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A E Takemori

Publications and source records attributed to A E Takemori.

At least 19 recordsLinked to original sources
PubMed1992

Opioid agonist and antagonist activities of morphindoles related to naltrindole.

A series of naltrindole-related ligands (4-10) with an N-methyl,N-phenethyl,N-cinnamyl, or an unsubstituted basic nitrogen were synthesized and tested for opioid agonist and antagonist activity in smooth muscle preparations and in mice. The nor compounds (4 and 6) and the phenethyl derivatives (5 and 8) displayed full agonist activity (IC50 = 85-179 nM) in the mouse vas deferens preparation (MVD) while the other members of the series exhibited partial agonist or weak antagonist activity. In the guinea pig ileum preparation (GPI), all compounds except 8 were partial agonists. The ligands that were evaluated in mice were found to produce antinociception that was not selectively mediated via delta opioid receptors. However, two of these ligands (4 and 5) appeared to be delta-selective opioid receptor antagonists at subthreshold doses for antinociception. The finding that all of the compounds bind selectively to delta opioid receptors in guinea pig brain membranes together with the in vitro pharmacology and in vivo antagonist studies suggests that the lack of delta agonist selectivity in vivo may be due to a number of factors, including a basic difference between the delta receptor system in the MVD and in the mouse brain. Further, it is suggested that the constellation of message and address components in the morphindole nucleus may tend to stabilize delta receptors in the brain in antagonist state.

Analgesia↗
PubMed1992

Stimulation by corticotropin-releasing factor of the release of immunoreactive dynorphin A from mouse spinal cords in vitro.

Corticotropin-releasing factor (CRF) has been shown to release endogenous opioid peptides from several rat brain regions. Since we have demonstrated previously that the actions produced by intrathecally administered CRF in mice involve spinal kappa opioid receptors, experiments were conducted in this study to test the possibility that CRF may release dynorphin A, a putative endogenous kappa opioid agonist, from the mouse spinal cord. Using a superfusion system in vitro, mouse spinal cords were superfused with aerated (95% O2, 5% CO2) Krebs-Ringer buffer. Fractions of superfusion were collected and dynorphin A levels in each fraction were monitored by radioimmunoassay. The presence of CRF in the perfusion buffer stimulated significantly the release of immunoreactive dynorphin A. The releasing rate of immunoreactive dynorphin A returned to the basal level after withdrawing CRF from the superfusion buffer. The stimulatory effect of CRF on the release of immunoreactive dynorphin A was abolished by alpha-helical CRF-(9-41), a CRF receptor antagonist, indicating that the dynorphin-releasing effect of CRF was mediated by CRF receptors in the spinal cord. Also the dynorphin-releasing effect of CRF was a concentration-related phenomenon, with an estimated EC50 value of 5.3 nM. The results from this study support the hypothesis that intrathecally administered CRF may produce its effects by releasing endogenous dynorphin from the terminals of dynorphin-containing neurons in the spinal cord. This study also provides evidence to support the notion that there is a close communication between CRF- and opioid peptide-containing neuronal pathways in the central nervous system.

Animals↗
PubMed1992

Delta opioid antagonist activity and binding studies of regioisomeric isothiocyanate derivatives of naltrindole: evidence for delta receptor subtypes.

The isothiocyanate group was attached to the 4'-, 5'-, 6'-, or 7'-position of naltrindole in an effort to determine the importance of the position of this electrophilic group on the selectivity for subtypes of delta opioid receptors. All of the ligands were delta-selective when tested against standard agonists in smooth muscle preparations. However, the rank-order delta antagonism of antinociception in mice did not parallel the in vitro pharmacologic data. The 5'-isothiocyanate 2 was the most potent and selective antagonist in vivo, causing a 52-fold increase of the ED50 for [D-Ser2,D-Leu5]enkephalin-Thr6 (DSLET) and no increase for [D-Pen2,D-Pen5]enkephalin (DPDPE). The effect of each of the ligands on the binding of [3H]DSLET and [3H]DPDPE to guinea pig brain membranes clearly differentiated between the binding sites that recognize these radioligands. These studies provide additional evidence for the presence of two subtypes of delta opioid receptors.

