Apparent efficacy of κ-opioid receptor ligands on serum prolactin levels in rhesus monkeys

Butelman, Eduardo R.; Harris, Todd J.; Kreek, Mary-Jeanne

doi:10.1016/s0014-2999(99)00640-8

Cited by 20 publications

(21 citation statements)

References 8 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This is consistent with the conclusion that β-endorphin caused smaller maximal effects than either non-peptidic compound in this assay. Prior studies with κ-opioids in this assay show that opioid agonists with lower efficacy (e.g., partial agonists) tend to show lower maximal effects than higher efficacy agonists (Butelman et al, 1999a). However, in vitro studies support the conclusion that β-endorphin, like loperamide and fentanyl, acts as a relatively high efficacy agonist at β-receptors (Selley et al, 1997;Alt et al, 1998;DeHavenHudkins et al, 1999).…”

Section: Discussionmentioning

confidence: 82%

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

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 82%

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

View full text Add to dashboard Cite

show abstract

“…Studies in the prolactin assay were identical to those above, with the following exceptions: a) bremazocine, U69,593 and U50,488 were not presently studied. Comparison ED 50 values for two of these agonists were previously obtained using identical experimental procedures (Butelman et al 1999); b) the dose-effect curves for spiradoline, nalbuphine and fentanyl were also re-determined following pretreatment with nalmefene (0.01 or 0.1 mg/kg). Nalmefene was not studied in the drug discrimination assay, to avoid the potential disruptive effects of opioid antagonists which may be observed in food-reinforced procedures (France and Morse 1989).…”

Section: Designmentioning

confidence: 99%

“…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: 99%

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

2002

Self Cite

View full text Add to dashboard Cite

show abstract

“…Human studies have shown that the mu-opioid receptor agonist methadone and the kappa-opioid receptor agonist dynorphin A(1-13) each stimulate prolactin release; and non-human primate and human studies have shown that the increase in serum prolactin following acute administration of mu-and kappaopioid agonists is blocked by administration of an opioid antagonist (Kreek, 1978;Wehrenberg et al, 1981;Pfeiffer et al, 1986;VanVugt et al, 1989a;Ur et al, 1997;Kreek et al, 1999). While mu-and kappa-opioid antagonists have generally been shown to have no effect on serum prolactin, there are conflicting data in females indicating that prolactin response to these antagonists may be affected by menstrual cycle phase (Ellingboe et al, 1980;Mendelson et al, 1986;VanVugt et al, 1989b;Butelman et al, 1999;Mello et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Nalmefene Induced Elevation in Serum Prolactin in Normal Human Volunteers: Partial Kappa Opioid Agonist Activity?

Bart

Schluger

Borg

et al. 2005

Neuropsychopharmacol

126

View full text Add to dashboard Cite

In humans, mu-and kappa-opioid receptor agonists lower tuberoinfundibular dopamine, which tonically inhibits prolactin release. Serum prolactin is, therefore, a useful biomarker for tuberoinfundibular dopamine. The current study evaluated the unexpected finding that the relative mu-and kappa-opioid receptor selective antagonist nalmefene increases serum prolactin, indicating possible kappa-opioid receptor agonist activity. In all, 33 healthy human volunteers (14 female) with no history of psychiatric or substance use disorders received placebo, nalmefene 3 mg, and nalmefene 10 mg in a double-blind manner. Drugs were administered between 0900 and 1000 on separate days via 2-min intravenous infusion. Serial blood specimens were analyzed for serum levels of prolactin. Additional in vitro studies of nalmefene binding to cloned human kappa-opioid receptors transfected into Chinese hamster ovary cells were performed. Compared to placebo, both doses of nalmefene caused significant elevations in serum prolactin (po0.002 for nalmefene 3 mg and po0.0005 for nalmefene 10 mg). There was no difference in prolactin response between the 3 and 10 mg doses. Binding assays confirmed nalmefene's affinity at kappa-opioid receptors and antagonism of mu-opioid receptors. [ 35 S]GTPgS binding studies demonstrated that nalmefene is a full antagonist at mu-opioid receptors and has partial agonist properties at kappa-opioid receptors. Elevations in serum prolactin following nalmefene are consistent with this partial agonist effect at kappa-opioid receptors. As kappaopioid receptor activation can lower dopamine in brain regions important to the persistence of alcohol and cocaine dependence, the partial kappa agonist effect of nalmefene may enhance its therapeutic efficacy in selected addictive diseases.

show abstract

Apparent efficacy of κ-opioid receptor ligands on serum prolactin levels in rhesus monkeys

Cited by 20 publications

References 8 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

Nalmefene Induced Elevation in Serum Prolactin in Normal Human Volunteers: Partial Kappa Opioid Agonist Activity?

Contact Info

Product

Resources

About