title: Limited effects of beta-endorphin compared to loperamide or fentanyl in a neuroendocrine biomarker assay in non-human primates.
abstract: The in vivo pharmacodynamics of the opioid neuropeptide beta-endorphin (a major endogenous agonist at the mu-opioid receptor) is 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. beta-endorphin (0.01-0.32 mg/kg; i.v.) in gonadally intact male rhesus monkeys (n=4) to that of the peripherally selective mu-agonist loperamide (0.01-0.32 mg/kg; i.v.) and the centrally penetrating mu-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). Beta-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 beta-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 beta-endorphin pharmacodynamics in vitro. In vivo biotransformation studies with MALDI-mass spectrometry determined that full-length beta-endorphin was detectable in all subjects up to at least 5 min after i.v. administration. Thus, the relative ineffectiveness of i.v. beta-endorphin in this assay does not appear to be principally due to rapid generation of non-opioid fragments of this neuropeptide.
authors.affiliation: Laboratory on the Biology of Addictive Diseases, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA. butelme@rockefeller.edu
authors.forename: Eduardo R
authors.initials: ER
authors.lastname: Butelman
authors.forename: Brian
authors.initials: B
authors.lastname: Reed
authors.forename: Brian T
authors.initials: BT
authors.lastname: Chait
authors.forename: Marek
authors.initials: M
authors.lastname: Mandau
authors.forename: Vadim
authors.initials: V
authors.lastname: Yuferov
authors.forename: Mary Jeanne
authors.initials: MJ
authors.lastname: Kreek
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D000930:Antidiarrheals / Q000494:pharmacology*; D015415:Biomarkers; D001711:Biotransformation; D004305:Dose-Response Relationship, Drug; D005283:Fentanyl / Q000494:pharmacology*; D007275:Injections, Intravenous; D008139:Loperamide / Q000494:pharmacology*; D008253:Macaca mulatta; D008297:Male; D009271:Naltrexone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009490:Neurosecretory Systems / Q000187:drug effects*; D020641:Polymorphism, Single Nucleotide; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000235:genetics; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D001615:beta-Endorphin / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000701:Analgesics, Opioid; D000930:Antidiarrheals; D015415:Biomarkers; D009292:Narcotic Antagonists; D017450:Receptors, Opioid, mu; D009271:Naltrexone; D001615:beta-Endorphin; D008139:Loperamide; D005283:Fentanyl