Animals↗
PubMed1992

Suppression by dynorphin A-(1-13) of the expression of opiate withdrawal and tolerance in mice.

Dynorphin A-(1-13) has been shown to suppress the expression of opiate withdrawal and tolerance dose dependently in morphine-dependent mice when administered i.v. The ED50 of naloxone to precipitate withdrawal jumping was increased by 1.5- and 7-fold when morphine-dependent mice were pretreated with 2.5 and 5.0 mumol/kg of dynorphin A-(1-13), respectively. When dynorphin A-(1-13) (5.0 mumol/kg, i.v.) was administered after the precipitation of withdrawal with naloxone, the ED50 of naloxone was still increased by over 2-fold. Also, the expression of tolerance which was estimated by noting the antinociceptive ED50 of morphine, was inhibited by over 70% with a dynorphin A-(1-13) dose of 2.5 mumol/kg and completely suppressed by pretreatment with 5.0 mumol/kg of dynorphin A-(1-13) i.v. The mechanism by which dynorphin A-(1-13) produces these effects when given i.v. remains to be elucidated.

Animals↗
PubMed1992

A highly selective delta 1-opioid receptor antagonist: 7-benzylidenenaltrexone.

In guinea pig brain membranes 7-benzylidenenaltrexone (BNTX) possesses 100-fold greater affinity (Ki = 0.1 nM) for [3H]DPDPE [3H][D-Pen2,D-Pen5]enkephalin) binding sites (delta 1) relative to those of [3H]DSLET ([3H][D-Ser2,Leu5]enkephalin-Thr6) (delta 2). The ED50 dose ratio (tail flick) in mice for the antagonism of DPDPE-induced antinociception of BNTX (6.3 pmol i.c.v.) was 7.2, whereas for DSLET, morphine and U69593 it was not significantly different from unity. The fact that there was no correlation of the binding or in vivo data for BNTX with antagonist potency in smooth muscle preparations suggests that the in vitro pharmacologic activity is mediated by delta-opioid subtypes that are different from those in the brain.

Animals↗
PubMed1992

delta-Opioid receptor binding in mouse brain: evidence for heterogeneous binding sites.

In this study we investigated the characteristics of binding sites with which delta opioid receptor agonists interact in homogenates of mouse brain using Krebs-HEPES medium. [3H][D- Ser2,Leu5,Thr6]enkephalin (DSLET), [3H][D-Ala2,D-Leu5]enkephalin (DADLE) and [3H][D-Pen2,D-Pen5]enkephalin (DPDPE) were used to label delta opioid binding sites. The analyses of the saturation binding data of these ligands (Scatchard plots) gave best fits to single rather than multiple site models. The binding capacity (Bmax) labelled by [3H]DSLET was found to be significantly greater than those of [3H]DADLE and [3H]DPDPE in brains of mice. Naltriben (the benzofuran analogue of naltrindole) was equally effective in competing for [3H]DSLET, [3H]DPDPE and [3H]DADLE binding sites. On the other hand, DADLE was significantly more potent in competing for [3H]DADLE and [3H]DPDPE binding sites than for [3H]DSLET binding sites. Also, DPDPE was more potent in competing for the binding sites of [3H]DADLE and [3H]DPDPE than for those of [3H]DSLET. DSLET was found to be equipotent in competing for [3H]DSLET, [3H]DPDPE and [3H]DADLE binding sites. These results suggest a heterogeneity of delta opioid receptors which may be explained possibly by the existence of delta opioid receptor subtypes.

Animals↗
PubMed1992

Maintenance of acute morphine tolerance in mice by selective blockage of kappa opioid receptors with norbinaltorphimine.

