Selective ? receptor partial agonist HS666 produces potent antinociception without inducing aversion after i.c.v. administration in mice.

ABSTRACT: The ? receptor has a central role in modulating neurotransmission in central and peripheral neuronal circuits that subserve pain and other behavioural responses. Although ? receptor agonists do not produce euphoria or lead to respiratory suppression, they induce dysphoria and sedation. We hypothesized that brain-penetrant ? receptor ligands possessing biased agonism towards G protein signalling over ?-arrestin2 recruitment would produce robust antinociception with fewer associated liabilities.Two new diphenethylamines with high ? receptor selectivity, HS665 and HS666, were assessed following i.c.v. administration in mouse assays of antinociception with the 55°C warm-water tail withdrawal test, locomotor activity in the rotorod and conditioned place preference. The [35 S]-GTP?S binding and ?-arrestin2 recruitment in vitro assays were used to characterize biased agonism.HS665 (? receptor agonist) and HS666 (? receptor partial agonist) demonstrated dose-dependent antinociception after i.c.v. administration mediated by the ? receptor. These highly selective ? receptor ligands displayed varying biased signalling towards G protein coupling in vitro, consistent with a reduced liability profile, reflected by reduced sedation and absence of conditioned place aversion for HS666.HS665 and HS666 activate central ? receptors to produce potent antinociception, with HS666 displaying pharmacological characteristics of a ? receptor analgesic with reduced liability for aversive effects correlating with its low efficacy in the ?-arrestin2 signalling pathway. Our data provide further understanding of the contribution of central ? receptors in pain suppression, and the prospect of dissociating the antinociceptive effects of HS665 and HS666 from ? receptor-mediated adverse effects.

SUBMITTER: Spetea M 

PROVIDER: S-EPMC5513865 | biostudies-other | 2017 Aug

REPOSITORIES: biostudies-other