Peripherally acting opioid receptor antagonists blocked systemic loperamide-induced anti-heat hyperalgesia in rats after an L5 spinal nerve ligation (SNL). (a–b) The antihyperalgesic effect of systemic loperamide was blocked by systemic pretreatment with intraperitoneal (i.p.) injection of naloxone methiodide (a, 5 mg/kg, i.p.), but was not blocked by delta-opioid receptor antagonist naltrindole (b, 5.0 mg/kg, i.p.) or saline (data not shown). SNL rats were pre-treated with saline or opioid receptor antagonist followed 5 min later by subcutaneous (s.c.) loperamide (1.5 mg/kg). Paw withdrawal latency (PWL) was examined at pre- and 30 min after loperamide injection. (c) Systemic loperamide-induced anti-heat hyperalgesia was not blocked by pretreatment with intrathecal (i.t.) injection of naltrexone (20 μg/10 μL). (d) Intrathecal injection of naltrexone (20 μg/10 μL), followed by systemic administration of 20% CDEX (vehicle for loperamide, s.c.), did not change PWLs. Data are presented as means ± SEM. ***P < 0.001 versus pre-injection level. ##P < 0.01, ###P < 0.001 versus pre-SNL.