FIGURE 4.

Inhibition of CYP3A by ketoconazole pretreatment prevents mitragynine but not 7‐OH mitragynine‐induced anti‐nociception: (a, b) 7‐OH mitragynine (1.9 mg·kg⁻¹) and mitragynine (5.5 mg·kg⁻¹) induced significant anti‐nociception in vehicle‐pretreated mice; however, only 7‐OH induced significant anti‐nociception in ketoconazole‐pretreated mice. (c, d) 7‐OH mitragynine induced the same degree of anti‐nociception in both vehicle‐ and ketoconazole‐pretreated mice whereas mitragynine was significantly reduced by ketoconazole treatment as well as not being significant from vehicle. N = 10 for all groups. All drugs administered by oral gavage dosing. In (b), * P < 0.05, significantly different as indicated; two‐way ANOVA with Dunnett's multiple comparisons. In (c) and (d), * P < 0.05, significantly different, ns not significantly different, as indicated; 2 × 2 factorial by two‐way ANOVA with Bonferroni's multiple comparisons. See Table S1 for full test statistics