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

Abstract

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.

Behavioral Effects and Central Nervous System Levels of the Broadly Available κ-Agonist Hallucinogen Salvinorin A Are Affected by P-Glycoprotein Modulation In Vivo

“…The selected dose ranges for loperamide and tariquidar were consistent with studies that focused on their pharmacodynamic profile in humans or nonhuman primates, including PET studies of P-glycoprotein function (Butelman et al, 2008;Wagner et al, 2009;Bauer et al, 2010;Kreisl et al, 2010). The similarity of these conditions is supportive of the translational value of these simple behavioral and CNS penetration measures (see below) as endpoints to study P-glycoprotein modulation in vivo.…”

The Effects of Herkinorin, the First μ-Selective Ligand from a Salvinorin A-Derived Scaffold, in a Neuroendocrine Biomarker Assay in Nonhuman Primates

“…These data are consistent with the in vitro profile of herkinorin, which shows relative (approximately 8-fold) binding selectivity for μ- over κ- receptors (Harding et al, 2005). As a direct confirmation in this setting, the smaller dose of nalmefene (0.01 mg/kg) was indeed sufficient to cause complete blockade of the effects of the selective μ-agonist fentanyl (see also Butelman et al, 2008). This confirms that an agonist thought to act solely through μ-receptors in this assay is fully blocked by the smaller nalmefene dose under these experimental conditions.…”

“…compared to repeated vehicle injection, for control purposes. The effects of loperamide (0.01-0.32 mg/kg males and females) and salvinorin A (0.001-0.032 mg/kg [males] and 0.00032-0.01 mg/kg [females], based on prior studies; Butelman et al, 2007; Butelman et al, 2008) were also studied under identical cumulative dosing procedures.…”

“…The present study focuses on an initial evaluation of the in vivo opioid agonist effects of herkinorin in rhesus monkeys, using a translationally viable neuroendocrine biomarker assay, release of the anterior pituitary hormone prolactin. Different factors render this neuroendocrine biomarker a practical approach for initial evaluation of herkinorin: a) Prolactin levels are increased by both μ- and κ- agonists in mammals including humans (δ-agonists appear not be to be active) (Hoehe et al, 1988; Ur et al, 1997; Kreek et al, 1999; Bowen et al, 2002; Butelman et al, 2007), and b) Effects of these opioids are at least partially mediated by opioid receptors outside the blood-brain barrier (e.g., in particular hypothalamic nuclei) (Merchenthaler, 1991; Butelman et al, 2004; Zheng et al, 2005; Butelman et al, 2008), and may therefore be used to determine the pharmacodynamic effects of compounds with limited ability to cross the blood-brain barrier.…”

Beta-endorphin levels in both painful and painless diabetic peripheral neuropathy and its relations to pain characters and severity

“…Veening et al, also reported that half-life values of b-endorphin vary from 20 to 50 min in the human circulation [34]. Butelman et al, reported that full-length b-endorphin was detectable in all subjects up to 5 minutes after intravenous administration [37]. Moreover, Bruehl et al, reported that chronic pain may initially be associated with upregulation of endogenous opioid analgesic systems, which then may become dysfunctional over time [38].…”