μ-, δ- and κ-opioid receptor populations are differentially altered in distinct areas of postmortem brains of Alzheimer’s disease patients

Mathieu-Kia, Anne-Marie; Fan, Liqing; Kreek, Mary Jeanne; Simon, Eric J.; Hiller, Jacob M.

doi:10.1016/s0006-8993(00)03302-3

Cited by 102 publications

(58 citation statements)

References 60 publications

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“…As shown in Fig. 3, Salvinorin A was a potent KOR agonist with an EC 50 for inhibition of adenylate cyclase of 1.05 nM as compared with an EC 50 for the KOR agonist U69593 of 1.2 nM (Table 2). Salvinorin A was also a potent agonist at gpKOR expressed in situ with an EC 50 for [ 35 (Table 2).…”

Section: Salvinorin a Is A Potent Kor Agonist At Recombinant Kors Andmentioning

confidence: 88%

“…Prior studies evaluating KORs in schizophrenia have yielded conflicting results (46)(47)(48), whereas one study examining affective disorder was negative (47). On the other hand, two well-controlled studies have demonstrated an up-regulation of KORs in Alzheimer's disease (49,50), whereas MORs and DORs were down-regulated (50) or unchanged (49).…”

Section: Discussionmentioning

confidence: 99%

“…After incubation at 37°C for 15 min, the reaction was terminated and cAMP content determined as described previously (13). All data reported here represent the results of at least four separate experiments with EC 50 and E max values calculated by using GRAPHPAD PRIZM (Graph PAD, San Diego).…”

Section: Methodsmentioning

confidence: 99%

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Salvinorin A: A potent naturally occurring nonnitrogenous κ opioid selective agonist

Roth

Baner

Westkaemper

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

736

739

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Salvia divinorum, whose main active ingredient is the neoclerodane diterpene Salvinorin A, is a hallucinogenic plant in the mint family that has been used in traditional spiritual practices for its psychoactive properties by the Mazatecs of Oaxaca, Mexico. More recently, S. divinorum extracts and Salvinorin A have become more widely used in the U.S. as legal hallucinogens. We discovered that Salvinorin A potently and selectively inhibited 3 H-bremazocine binding to cloned opioid receptors. Salvinorin A had no significant activity against a battery of 50 receptors, transporters, and ion channels and showed a distinctive profile compared with the prototypic hallucinogen lysergic acid diethylamide. Functional studies demonstrated that Salvinorin A is a potent opioid agonist at cloned opioid receptors expressed in human embryonic kidney-293 cells and at native opioid receptors expressed in guinea pig brain. Importantly, Salvinorin A had no actions at the 5-HT 2A serotonin receptor, the principal molecular target responsible for the actions of classical hallucinogens. Salvinorin A thus represents, to our knowledge, the first naturally occurring nonnitrogenous opioid-receptor subtype-selective agonist. Because Salvinorin A is a psychotomimetic selective for opioid receptors, opioid-selective antagonists may represent novel psychotherapeutic compounds for diseases manifested by perceptual distortions (e.g., schizophrenia, dementia, and bipolar disorders). Additionally, these results suggest that opioid receptors play a prominent role in the modulation of human perception.

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Section: Salvinorin a Is A Potent Kor Agonist At Recombinant Kors Andmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Salvinorin A: A potent naturally occurring nonnitrogenous κ opioid selective agonist

Roth

Baner

Westkaemper

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

736

739

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“…Given the distinct and even opposing roles of DOR, kappa-opioid receptor (KOR), and μ-opioid receptor (MOR) in modulating animal behaviors [33], the efficacy of selective opioid receptor antagonists for AD treatment needs to be further investigated. Recently, it has been reported that the levels of opioid receptors are differentially altered in distinct areas of postmortem brains of AD patients [34]. The levels of leu-enkephalin and dynorphin A (the endogenous opioid peptide for DOR and KOR, respectively) are also increased in the frontal cortex of patients with AD as compared to the control group [35].…”

Section: Introductionmentioning

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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“…In support of the possibility of species-dependent drug effects, there are significant species differences in opioid receptor distribution between rodents and primates (Mansour et al, 1987;Mansour et al, 1988;Hiller and Fan, 1996;Peckys and Landwehrmeyer, 1999;Mathieu-Kia et al, 2001;Mennicken et al, 2003). Delta receptors, for example, are diffusely expressed in the spinal cord of rats and mice, whereas their expression in non-human primates and humans is limited to the superficial laminae of the spinal dorsal horn (Mennicken et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Electroencephalographic and convulsant effects of the delta opioid agonist SNC80 in rhesus monkeys

Danielsson

Gąsior

Stevenson

et al. 2006

Pharmacology Biochemistry and Behavior

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Non-peptidic delta opioid receptor agonists are being evaluated for a wide range of clinical applications; however, the clinical utility of piperazinyl benzamide delta agonists such as SNC80 may be limited by convulsant activity. The purpose of the present study was to evaluate the electroencephalographic and convulsant activity produced by a high dose of 10 mg/kg SNC80 IM in rhesus monkeys. EEG and behavioral activity were examined in four adult male rhesus monkeys after IM administration of SNC80. Monkeys were seated in a standard primate restraint chair, and EEG activity was recorded using an array of 16 needle electrodes implanted subcutaneously in the scalp in a bipolar (scalp-to scalp) montage in a longitudinal direction, with bilateral frontal, central, temporal, and occipital leads. Behavior was recorded using video monitoring equipment. Initially, all monkeys were tested with 10 mg/kg SNC80, which is a relatively high dose 3-10 fold greater than doses necessary to produce a variety of other behavioral effects. Behavioral convulsions and EEG seizures were observed in one of the four monkeys. In this monkey, neither behavioral convulsions nor EEG seizures were observed when a lower dose of 3.2 mg/kg was administered nine weeks later or when the same dose of 10 mg/kg SNC80 was administered one year later. These results suggest that IM administration of SNC80 is less potent in producing convulsant effects than in producing other, potentially useful behavioral effects (e.g. antinociception) in rhesus monkeys.

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μ-, δ- and κ-opioid receptor populations are differentially altered in distinct areas of postmortem brains of Alzheimer’s disease patients

Cited by 102 publications

References 60 publications

Salvinorin A: A potent naturally occurring nonnitrogenous κ opioid selective agonist

Salvinorin A: A potent naturally occurring nonnitrogenous κ opioid selective agonist

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

Electroencephalographic and convulsant effects of the delta opioid agonist SNC80 in rhesus monkeys

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