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 b-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 (1.0e6.0 mg kg À1 ) and oxycodone (0.1e0.6 mg kg À1 ) induced dosedependent 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 (0.03e0.3 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.

Functional Profile of Systemic and Intrathecal Cebranopadol in Nonhuman Primates

“…The current study was reported in accordance with the Animal Research: Reporting of In Vivo Experiments 26 and designed in settings similar to those reported previously. 27 Acute thermal Nociception μ Receptor agonists change nociceptive thresholds and produce antinociception in both nonhuman primates and humans. Warm water tail-withdrawal assays 27,28 were conducted to examine the thermal antinociceptive effects of cebranopadol and fentanyl.…”

“…27 Acute thermal Nociception μ Receptor agonists change nociceptive thresholds and produce antinociception in both nonhuman primates and humans. Warm water tail-withdrawal assays 27,28 were conducted to examine the thermal antinociceptive effects of cebranopadol and fentanyl. Monkeys were seated in primate restraint chairs, and the lower parts of their shaved tails (~15 cm) were immersed in water maintained at 42°, 46°, or 50°C.…”

Biased Opioid Ligands: Revolution or Evolution?

“…Using a model closer to the human behavior, intravenous self-administration procedure in rats, Austin Zamarripa and colleagues demonstrated that TRV130 was equi-potent to oxycodone (33). More recently, whereas PZM21 demonstrated a lack of effect in the conditioned place preference paradigm in two independent studies in mice (27,28), reinforcing effects, here again comparable to those induced by oxycodone, were demonstrated using a self-administration procedure in monkeys (34), but not in rats (28). All these data from animal studies could suggest that the MOR biased compounds could have reinforcing effects in humans.…”

Influence of G protein-biased agonists of μ-opioid receptor on addiction-related behaviors

“…Although it causes antinociceptive tolerance and withdrawal symptoms, no rewarding or reinforcing properties of PZM21 were reported. However, more recent data provide observations regarding effects of PZM21 in nonhuman primates [ 84 ]. According to this study, PZM21 produces comparable to oxycodone reinforcing effects in self-administration test.…”

“…Reinforcing effects of G protein-biased μ-OR agonists are also a matter of debate and probably are dependent on the dose and specific methodological issues, as the literature provides us with both positive and negative results regarding the effects of the compounds on operant behavior. It should be also noted, that investigation of subjective effects of addiction in rodents is fraught with some risk and methodological weaknesses and such results do not have to translate into similar observations in primates, including humans, for example, PZM21 was not self-administered by rodents [ 83 ], while an opposite effect was observed in monkeys [ 84 ].…”