Fig. 1: Kurkinorin and kurkinol have MOR-dependent antinociceptive effects similar to morphine, but with reduced tolerance, while knockout of βArr2 increases antinociceptive potency for some drugs but has no effect on the development of tolerance.
A Chemical structures of kurkinorin, kurkinol, and other relevant compounds with in vitro MOR EC50 and G-protein bias data (relative to DAMGO, values > 1 indicate G-protein bias) calculated from Crowley et al. 2016, 2020. Colors represent structural modifications. Time-dependent B and overall (AUC; C, D) antinociceptive effects of morphine, kurkinorin, and kurkinol in the hotplate assay in male and female mice (pooled). Time-dependent E and overall (AUC; F) antinociceptive effects of morphine, kurkinorin, and kurkinol in the hotplate assay in MOR knockout male mice. G Antinociceptive effects of morphine, kurkinorin, and kurkinol in the warm-water tail withdrawal assay in MOR knockout male mice. Cumulative dose response curves and calculated ED50 values (± 95% confidence intervals) for morphine H, kurkinorin I, and kurkinol J in the warm-water tail withdrawal assay in βArr2 knockout male mice before (day 1) and after (day 9) seven days of treatment with a ~ 2×ED50 dose of drug. Drug doses are mg/kg. Data are presented as mean ± SEM unless otherwise stated. n = 10–12/treatment B–D, n = 6/treatment/genotype (E-G), n = 5–6/treatment H–J. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001 compared to vehicle treatment or as indicated, one or two-way ANOVA. ED50 values calculated by non-linear regression. #95% confidence intervals.