In this study we investigated the effect of the highly selective kappa opioid antagonist, norbinaltorphimine (norBNI) on the development of tolerance to a single dose of morphine. Mice were pretreated with 100 mg/kg of morphine sulfate (morphine), s.c. and 2 h later, norBNI (20 mg/kg s.c.) was administered and various times after this pretreatment, antinociceptive ED50 value of morphine was determined in the tail-flick assay. Twenty-four and 72 h after morphine injection, ED50 values of morphine were significantly increased by about 2.5-fold from those of their control mice that received saline instead of the tolerance-inducing dose of morphine. In a second set of experiments, animals were pretreated similarly with morphine and norBNI and 72 h after morphine injection, various opioid agonists were applied by the i.c.v. or i.t. route to see whether or not any cross-tolerance had developed to these agonists. The ED50 of i.c.v.-administered morphine was significantly greater than that of the non-pretreated controls. A small degree of cross-tolerance was observed with U-50,488H but not with DPDPE [D-Pen2,D-Pen5]enkephalin (DPDPE) at the supraspinal site. At the spinal site, tolerance to morphine was not observed. These results suggest that antagonism at kappa opioid sites after morphine administration, modulates positively the development of opioid tolerance.

Animals↗
PubMed1992

Modulation of acute morphine tolerance by corticotropin-releasing factor and dynorphin A in the mouse spinal cord.

Previously, we have demonstrated that intrathecally (i.t.) administered corticotropin-releasing factor (CRF) in mice produces stimulus-specific antinociception and modulation of morphine-induced antinociception by mechanisms involving spinal kappa opioid receptors. Recently, we also have found that CRF releases immunoreactive dynorphin A, a putative endogenous kappa opioid receptor agonist, from superfused mice spinal cords in vitro. Dynorphin A administered intracerebroventricularlly (i.c.v.) to mice has been shown to modulate the expression of morphine tolerance. In the present study, the possible modulatory effects of i.t. administered CRF as well as dynorphin A on morphine tolerance were studied in an acute tolerance model. Subcutaneous administration of 100 mg/kg of morphine sulfate (MS) to mice caused an acute tolerance to morphine-induced antinociception. The antinociceptive ED50 of MS was increased from 4.4 mg/kg (naive mice) to 17.9 mg/kg (4 hours after the injection of 100 mg/kg MS). To study the modulatory effects of spinally administered CRF and dynorphin A on the expression of morphine tolerance, CRF and dynorphin A were injected i.t. at 15 min and 5 min, respectively, before testing the tolerant mice by the tail-flick assay. The antinociceptive ED50 of MS in tolerant mice was decreased to 8.8 mg/kg and 7.1 mg/kg, respectively, after i.t. administration of CRF (0.1 nmol) and dynorphin A (0.2 nmol). In contrast, 0.5 nmol of alpha-helical CRF (9-41), a CRF antagonist and 0.4 nmol of norbinaltorphimine, a highly selective kappa opioid receptor antagonist, when administered i.t. at 15 min before the tail-flick test in tolerant mice, increased the antinociceptive ED50 of MS to 56.6 mg/kg and 88.8 mg/kg, respectively. These data confirmed the modulatory effect of dynorphin A on morphine tolerance and suggested that CRF, which releases dynorphin A in several central nervous system regions, also plays a modulatory role in the expression of morphine tolerance.

Animals↗
PubMed1992

Agonist and antagonist activities of ligands derived from naltrexone and oxymorphone.

The pharmacological profile of naltrindole (NTI) and three of its analogues, N-methyl-NTI (N-Me-NTI), oxymorphindole (OMI) and naltriben (NTB) were studied in antinociceptive assays. The compounds were found to have agonist activities that appear to be mediated mainly by kappa opioid receptors because norbinaltorphimine (nor-BNI), the selective kappa opioid receptor antagonist inhibited their effects significantly. All of the compounds, behaved as antagonists at doses that were lower than those that produced agonist effects and they possessed a profile that was very selective for inhibiting the antinociceptive activities of delta opioid receptor agonists. Differential antagonism by NTB of the activities of DSLET and DPDPE was demonstrated.

Animals↗
PubMed1992

Selective naltrexone-derived opioid receptor antagonists.

