the spinal cord of rats was involved in development of tolerance and dependence to morphine that was administered systemically by s.c. morphine-pellet implantation. Rats, surgically fitted with intrathecal catheters, were injected intrathecally (i.t.) with saline or 2.4 nmol beta-chlornaltrexamine (beta-CNA), an irreversible opiate antagonist. Twenty-four h later, animals were implanted s.c. with either placebo or morphine pellets. Seventy-two h after implanting pellets, development of tolerance or dependence was assessed. Control animals implanted with morphine pellets became tolerant to analgesia induced by i.p. injections of morphine as determined by the use of tail flick and hot plate analgesic assays. beta-CNA pretreatment antagonized the effects of i.p. injections of morphine and blocked development of tolerance in morphine-implanted animals. Dependence was assessed by observing several characteristic signs of precipitated withdrawal. Treatment with beta-CNA before morphine treatment antagonized naloxone-induced expression of withdrawal for all signs observed, except weight loss. We conclude that the spinal cord plays a significant role in development of tolerance and dependence induced by systemically administered opiates.

Animals↗