Rationale: E-2078 ([N-methyl-Tyr1, N-methyl-Arg7, D-Leu8] dynorphin A(1-8) ethylamide) is a dynorphin A(1-8) analog with a reduced tendency to be biotransformed, when compared to the unmodified opioid peptide. E-2078 has been found to produce kappa-opioid agonist effects in vivo in rodents.
Objective: In the present studies, we investigated whether systemically administered E-2078 could produce kappa-agonist effects in rhesus monkeys, in tests of antinociception, diuresis and ethyl-ketocyclazocine (EKC) discrimination.
Methods: E-2078 (0.32-18 mg/kg, SC, IM or IV) was tested in the warm water (50 degrees, 55 degrees C) tail withdrawal assay of thermal antinociception. The diuretic effects of E-2078 (0.056-1.8 mg/kg, SC) were also compared to those of the kappa-agonist, U69,593 (0.01-0.32 mg/kg, SC). Lastly, the effects of E-2078 (0.1-3.2 mg/kg, SC or IV) were studied in rhesus monkeys trained to discriminate EKC (0.0056 mg/kg SC) from vehicle, in a food-reinforced operant procedure.
Results: E-2078 did not produce thermal antinociception in rhesus monkeys following SC or IM administration, up to the largest doses presently studied (i.e., 18 and 10 mg/kg, respectively). E-2078 caused thermal antinociception by the IV route, but this effect was not apparently mediated by kappa- or mu-opioid receptors, as shown by its insensitivity to quadazocine (1 mg/kg) pretreatment. However, SC E-2078 caused diuresis, and this effect was blocked by quadazocine pretreatment, consistent with mediation by kappa-opioid receptors. E-2078 generalized in EKC-discriminating monkeys, but only after the largest dose (3.2 mg/kg), and only following IV administration.
Conclusions: The present studies suggest that systemically administered E-2078 can produce some kappa-receptor mediated effects in rhesus monkeys, but its profile of action is not identical to non-peptidic kappa-agonists following all routes of administration, or across all experimental situations.