Naltrindole, a highly selective and potent non-peptide δ opioid receptor antagonist

Portoghese, Philip S.; Sultana, Marjia; Takemori, A. E.

doi:10.1016/0014-2999(88)90502-x

Cited by 586 publications

(225 citation statements)

References 3 publications

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“…Our results indicated that delta opioid receptors are not involved in the development of behavioral sensitization to ethanol, as we found that naltrindole, an antagonist selective for delta opioid receptors (Portoghese et al, 1988) failed to prevent the development of ethanol sensitization. It seems unlikely that the lack of effect of naltrindole on ethanol sensitization could be explained by an insufficient dose, as we used doses similar or even higher than those reported to be effective in reducing, for instance, voluntary ethanol consumption or the conditioned reinstatement of ethanol-seeking behavior (Ciccocioppo et al, 2002;Hyytia and Kiianmaa, 2001;Kim et al, 2000).…”

Section: Discussionmentioning

confidence: 54%

The Role of Opioid Receptor Subtypes in the Development of Behavioral Sensitization to Ethanol

Pastor

Aragón

2005

Neuropsychopharmacol

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Nonspecific blockade of opioid receptors has been found to prevent development of behavioral sensitization to ethanol. Whether this effect is achieved through a specific opioid receptor subtype, however, is not clear. The present study investigated, for the first time, the role of specific opioid receptor subtypes in the development of ethanol-(2.5 g/kg/day; six sessions) induced locomotor sensitization in mice. We confirmed previous results showing that the nonspecific antagonism of opioid receptors (naltrexone; 0-2 mg/kg) prevented the development of behavioral sensitization to ethanol, an effect attained at doses presumed to occupy only mu opioid receptors. This was confirmed by using the selective mu opioid receptor antagonist CTOP (0-1.5 mg/kg), which also blocked sensitization to ethanol. The selective delta receptor antagonist, naltrindole (0-10 mg/kg), however, did not alter sensitization. We further assessed the role of mu opioid receptors in sensitization to ethanol by exploring the involvement of mu 1 , mu 1 + 2 , and mu 3 opioid receptor subtypes. Results of these experiments revealed that the blockade of mu 1 (naloxonazine; 0-30 mg/kg) or mu 3 opioid receptors (3-methoxynaltrexone; 0-6 mg/kg) did not prevent locomotor sensitization to ethanol. Using naloxonazine under treatment conditions that block mu 1 + 2 opioid receptor subtypes we observed a retarded sensitization. The present data suggest that the concurrent inactivation of all mu opioid receptor subtypes may be required to prevent the neural adaptations underlying the development of behavioral sensitization to ethanol. In addition, these results support previous data suggesting a putative role for the mu opioid receptor endogenous ligand, b-endorphin, and the hypothalamic arcuate nucleus in ethanol sensitization.

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Section: Discussionmentioning

confidence: 54%

The Role of Opioid Receptor Subtypes in the Development of Behavioral Sensitization to Ethanol

Pastor

Aragón

2005

Neuropsychopharmacol

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“…(Student's t-test; *P < 0.05, **P < 0.01). 47,48]. Both NTI and β-FNA have good blood-brainbarrier permeability and bioavailability [49,50].…”

Section: Antagonization Of Dor By Nti Mitigates Ad-like Pathology In mentioning

confidence: 99%

A GPCR/secretase complex regulates β- and γ-secretase specificity for Aβ production and contributes to AD pathogenesis

