Fig. 5.

Loss of tolerance and retained signs of dependence in phosphorylation-deficient MOP knock-in mice. a Schematic representation of the tolerance paradigm. Acute antinociceptive response measured in the mouse hot-plate test after fentanyl (15 min) or morphine (30 min) using a cumulative dosing regimen prior (day −1) and after (day 7) to osmotic pump implantation. Withdrawal was precipitated on day 8 by naloxone injection. b, c Cumulative analgesic dose-response curves before (day −1) and after (day 7) chronic treatment with osmotic pumps delivering b, fentanyl (2 mg kg⁻¹ day^-1) or c, morphine (17 mg kg⁻¹ day⁻¹) measured in the hot-plate test (n = 9−12). Responses are reported as percent maximum possible effect (% MPE). The cumulative analgesic dose-response curves of WT mice before and after treatment are shown as black and grey dotted lines, respectively, in the graphs of the transgenic mice for easier comparison. The bar graphs show the global withdrawal and weight loss after 2 mg kg⁻¹ naloxone on day 8 (n = 9–12). Data are the means ± s.e.m.; ^# indicates statistically significant differences from comparisons of the fold shift in agonist efficacy to that in WT (fentanyl: F_{(3, 44)} = 72.97, P < 0.0001; morphine: F_{(3, 39)} = 9.103, P = 0.0001), one-way ANOVA with Bonferroni post hoc test.; * indicates statistically significant differences compared to WT, unpaired, two-tailed t-test