Figure 8. Repeated drug administration induces tolerance to the anti-allodynic effect of dermorphin [D-Arg2, Lys4] (1–4) amide (DALDA) in nerve-injured rats and elicits hyperalgesia in naïve rats.

(A) Left: DALDA (10 mg/kg, s.c., n=8), but not vehicle (saline, n=8), reversed the decrease in paw withdrawal threshold (PWT) of the ipsilateral hind paw in rats on days 5–7 after SNL. Sham operated rats that received saline injection were included as controls (n=8). The inhibition of mechanical hypersensitivity by DALDA decreased after repeated treatments. PWT was measured before and at 30–60 min after injection. Right: The protocol to induce tolerance. Two-way mixed model ANOVA with Bonferroni post hoc test. *P < 0.05, **P < 0.01 versus pre-drug on day5. (B–E) Opioid-induced hyperalgesia was examined by injecting naïve rats once daily with DALDA (10 mg/kg, n=8, s.c.) or vehicle (saline, n=6) for 10 consecutive days. (B) PWT was measured before and 60 min after drug administration on each treatment day. (C) Time course of change in pre-drug PWTs on each treatment day. (D) Paw withdrawal latency (PWL) to heat stimulation was measured before and 30 min after drug administration. (E) Time course of change in pre-drug PWLs on each treatment day. B,D: paired t-test, *P < 0.05, **P < 0.01, ***P < 0.001 versus the pre-drug baseline. C,E: One-way repeated measures ANOVA with Bonferroni post hoc test, *P < 0.05, **P < 0.01 versus the pre-drug baseline of day 1. Data are expressed as mean ± SD. ANOVA, analysis of variance; SNL, spinal nerve ligation.