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

SummaryThe in vivo pharmacodynamics of the opioid neuropeptide β-endorphin (a major endogenous agonist at the μ-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. 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.