TY - JOUR
T1 - Systemic effects of E-2078, a stabilized dynorphin A(1-8) analog, in rhesus monkeys
AU - Butelman, Eduardo R.
AU - Vivian, Jeffrey A.
AU - Yu, Jim
AU - Kreek, Mary Jeanne
AU - Woods, James H.
N1 - Funding Information:
Acknowledgements The authors would like to gratefully acknowledge the technical assistance of Dr. Y. Ai, Ms. Lisa MacMahan and Mr. Todd Harris. Support for this research was provided by USPHS Grants DA 00254, DA 01113, DA05130 and DA00049.
PY - 1999
Y1 - 1999
N2 - Rationale: E-2078 ([N-methyl-Tyr1, N-methyl-Arg7, v-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 κ-opioid agonist effects in vivo in rodents. Objective: In the present studies, we investigated whether systemically administered E-2078 could produce κ-agonist effects in rhesus monkeys, in tests of antinociception, diuresis and ethylketocyclazocine (EKC) discrimination. Methods: E-2078 (0.32-18 mg/kg, SC, IM or IV) was tested in the warm water (50°, 55°C) tail withdrawal assay of thermal antinociception. The diuretic effects of E-2078 (0.0561.8 mg/kg, SC) were also compared to those of the κ-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 κ- or μ-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 κ-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 κ-receptor mediated effects in rhesus monkeys, but its profile of action is not identical to non- peptidic κ-agonists following all routes of administration, or across all experimental situations.
AB - Rationale: E-2078 ([N-methyl-Tyr1, N-methyl-Arg7, v-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 κ-opioid agonist effects in vivo in rodents. Objective: In the present studies, we investigated whether systemically administered E-2078 could produce κ-agonist effects in rhesus monkeys, in tests of antinociception, diuresis and ethylketocyclazocine (EKC) discrimination. Methods: E-2078 (0.32-18 mg/kg, SC, IM or IV) was tested in the warm water (50°, 55°C) tail withdrawal assay of thermal antinociception. The diuretic effects of E-2078 (0.0561.8 mg/kg, SC) were also compared to those of the κ-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 κ- or μ-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 κ-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 κ-receptor mediated effects in rhesus monkeys, but its profile of action is not identical to non- peptidic κ-agonists following all routes of administration, or across all experimental situations.
KW - Antinociception
KW - Diuresis
KW - Macaca mulatta
KW - κ-Opioid receptors
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U2 - 10.1007/s002130050935
DO - 10.1007/s002130050935
M3 - Article
C2 - 10326782
AN - SCOPUS:0032894930
VL - 143
SP - 190
EP - 196
JO - Psychopharmacology
JF - Psychopharmacology
SN - 0033-3158
IS - 2
ER -