Progress in opioid research relies heavily on ligands as probes to evaluate selectivity of action. The design of such ligands using naltrexone as a precursor has afforded a number of highly selective antagonists. These include the kappa opioid receptor antagonist, norBNI, and delta opioid receptor antagonists, NTI and NTB. The unifying concept in the development of these antagonists was the enhancement of selectivity through simultaneous occupation of two neighboring recognition sites by a single ligand. These selective naltrexone-derived antagonists have been used widely to study the involvement of kappa and delta opioid receptors in a variety of pharmacologic, physiologic, and biochemical effects.

Animals↗
PubMed1992

Spinal opioid delta antinociception in the mouse: mediation by a 5'-NTII-sensitive delta receptor subtype.

Previous studies from our laboratory have indicated that i.c.v. pretreatment of mice with the novel, selective opioid delta receptor antagonists, [D-Ala2,Leu5,Cys6]enkephalin (DALCE) and naltrindole-5'-isothiocyanate (5'-NTII), differentially antagonized the direct antinociceptive effects of [D-Pen2,D-Pen5]enkephalin (DPDPE) and [D-Ala2]deltorphin II (DELT). These findings, and others, suggested the existence of subtypes of opioid delta receptors which could be classified as activated by DPDPE and DALCE sensitive (delta 1 receptor), or selectively activated by DELT and 5'-NTII sensitive (delta 2 receptor). The present study has extended these observations to the characterization of delta-mediated antinociception effects of DPDPE and DELT after i.t. administration in mice using pretreatment with DALCE and 5'-NTII in order to selectively antagonize the delta subtypes. Additionally, the acute antinociceptive actions of DALCE itself were studied to ensure activity of this compound at the spinal level. The respective antinociceptive A50 value (95% CL) for i.t. DPDPE, DELT and DALCE were 19.0 (12.9-28.1), 19.3 (16.1-23.1) and 2.0 (1.4-3.0) nmol. The delta antagonist, N,N-diallyl-Try-Aib-Aib-Phe-Leu-OH (ICI 174,864) (where Aib is alpha-aminoisobutyric acid) blocked the antinociceptive effects of DPDPE and DELT, but not those of i.t. morphine or [D-Ala2,NMPhe4,Gly-ol5]enkephalin (DAMGO), indicating that the observed antinociceptive effects of DPDPE and DELT were delta mediated. Pretreatment 24 hr before testing with graded doses of i.t. 5'-NTII blocked the i.t. antinociceptive effects of DPDPE and DELT, although at least a 10-fold higher dose of 5'-NTII was needed to produce equivalent antagonism of DPDPE.(ABSTRACT TRUNCATED AT 250 WORDS)

Affinity Labels↗
PubMed1992

Mediation of swim-stress antinociception by the opioid delta 2 receptor in the mouse.

The present study has characterized the antinociceptive response to cold water swim-stress (CWSS) in mice using opioid-selective antagonists as well as tolerance and cross-tolerance approaches. Mice subjected to CWSS using water at 5 degrees C for 3 min showed a marked antinociceptive response in the tail-flick test, which reached approximately 90% after +10 min, and which persisted for 15 to 20 min. This antinociceptive response (at +10 min) was antagonized by naloxone or by the delta antagonist ICI 174,864. Additionally, the CWSS response was antagonized by the opioid delta 2 antagonist, naltrindole-5'-isothiocyanate, but not by the delta 1 antagonist, [D-Ala2,Leu5,Cys6]enkephalin, or by the mu antagonist, beta-funaltrexamine or by the kappa antagonist, norbinaltorphimine. Although the CWSS-induced antinociceptive effect was blocked by some delta antagonists and tolerance resulted from the CWSS-induced response, the decrease in body temperature after each CWSS exposure was not affected by the opioid antagonists and reliably occurred in CWSS-tolerant mice, suggesting that the observed antinociception was independent of changes in body temperature. In mice rendered tolerant to the antinociceptive actions of the mu agonist, [D-Ala2,NMPhe4,Gly-ol] enkephalin, or to [D-Pen2,D-Pen5]enkephalin (predominantly a delta 1 agonist), the CWSS-induced antinociceptive response was unaltered. In contrast, in mice tolerant to the delta 2 agonist, [D-Ala2,Glu4]deltorphin, the CWSS-induced antinociceptive response was markedly and significantly reduced.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesia↗
PubMed1992

Modulation of mu-mediated antinociception in the mouse involves opioid delta-2 receptors.

