Opioid antinociceptive effects of delta-receptor antagonists

The antinociceptive effects of delta opioid receptor antagonists (ICI 154129 and ICI 174864) have been studied using the mouse writhing assay. When administered intracerebroventricularly (ICV), ICI 154129 and ICI 174864 produced dose-related inhibition of writhing with respective ED50's of 97 micrograms/mouse and 1.4 micrograms/mouse. Inhibition of writhing by ICI 174864 (3 micrograms, ICV) was antagonized by subcutaneous (SC) naloxone doses of 0.1 mg/kg and greater. Pretreatment of mice with 80 mg/kg (SC) of beta-funaltrexamine (beta-FNA), an irreversible mu-receptor antagonist, 28 hr before ICV injection of ICI 174864 shifted the dose-effect curve for ICI 174864 to the right (ED50 of 7.3 micrograms/mouse). When administered SC, ICI 174864 inhibited writhing with an ED50 of 8.5 mg/kg. Maximal inhibition occurred 30 min after SC administration and decreased 50% by 2 hr. After beta-FNA pretreatment, doses of ICI 174864 as high as 80 mg/kg (SC) did not inhibit writhing. There was no antinociceptive effect of ICI 174864 in mice chronically maintained on morphine, i.e., chronic morphine produced cross-tolerance to the delta antagonist. These results show that delta-selective receptor antagonists produced antinociception which was related to the mu-receptor, but was probably not a result of direct agonist action.