Combination of Cell Culture Assays and Knockout Mouse Analyses for the Study of Opioid Partial Agonism

Abstract

Nonselective opioid partial agonists, such as buprenorphine, butorphanol, and pentazocine, have been widely used as analgesics and for anti-addiction therapy. However, the precise molecular mechanisms underlying the therapeutic and rewarding effects of these drugs have not been clearly delineated. Recent success in developing mu-opioid receptor knockout (MOP-KO) mice has elucidated the molecular mechanisms underlying the effects of morphine and other opioids. We have revealed the in vivo roles of MOPs in the effects of opioid partial agonists by using MOP-KO mice for behavioral tests (e.g., several kinds of antinociceptive tests for analgesic effects, conditioned place preference test for dependence). The combination of the cell culture assays using cDNA for mu, delta, and kappa opioid receptors and the behavioral tests using MOP-KO mice has provided novel theories on the molecular mechanisms underlying the effects of opioid ligands, especially opioid partial agonists.

Amelioration of the Reduced Antinociceptive Effect of Morphine in the Unpredictable Chronic Mild Stress Model Mice by Noradrenalin but Not Serotonin Reuptake Inhibitors

“…A commercially available apparatus consisting of an acrylic resin cylinder (φ20 × 25 cm, diameter × height) and a thermo-controlled aluminum plate (Model MK-350HC, Muromachi Kikai Co., Tokyo, Japan) was used. Mice were placed on a 52 ± 0.5°C hot plate, and latencies to hind-paw licking or jumping were recorded with a cut-off time of 60 s. The analyses of dose-dependency were conducted by the cumulative dose–response schedule [ 25 ], in which the 3 doses of drugs are administered to the same mouse and hot-plate tests was performed 4 times (pre and after drug injections) in the present study. Morphine was repetitively administered to the mouse by i.p.…”

Manipulating Pharmacodynamic Efficacy with Agonist + Antagonist Mixtures: In Vitro and In Vivo Studies with Opioids and Cannabinoids

“…Although research on molecular mechanisms that govern efficacy is advancing, these mechanisms remain incompletely understood (Ide et al, 2010;Huang et al, 2015;Sounier et al, 2015;Sutcliffe et al, 2017). As a result, the discovery of low-and intermediate-efficacy…”