Fig. 1.
Systemic administration of dermorphin [d-Arg2, Lys4] (1–4) amide (DALDA) inhibits mechanical hypersensitivity in nerve-injured male rats through activation of peripheral opioid receptors. (A, left) Subcutaneous (s.c.) injection of DALDA (0.2, 2, 5, and 10 mg/kg, n = 6 to 8/dose) dose-dependently inhibited mechanical allodynia in male rats at 2 to 3 weeks after spinal nerve ligation (SNL), as indicated by the significant increase in ipsilateral paw withdrawal threshold (PWT). The time course shows peak drug effect at 45 min after injection. *P < 0.05 versus predrug (5 and 10 mg/kg), two-way mixed model ANOVA. (A, right) The maximum possible effect (MPE) of DALDA at 45 min postdrug was calculated. MPE (%) = [1 − (Preinjury PWT − Postdrug PWT)]/[Preinjury PWT − Predrug PWT] × 100. **P < 0.01, ***P < 0.001 versus saline group (n = 11), one-way ANOVA. (B, left) Pretreatment with an intraperitoneal (i.p.) injection of methylnaltrexone bromide (MNTX, 5 mg/kg, 10-min pretreatment, n = 7), but not saline (n = 7), blocked the inhibitory effect of DALDA (10 mg/kg, s.c.) on mechanical hypersensitivity in male SNL rats. Injection of MNTX (5 mg/kg, i.p., n = 7) followed by saline (s.c.) did not change PWT from predrug baseline. (B, right) The MPEs at 30 and 45 min after the second drug administration were calculated for each group. (C, left) Intrathecal (i.t.) pretreatment with the highly selective MOR antagonist d-Phe-Cys-Tyr-d-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP, 5 μg/10 μl, n = 5), but not saline (n = 5), blocked inhibition of mechanical hypersensitivity by i.t. DALDA (0.5 μg/10 μl) in male SNL rats. However, the same CTOP treatment did not block inhibition of mechanical hypersensitivity by systemic DALDA (10 mg/kg, s.c., n = 7). Intrathecal CTOP (5 μg/10 μl, n = 5) followed by saline injection (s.c.) did not change PWT from predrug baseline. (D, left) DALDA (10 mg/kg, n = 6, s.c.), but not saline (n = 6), also inhibited mechanical allodynia in female rats at 2 to 3 weeks after SNL. (D, right) The MPE at 45 and 120 min postdrug was calculated. (B–D, left) *P < 0.05, **P < 0.01 versus predrug, two-way mixed model ANOVA. (B-D, right) *P < 0.05, **P < 0.01 versus saline, one-way ANOVA. Data are expressed as mean ± SEM.