Fig. 1.

Pharmacological or genetic blockade of 5-HT_2AR augments oxycodone-induced antinociception in male but not female mice. (A) Adjunctive effect of different doses of the 5-HT_2AR antagonist volinanserin or vehicle on the cumulative dose-response induced by oxycodone in the TFR test in male 5-HT_2AR^+/+ mice (n = 10 mice per group) (Oxycodone effect F[7,288] = 150.8, p < 0.001; Volinanserin effect F[3,288] = 14.04, p < 0.001). (B) Time-course of the effect of volinanserin (0.12 mg/kg) on oxycodone (4 mg/kg)-induced antinociception in male 5-HT_2AR^+/+ mice (n = 9-10 mice per group) (Time effect F[8,272] = 159.5, p < 0.001; Volinanserin/Oxycodone effect F[3,34] = 32.23, p < 0.001). (C) Adjunctive effect of volinanserin (0.125 mg/kg) or vehicle on the cumulative dose-response induced by the cannabinoid receptor agonist CP55,490 in the TFR test in male 5-HT_2AR^+/+ mice (n = 9-10 mice per group) (Oxycodone effect F[8,135] = 33.23, p < 0.001; Volinanserin effect F[1,135] = 3.61, p < 0.05). (D) Adjunctive effect of different doses of volinanserin or vehicle on the cumulative dose-response induced by oxycodone in the TFR test in female 5-HT_2AR^+/+ mice (n = 15 mice per group) (Oxycodone effect F[7,448] = 239.1, p < 0.001; Volinanserin effect F[3,488] = 2.26, p > 0.05). (E) Adjunctive effect of volinanserin (0.125 mg/kg) or vehicle on the cumulative dose-response induced by oxycodone in the TFR test in male 5-HT_2AR^+/+ and 5-HT_2AR^−/− mice (n = 10 mice per group) (Oxycodone effect F[7,216] = 105.9, p < 0.001; Genotype effect F[2,216] = 8.619, p < 0.001). (F) Cumulative dose-response induced by oxycodone in the TFR test in female 5-HT_2AR^+/+ and 5-HT_2AR^−/− mice (n = 14 mice per group) (Oxycodone effect F[7,208] = 106.0, p < 0.001; Genotype effect F[1,208] = 0.003, p > 0.05). Two-way ANOVA (A, C, D, E, F) or two-way repeated measures ANOVA (B) followed by Bonferroni’s multiple comparison test. *p < 0.05, **p < 0.01, ***p < 0.001, n.s., not significant. Data are mean ± S.E.M.