et al. 2010

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Dysregulation of β-site APP-cleaving enzyme (BACE) and/or γ-secretase leads to anomalous production of amyloid-β peptide (Aβ) and contributes to the etiology of Alzheimer's disease (AD). Since these secretases mediate proteolytic processing of numerous proteins, little success has been achieved to treat AD by secretase inhibitors because of inevitable undesired side effects. Thus, it is of importance to unravel the regulatory mechanisms of these secretases. Here, we show that δ-opioid receptor (DOR) promotes the processing of Aβ precursor protein (APP) by BACE1 and γ-secretase, but not that of Notch, N-cadherin or APLP. Further investigation reveals that DOR forms a complex with BACE1 and γ-secretase, and activation of DOR mediates the co-endocytic sorting of the secretases/ receptor complex for APP endoproteolysis. Dysfunction of the receptor retards the endocytosis of BACE1 and γ-secretase and thus the production of Aβ. Consistently, knockdown or antagonization of DOR reduces secretase activities and ameliorates Aβ pathology and Aβ-dependent behavioral deficits, but does not affect the processing of Notch, N-cadherin or APLP in AD model mice. Our study not only uncovers a molecular mechanism for the formation of a DOR/secretase complex that regulates the specificity of secretase for Aβ production but also suggests that intervention of either formation or trafficking of the GPCR/secretase complex could lead to a new strategy against AD, potentially with fewer side effects.

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“…Dose-response curves were established by expressing the data as a percentage of control using the following equation: % of control = (test latency -control latency)/(cut-off time -control latency) x 100. Chemicals BDNL (Boc-Tyr(SO3H)-Nle-Gly-Trp-Nle-Asp-Phe-NH2, RuizGayo et al, 1985), BC264 (Boc-Tyr(S03H)-gMe-mGly-Trp-(NMe)-Nle-Asp-Phe-NH2, Charpentier et al, 1988) FournieZaluski et al, 1992) and naltrindole (NTI, 17-cyclopropylmethyl-6,7-dehydro-4,5a-epoxy-3,14-dihydroxy-6, 7,2',3'-indolomorphinan, Portoghese et al, 1988) were synthesized in the laboratory following previously reported methods. DAMGO (Tyr-D-Ala-Gly-(NMe)Phe-Gly-ol) was purchased from Bachem AG (Switzerland) and naloxone from Mallet SA (France).…”

Section: Hot-plate Testmentioning

confidence: 99%

Modulation of opioid antinociception by CCK at the supraspinal level: evidence of regulatory mechanisms between CCK and enkephalin systems in the control of pain

Noble

Derrien

Roques

1993

British J Pharmacology

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1 Much evidence in the literature supports the idea that cholecystokinin (CCK) interacts with opioids in pain mechanisms. In this work, we have investigated the supraspinal interactions between enkephalins and CCK, using the hot plate test in mice. 2 Intracerebroventricular (i.c.v.) administration of BDNL (a mixed CCKA/CCKB agonist) induced dose-dependent antinociceptive responses on both paw lick and jump responses. In contrast, using the same test, the i.c.v. injection of BC 264 (a selective CCKB agonist) induced a hyperalgesic effect, which was restricted to paw licking and occurred only at a high dose of 2.5 nmol. 3 In addition, i.c.v. administration of BDNL potentiated the antinociceptive effects of the mixed inhibitor of enkephalin degrading enzymes, RB 101 and of the ni-agonist, DAMGO, while BC 264 reduced these effects. 4 Furthermore, at a dose where it interacts selectively with b-opioid receptors, the opioid agonist BUBU reversed the hyperalgesic responses of BC 264 (2.5 nmol) but was unable to modify the effects induced by BDNL. 5 Taken together, these results suggest the existence of regulatory mechanisms between CCK and enkephalin systems in the control of pain. These regulatory loops could enhance the antinociceptive effects of morphine allowing the opiate doses used to be reduced and thus, possibly, the side-effects to be minimized.

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Naltrindole, a highly selective and potent non-peptide δ opioid receptor antagonist

Cited by 586 publications

References 3 publications

The Role of Opioid Receptor Subtypes in the Development of Behavioral Sensitization to Ethanol

The Role of Opioid Receptor Subtypes in the Development of Behavioral Sensitization to Ethanol

A GPCR/secretase complex regulates β- and γ-secretase specificity for Aβ production and contributes to AD pathogenesis

Modulation of opioid antinociception by CCK at the supraspinal level: evidence of regulatory mechanisms between CCK and enkephalin systems in the control of pain

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