naltrindole and 18-19-dihydroetorphine

The antinociceptive potency of dihydroetorphine in diabetic mice was examined. Subcutaneous administration of dihydroetorphine produced a dose-dependent antinociception in both non-diabetic and diabetic mice. The antinociceptive potency of s.c. dihydroetorphine was less in diabetic mice than in non-diabetic mice. The antinociception induced by i.c.v. dihydroetorphine (0.02 microgram) was also significantly less in diabetic mice than in non-diabetic mice. The antinociceptive effects of dihydroetorphine (10 micrograms/kg i.p.) in both diabetic and non-diabetic mice were significantly antagonized by s.c. administration of beta-funaltrexamine, a selective mu-opioid receptor antagonist. Furthermore, the antinociceptive effect of dihydroetorphine (10 micrograms/kg i.p.) in non-diabetic mice, but not in diabetic mice, was also significantly antagonized by naloxonazine, a selective mu 1-opioid receptor antagonist. The time course and the potency of the antinociceptive effect of dihydroetorphine (10 micrograms/kg i.p.) in diabetic mice were similar to those in naloxonazine-treated non-diabetic mice. Naltrindole, a selective delta-opioid receptor antagonist, or nor-binaltorphimine, a selective kappa-opioid receptor antagonist, had no significant effect on the antinociceptive effect of dihydroetorphine (10 micrograms/kg i.p.) in both diabetic and non-diabetic mice. These results suggest that dihydroetorphine produces an antinociceptive effect through the activation of both mu 1- and mu 2-opioid receptors in mice. Furthermore, the reduction in dihydroetorphine-induced antinociception in diabetic mice, as compared with non-diabetic mice, may be due to the hyporesponsive to supraspinal mu 1-opioid receptor-mediated antinociception in diabetic mice.

Topics: Analgesia; Analgesics, Opioid; Animals; Binding, Competitive; Diabetes Mellitus, Experimental; Dose-Response Relationship, Drug; Etorphine; Injections, Intraperitoneal; Injections, Intraventricular; Injections, Subcutaneous; Male; Mice; Mice, Inbred ICR; Naloxone; Naltrexone; Narcotic Antagonists; Pain Measurement; Receptors, Opioid, delta; Receptors, Opioid, mu

The profile of actions of dihydroetorphine (DHE) concerning antinociception, tolerance and dependence was compared with those of morphine in mice. DHE at 1, 5, 10 or 20 micrograms/kg produced an antinociceptive effect in a dose dependent manner and 10 micrograms/kg was nearly equipotent to that of 10 mg/kg of morphine. The antinociceptive effect of both drugs was completely suppressed by 1 mg/kg of naloxone, while neither 10 mg/kg of naltrindole nor 1 mg/kg of nor-binaltorphimine had any suppressive effect. Mice tolerant to morphine antinociception were tolerant to DHE and vice versa. The naloxone-sensitive, locomotor accelerating activity was progressively enhanced by daily administration of DHE and morphine and a cross reverse tolerance developed between these compounds, suggesting that common mechanisms, especially mediating opioid receptors, underlay the activity enhancement. The development of physical dependence as evidenced by naloxone precipitated withdrawal signs, however, was not observed with daily treatment with DHE, 10, 20 and 100 micrograms/kg for 6 d. Thus, we demonstrated that DHE produces the antinociceptive effect mediated through mu opioid receptors without causing development of a physical dependence, suggesting that it is safe to use in the clinical therapy of patients suffering severe pain such as that accompanying cancer.

Topics: Analgesics; Animals; Body Weight; Drug Tolerance; Etorphine; Male; Mice; Mice, Inbred Strains; Morphine; Motor Activity; Naloxone; Naltrexone; Narcotic Antagonists; Pain Measurement; Substance-Related Disorders