Fig. 6.
Cross-tolerance between morphine and compound 1. (A) Subchronic antinociceptive effects of morphine and compound 1 in wild-type C57BL/6 mice. Mice in each group were first treated with vehicle on day 0 and were then subchronically injected with equi-antinociceptive doses of morphine (4 mg/kg) or compound 1 (20 mg/kg) twice daily for 5 days. The antinociceptive effect of each treatment was determined by testing the radiant heat tail-flick latency on days 0, 1, 2, 3, 4, and 5. *P < 0.001 versus vehicle group. †P < 0.01 versus morphine group, two-way ANOVA with appropriate post hoc tests. n = 5 per group. (B) The flowchart of the experiments used to test the cross-tolerance effects of morphine and compound 1. The time–response curve of acute morphine (4 mg/kg) or compound 1 (20 mg/kg) was determined by testing the radiant heat tail-flick latency before the chronic treatment of vehicle, morphine, or compound 1. For subchronic treatment, mice were then injected intravenously with vehicle or drugs (morphine: 10 mg/kg; compound 1: 20 mg/kg; twice daily for 5 days) to generate morphine- or compound 1–tolerant mice, and time–response curves of morphine (4 mg/kg) or compound 1 (20 mg/kg) were then determined once more. (C, E) The antinociceptive effects of compound 1 (C) or morphine (E) after each treatment were determined by using the tail-flick test. *P < 0.001 versus pretest group. †P < 0.01. ‡P < 0.001 versus posttest (subchronic vehicle) group, two-way ANOVA with appropriate post hoc tests. Data in C and E, n = 6 per group. (D, F) Quantitative results from C and E are represented as the area under the curve (AUC). *P < 0.001 versus pretest group. †P < 0.01. ‡P < 0.001 versus posttest (subchronic vehicle), one-way ANOVA with appropriate post hoc tests. Data in D and F, n = 6 to 7 per group. The values indicate the mean ± SD.