Recently, subtypes of the opioid delta receptor have been identified. It is not known, however, if a subtype of opioid delta receptor can be associated with the known modulatory action of delta agonists on mu-mediated antinociception. Thus, the present study has used the delta subtype-selective antagonists, [D-Ala2,Leu5,Cys6]enkephalin (DALCE) (delta 1 antagonist) and naltrindole-5'-isothiocyanate (5'-NTII) (delta 2 antagonist) in an effort to determine whether the positive and negative modulation of morphine antinociception produced by opioid delta agonists was the result of activity at specific subtypes of opioid delta receptors. Intracerebroventricular morphine produced a dose-related antinociceptive effect which was not antagonized by coadministration of the delta antagonist, ICI 174,864, or by pretreatment 24 hr before testing with the DALCE or 5'-NTII. Coadministration with morphine of a nonantinociceptive dose of DPDPE or [D-Ala2,Glu4]deltorphin resulted in a leftward displacement of the morphine dose-effect curve (i.e., positive modulation), whereas coadministration of a nonantinociceptive dose of [Met5]enkephalin with morphine resulted in a rightward displacement of the morphine dose-effect curve (i.e., negative modulation). Both the positive and the negative modulatory actions were antagonized when the experiment was conducted in the presence of the delta antagonist, ICI 174,864, or when the mice were pretreated with the delta 2 antagonist, 5'-NTII. In contrast, pretreatment with the delta 1 antagonist, DALCE, failed to affect either the positive or the negative modulatory actions of these delta agonists on morphine antinociception. The data suggest the involvement of an opioid delta 2 receptor in the modulation of morphine antinociception.

Animals↗
PubMed1991

Selective blockage of delta opioid receptors prevents the development of morphine tolerance and dependence in mice.

Recently, we demonstrated that delta opioid binding sites are involved in the development of morphine tolerance and dependence. In our present work, we studied the effect of the potent and selective delta antagonist, naltrindole (NTI), and its nonequilibrium analog, naltrindole 5'-isothiocyanate (5'-NTII), on the development of morphine tolerance and dependence in mice. In the acute model, mice injected with 100 mg/kg of morphine sulfate s.c. displayed acute tolerance 4 hr later as evidenced by a greater than 3-fold increase of the ED50 of morphine sulfate when compared to that of control mice. The acute tolerance was accompanied by the development of acute physical dependence as seen by the dramatic decrease in the amount of naloxone required to precipitate withdrawal jumping. Likewise, in the chronic model s.c. implantation of morphine pellets (75 mg free base) for 3 days produced tolerance and physical dependence. The ED50 of morphine sulfate in this case was increased by about 19-fold and the amount of naloxone needed to precipitate withdrawal jumping was 40 times lower than that required for acutely dependent mice. The development of acute tolerance and dependence was suppressed markedly in mice pretreated with NTI before induction of tolerance and dependence with 100 mg/kg of morphine sulfate. Multiple administration of either NTI or 5'-NTII before and during implantation with morphine base pellets also inhibited substantially the development of morphine tolerance and dependence.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Characteristics of mu and delta opioid binding sites in striatal slices of morphine-tolerant and -dependent mice.

