Comparison of Reinforcing and Antinociceptive Effects of Agonists with Mixed NOP and MOP Receptor Agonist Action in Nonhuman Primates
Abstract
Agonists with mixed nociceptin/orphanin FQ peptide (NOP) and mu opioid peptide (MOP) receptor agonist activities have been demonstrated as effective analgesics with fewer side effects. However, these newly developed compounds with different efficacies at the NOP and MOP receptors have not been compared in terms of their reinforcing and antinociceptive effects. The aim of this study was to determine and compare effects of AT‐121 and BU08028 (NOP/MOP partial agonists), AT‐175 (NOP full/MOP partial agonist), and cebranopadol (mixed NOP and opioid full agonist) in a series of behavioral assays established in rhesus monkeys (Macaca mutatta). Following systemic administration, AT‐121 (3–30 ug/kg), BU08028 (1–10 ug/kg), AT‐175 (1–10 ug/kg), and cebranopadol (1–5.6 ug/kg) all dose‐dependently produced antinociceptive effects against an acute noxious stimulus and attenuated capsaicin‐induced hypersensitivity. In the intravenous drug self‐administration assay, the relative reinforcing strengths (i.e., abuse potential) of these compounds were compared in monkeys under a progressive‐ratio schedule of reinforcement over a wide dose range. Unlike oxycodone and heroin producing robust reinforcing effects, AT‐121, BU08028, and AT‐175 did not significantly produce reinforcing effects. However, cebranopadol produced moderate reinforcing effects as compared to oxycodone and heroin. Taken together, these pharmacological studies in primates indicate that agonists with mixed NOP and MOP receptor agonist activities exert opioid‐like analgesic effects. Although the NOP receptor activation could attenuate the reinforcing effects mediated MOP partial agonist action, the NOP full agonist activity may not be able to completely attenuate the reinforcing effects mediated by MOP full agonist activity in primates.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Apr 01, 2019
- Source ID
- 10.1096/fasebj.2019.33.1_supplement.498.4
Entities
People
- Claudio Trapella
- Girolamo Calo’
- Huiping Ding
- Mei‐chuan Ko
- Norikazu Kiguchi
- Nurulain T Zaveri
- Paul W Czoty
- Stephen M. Husbands
Organizations
- National Institute on Drug Abuse
- United States Department of Defense
- University of Bath
- University of Ferrara
- Wakayama Medical University
- Wake Forest School of Medicine