Antinociceptive, Reinforcing, and Pruritic Effects of the G-protein Signalling-biased Mu Opioid Receptor Agonist PZM21 in Non-human Primates

Overview

Journal Br J Anaesth

Publisher Elsevier

Specialty Anesthesiology

Date 2020 Aug 22

PMID 32819621

Citations 19

Authors

Huiping Ding

Norikazu Kiguchi

David A Perrey

Thuy Nguyen

Paul W Czoty

Fang-Chi Hsu

Yanan Zhang

Mei-Chuan Ko

Affiliations

Soon will be listed here.

Abstract

Background: A novel G-protein signalling-biased mu opioid peptide (MOP) receptor agonist, PZM21, was recently developed with a distinct chemical structure. It is a potent G activator with minimal β-arrestin-2 recruitment. Despite intriguing activity in rodent models, PZM21 function in non-human primates is unknown. The aim of this study was to investigate PZM21 actions after systemic or intrathecal administration in primates.

Methods: Antinociceptive, reinforcing, and pruritic effects of PZM21 were compared with those of the clinically used MOP receptor agonists oxycodone and morphine in assays of acute thermal nociception, capsaicin-induced thermal allodynia, itch scratching responses, and drug self-administration in gonadally intact, adult rhesus macaques (10 males, six females).

Results: After subcutaneous administration, PZM21 (1.0-6.0 mg kg) and oxycodone (0.1-0.6 mg kg) induced dose-dependent thermal antinociceptive effects (P<0.05); PZM21 was 10 times less potent than oxycodone. PZM21 exerted oxycodone-like reinforcing effects and strength as determined by two operant schedules of reinforcement in the intravenous drug self-administration assay. After intrathecal administration, PZM21 (0.03-0.3 mg) dose-dependently attenuated capsaicin-induced thermal allodynia (P<0.05). Although intrathecal PZM21 and morphine induced MOP receptor-mediated antiallodynic effects, both compounds induced robust, long-lasting itch scratching.

Conclusions: PZM21 induced antinociceptive, reinforcing, and pruritic effects similar to clinically used MOP receptor agonists in primates. Although structure-based discovery of PZM21 identified a novel avenue for studying G-protein signalling-biased ligands, biasing an agonist towards G-protein signalling pathways did not determine or alter reinforcing (i.e. abuse potential) or pruritic effects of MOP receptor agonists in a translationally relevant non-human primate model.

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