Previously, we demonstrated the enhanced affinity of opioid receptors for naloxone in striatal slices from morphine-dependent mice. In our present study, binding characteristics of the mu opioid receptor agonists, [D-Ala2,MePhe4,Gly-ol5]enkephalin (DAMGO) and dihydromorphine, the delta opioid receptor agonist, [D-Ala2, D-Leu5]enkephalin (DADLE), and the opioid antagonist, naloxone, were examined in striatal slices from morphine-tolerant and -dependent mice. Striatal slices from mice that were implanted with a morphine pellet for 3,7 and 21 days displayed significant decreases in Kd values (5.1, 4.6 and 5.5 nM, respectively) of [3H]DAMGO when compared to those in slices from control animals that were not implanted or implanted with placebo pellets (9.6 and 9.3 nM, respectively). Also, a significant increase in the binding affinity of naloxone, but not that of dihydromorphine, was observed in striatal slices of mice that were implanted with a morphine pellet for 3 days. Significant increases in the Bmax of delta binding sites in striatal slices of mice that were implanted with a morphine pellet for 3, 7 and 21 days (20.7, 18.1 and 17.7 pmol/mg tissue, respectively) were observed when compared to that in slices from control mice that were implanted with placebo pellets (11.4 pmol/mg tissue). The enhancement in the binding affinity of DAMGO and naloxone and the increased density of DADLE binding sites paralleled the development of morphine tolerance and dependence and [D-Pen2,D-Pen5]enkephalin cross-tolerance in whole animals. An antinociceptive potentiation between morphine and DAMGO was observed in morphine-tolerant and -dependent mice whereas in naive animals the effects of the two drugs were additive.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesics↗
PubMed1991

Involvement of spinal kappa opioid receptors in the antagonistic effect of dynorphins on morphine antinociception.

The modulatory effects of intrathecally (i.t.) administered dynorphin A(1-17) and dynorphin A(1-13) on morphine antinociception have been studied previously in rats by other investigators. However, both potentiating and attenuating effects have been reported. In this study, the modulatory effects of i.t. administered dynorphin A(1-17) as well as the smaller fragment, dynorphin A(1-8), were studied in mice. In addition, nor-binaltorphimine (nor-BNI), a highly selective kappa opioid receptor antagonist, and naltrindole (NTI), a highly selective delta opioid receptor antagonist, were used to characterize the possible involvement of spinal kappa and delta opioid receptors in the modulatory effects of the dynorphins. Dynorphin A(1-17) and dynorphin A(1-8) administered i.t. at doses that did not alter tail-flick latencies, were both able to antagonize in a dose-dependent manner, the antinociceptive action of s.c. administered morphine sulfate. The antinociceptive ED50 of morphine sulfate was increased 3.9- and 5.3-fold by 0.4 nmol/mouse of dynorphin A(1-17) and dynorphin A(1-8), respectively. Injections of 0.4 and 0.8 nmol/mouse of nor-BNI i.t., but not its inactive enantiomer (+)-1-nor-BNI, inhibited dose-dependently the antagonistic effects of the dynorphins. These doses of nor-BNI alone did not affect the antinociceptive action of morphine sulfate. Intrathecal administration of 5 nmol/mouse of NTI also did not affect the modulatory effects of dynorphins. These observations that dynorphins exert their antagonistic effects on morphine-induced antinociception stereoselectively through spinal kappa opioid receptors may suggest a coupling between spinal kappa and mu opioid receptors.

Animals↗
PubMed1991

Cross-tolerance studies in the spinal cord of beta-FNA-treated mice provides further evidence for delta opioid receptor subtypes.

In this study we investigated the development of cross-tolerance among intrathecally (i.t.)- administered mu and delta opioid receptor selective peptides in beta-funaltrexamine (beta-FNA)-treated mice. Tolerance to the antinociceptive effect of i.t. administered DPDPE was accomplished by administration of 16 nmol/mouse of DPDPE, i.t. 3 hr before testing in beta-FNA-treated mice (10 mumol/kg, s.c., 24 hr before the experiment). Cross-tolerance developed to the antinociceptive effect of i.t. administered DADLE but not to those of DSLET or DAMGO. DSLET (0.1 nmol/mouse i.t.) administration in beta-FNA-treated mice resulted in tolerance development to its antinociceptive effect. The same pretreatment resulted in a marginally significant increase in the antinociceptive ED50 value of DPDPE. There was no cross-tolerance to the antinociceptive effect of i.t. administered DADLE or DAMGO. These results provide further evidence for the existence of delta opioid receptor subtypes where DADLE and DPDPE interact with one site and DSLET with a different one.

Animals↗