Antinociceptive, reinforcing, and pruritic effects of the G-protein signalling-biased mu opioid receptor agonist PZM21 in non-human primates

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_i/o 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^-1) and oxycodone (0.1-0.6 mg kg^-1) 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.

Keywords: G protein; opioid; opoid addiction; pruritus; rhesus macaque; spinal analgesics.

Fig 1

Comparison of systemic oxycodone- and PZM21-induced antinociceptive effects as measured by warm water tail withdrawal latency in monkeys. Antinociception induced by oxycodone (a) and PZM21 (b) was measured against an acute noxious stimulus, 50°C water. Each data point represents the mean (standard deviation) (n=4). Both compounds were administered subcutaneously. ∗P<0.05, significantly different from vehicle condition from the first time point to the corresponding time point.

Fig 2

Comparison of oxycodone- and PZM21-induced reinforcing effects as measured by intravenous drug self-administration in monkeys. Number of injections received as a function of dose in monkeys responding to remifentanil (R, 0.3 μg kg⁻¹ per injection), saline (S, ∼0.14 ml kg⁻¹ per injection), oxycodone (0.3–3 μg kg⁻¹ per injection), or PZM21 (3–30 μg kg⁻¹ per injection) under a fixed ratio (FR30) schedule (a) or a progressive ratio (PR) schedule (b) of reinforcement. Each data point represents the mean (standard deviation) (n=4–6). ∗P<0.05, significantly different from saline.

Fig 3

Comparison of intrathecal morphine- and PZM21-induced antinociception and itch scratching in monkeys. Antinociception induced by intrathecal morphine (a) or PZM21 (b) against an acute noxious stimulus, 50°C water, n=4. (c) Itch scratching responses elicited by intrathecal morphine (0.03 mg) and PZM21 (0.3 mg), n=8. Each data point represents the mean (standard deviation). Both compounds were delivered intrathecally. ∗P<0.05, significantly different from the vehicle condition from the first time point to the corresponding time point. ∗P<0.05, significantly different from the vehicle condition from the second time point to the corresponding time point. #P<0.05, significantly different from morphine.

Fig 4

Comparison of intrathecal morphine- and PZM21-induced antiallodynia in monkeys. (a) Antiallodynic effects induced by PZM21 or morphine against capsaicin-induced allodynia in 46°C water. (b) Effects of the mu opioid peptide (MOP) receptor antagonist naltrexone (0.03 mg kg⁻¹) on antiallodynia induced by intrathecal PZM21 (0.3 mg) or morphine (0.03 mg). Individual data points with the mean (standard deviation) (n=4) are presented. Vehicle and naltrexone were delivered subcutaneously. PZM21 and morphine were delivered intrathecally. ∗P<0.05, significantly different from vehicle.