Fig. 4

PRDX6 mediates the long-lasting effects of norBNI and acute morphine tolerance. a, b Mice were injected with saline, MJ33 (1.25 mg kg⁻¹), AACOCF3 (10 mg kg⁻¹), or NAC (100 mg kg⁻¹) 1 h prior to norBNI (10 mg kg⁻¹). Three days later, tail withdrawal latency from 52.5 ± 0.3 °C water bath was measured prior to and 30 min after U50,488 (10 mg kg⁻¹). a The U50,488 stimulated increase in latency was blocked by norBNI following saline or AACOCF3 pretreatment, but not MJ33 (paired two-way ANOVA; significant effect of norBNI, U50,488, and interaction (P < 0.01); *P < 0.01, **P < 0.01, ****P < 0.0001, Holm–Sidak post hoc analysis of post vs. pre; ^# P < 0.05 and comparing post-U50,488 latency between groups ^# P < 0.05, ^## P < 0.01, ^### P < 0.001, n = 4–16). b NorBNI failed to block U50,488-stimulated analgesia when mice were pretreated with NAC (paired two-way ANOVA, significant effect of U50,488, norBNI, and interaction (P < 0.05; n = 8); *P < 0.05, ****P < 0.0001 Holm–Sidak post hoc). c, d Mice were injected with saline, AACOCF3, or MJ33 2 h prior to the initial injection of morphine (10 mg kg⁻¹) or fentanyl (0.3 mg kg⁻¹). Tail withdrawal latency was measured prior to and at 30 min intervals following morphine or fentanyl. For area under the curve (AUC) values see Supplementary Fig. 7b, c. c MJ33 pretreatment increased the analgesic response to the second morphine injection, compared to saline or AACOCF3 (paired two-way ANOVA; significant effect of time, subject matching, and interaction (P < 0.05); *(vs. saline (red) or AACOCF3 (black), P < 0.05), # (vs. 30 min, P < 0.01, Holm–Sidak post hoc; n = 6–8). d MJ33 pretreatment had no effect on the analgesic response to a second fentanyl injection (paired two-way ANOVA on second injection; significant effect of time only (P < 0.0001), n = 6–7; &, significant difference in AUC). e Mice were pretreated twice daily for 5 days with saline or MJ33 2 h prior to morphine (5 mg kg⁻¹), and tail withdrawal latency was measured prior to or 30 min after morphine. Data are represented as increase in latency following morphine. MJ33 pretreatment increased the analgesic response to repeated morphine and delayed tolerance (paired two-way ANOVA, significant effect of MJ33, morphine treatment, and interaction (P < 0.0001); vs. saline *(P < 0.05), **P < 0.01, ***P < 0.001, ****P < 0.0001, vs. first injection ^### P < 0.001, ^#### P < 0.00001, Holm–Sidak post hoc; n = 11–14). Error bars represent mean ± SEM