Human studies on the μ opiate receptor agonist fentanyl: Neuroendocrine and behavioral responses

Hoehe, Margret R.; Duka, T.; Doenicke, A.

doi:10.1016/0306-4530(88)90046-7

Cited by 34 publications

(17 citation statements)

References 41 publications

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“…The centrally-penetrating μ-agonist fentanyl produced robust dose-dependent prolactin release in all four subjects, as previously found for high efficacy μ-agonists in humans and non-human primates (Hoehe et al, 1988;Bowen et al, 2002;Butelman et al, 2002). Interestingly, quaternary naltrexone (1 mg/kg) only partially blocked this effect of fentanyl, whereas this quaternary naltrexone dose fully blocked the effects of loperamide herein.…”

Section: Discussionsupporting

confidence: 80%

Limited effects of β-endorphin compared to loperamide or fentanyl in a neuroendocrine biomarker assay in non-human primates

Butelman

Reed

Chait

et al. 2008

Psychoneuroendocrinology

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SummaryThe in vivo pharmacodynamics of the opioid neuropeptide β-endorphin (a major endogenous agonist at the μ-opioid receptor) are difficult to determine in non human primate models with translational value, or in humans. The present studies therefore employed a neuroendocrine biomarker assay, prolactin release, to systematically compare the in vivo profile of i.v. β-endorphin (0.01-0.32 mg/ kg; i.v.) in gonadally intact male rhesus monkeys (n=4) to that of the peripherally selective μ-agonist loperamide (0.01-0.32 mg/kg; i.v.) and the centrally-penetrating μ-agonist fentanyl (0.0056-0.018 mg/kg; i.v.). Studies utilized a standardized time course design (measuring prolactin levels 5-120 min after agonist administration).β-endorphin displayed only limited effectiveness in causing prolactin release when tested over this 30-fold dose range, compared to loperamide or fentanyl. Furthermore, two of the four subjects were only minimally responsive to β-endorphin. This differential responsiveness was not due to the presence of a previously described single nucleotide polymorphism at the OPRM1 gene (C77G), known to affect β-endorphin pharmacodynamics in vitro. In vivo biotransformation studies with MALDI mass spectrometry determined that full length β-endorphin was detectable in all subjects up to at least 5 min after i.v. administration. Thus, the relative ineffectiveness of i.v. β-endorphin in this assay does not appear to be principally due to rapid generation of non-opioid fragments of this neuropeptide.

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Section: Discussionsupporting

confidence: 80%

Limited effects of β-endorphin compared to loperamide or fentanyl in a neuroendocrine biomarker assay in non-human primates

Butelman

Reed

Chait

et al. 2008

Psychoneuroendocrinology

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“…Binding of dopamine or D 2 -like agonists to D 2 receptors on pituitary lactotrophs thus inhibits prolactin release (Moore and Lookingland 1995;Kelly et al 1997). kagonists (like -agonists) cause dose-dependent prolactin release in primates (including humans) (Pfeiffer et al 1986b;Hoehe et al 1988;Ur et al 1997;Butelman et al 1999;Bowen et al 2002). This neuroendocrine effect of k-and -agonists in primates may be mediated by hypothalamic opioid receptors that modulate the dopaminergic tuberoinfundibular system.…”

Section: Introductionmentioning

confidence: 95%

Comparison of the discriminative and neuroendocrine effects of centrally penetrating κ-opioid agonists in rhesus monkeys

2002

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“…Individual predisposition toward abuse likely involves genetic factors in addition to behavioral ones (3)(4)(5)(6)(7). As the main molecular target of opioid analgesics, the opioid receptor (MOR) 1 represents an obvious candidate in the search for genetic variations that affect the response of an individual to opioid analgesics.…”

mentioning

confidence: 99%

Single Nucleotide Polymorphisms in the Human μ Opioid Receptor Gene Alter Basal G Protein Coupling and Calmodulin Binding

Wang¹,

Quillan²,

Winans³

et al. 2001

Journal of Biological Chemistry

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Opioid analgesics are highly effective in controlling pain elicited by noxious stimuli, but their repeated use causes tolerance and physical dependence and can lead to addiction (1, 2). Individual predisposition toward abuse likely involves genetic factors in addition to behavioral ones (3-7). As the main molecular target of opioid analgesics, the opioid receptor (MOR) 1 represents an obvious candidate in the search for genetic variations that affect the response of an individual to opioid analgesics. Genotyping of the human MOR gene has revealed several single nucleotide polymorphisms (SNPs) that exist in the general population (7-9). One SNP mapping to the N-terminal region of the seven-transmembrane structure of MOR has already been shown to alter the binding affinity for ␤-endorphin (8), but the clinical significance of this genetic variation remains uncertain (10). We hypothesize that by analyzing the effect of additional polymorphisms on the complex signaling behavior of MOR, we might gain further clues as to the molecular basis of opioid drug response. Opioid receptors are functionally dynamic, seven-transmembrane-spanning proteins known to transmit signals via the GTP-binding proteins, G i /G o . However, they cannot be understood adequately in terms of acute G protein activation alone. Activation of MOR also results in long term changes associated with receptor phosphorylation, internalization, and alterations in gene expression (1). Recently, a direct interaction between the ubiquitous calcium-sensitive regulatory protein calmodulin (CaM) and the third intracellular (i3) loop of MOR has been demonstrated (11). The importance of the i3 loop to G protein coupling (12) and CaM binding (11,13), the presence of multiple phosphorylation consensus sequences (14), and recent observations that this region regulates spontaneous basal G protein coupling (11, 13, 15) all strengthen the rationale for examining i3 loop polymorphisms. A range of functional consequences could emanate from alterations in the i3 loop. At least three allelic, nonsynonymous SNPs that alter the MOR-i3 loop have so far been identified in single individuals, leading to the human variants 9). The allele frequency of these three sporadic variants is unknown. In this study we have genotyped exon 3 of the hMOR gene in 252 subjects (Coriell collection) to obtain more information on allele frequency and discover any further MOR variants. Examination of S268P-MOR had already revealed differences in G protein coupling efficiency and in desensitization kinetics, differences that could stem from structural changes induced by proline insertion and loss of the CaM-kinase II phosphorylation site at Ser 268 (14). Moreover, Befort et al. (16) have proposed that the S268P substitution significantly impaired agoniststimulated G protein coupling of MOR, a finding that we have re-examined in the present study.Recently, a significant level of basal G protein coupling has been demonstrated for MOR (11,13,15). Basal signaling is observable even at relatively low...

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Human studies on the μ opiate receptor agonist fentanyl: Neuroendocrine and behavioral responses

Cited by 34 publications

References 41 publications

Limited effects of β-endorphin compared to loperamide or fentanyl in a neuroendocrine biomarker assay in non-human primates

Limited effects of β-endorphin compared to loperamide or fentanyl in a neuroendocrine biomarker assay in non-human primates

Comparison of the discriminative and neuroendocrine effects of centrally penetrating κ-opioid agonists in rhesus monkeys

Single Nucleotide Polymorphisms in the Human μ Opioid Receptor Gene Alter Basal G Protein Coupling and Calmodulin Binding

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