Systemic effects of E-2078, a stabilized dynorphin A(1-8) analog, in rhesus monkeys.
BACKGROUND
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.
D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D003216:Conditioning, Operant / Q000187:drug effects; D004192:Discrimination, Psychological / Q000187:drug effects; D004231:Diuresis / Q000187:drug effects; D004399:Dynorphins / Q000008:administration & dosage / Q000494:pharmacology*; D016314:Ethylketocyclazocine / Q000494:pharmacology; D005260:Female; D005502:Food; D007273:Injections, Intramuscular; D007279:Injections, Subcutaneous; D008253:Macaca mulatta; D008297:Male; D010147:Pain Measurement / Q000187:drug effects; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology*; D017473:Receptors, Opioid, kappa / Q000819:agonists; D017450:Receptors, Opioid, mu / Q000187:drug effects