Physical dependence liability of dynorphin A analogs in rodents.
To assess the physical dependence liability of dynorphin A analogs, mice were given repeated injections of various dynorphin A analogs twice daily for 5 days, and rats were given repeated administration of [N-methyl-Tyr1,N-methyl-Arg7,D-Leu8]dynorphin-A-(1-8) ethylamide (E-2078) twice daily for up to 7 weeks. Mice that had received repeated [D-Cys2,Cys5,N-methyl-Arg7,D-Leu8]dynorphin-A-(1-9) amide displayed jumping behavior after subcutaneous injection of naloxone, an opioid receptor antagonist. In contrast, the animals that had received repeated E-2078 or [N-methyl-Tyr1,Phe4(p-NO2),N-methyl-Arg7,D-Leu8]dynorphin-A-(1-8) ethylamide displayed very few jumps after naloxone administration. Rats that had received repeated E-2078 administration did not display withdrawal signs, such as weight loss, after either abrupt withdrawal or naloxone administration. These results indicate that E-2078 and [N-methyl-Tyr1,Phe4(p-NO2),N-methyl-Arg7,D-Leu8]dynorphin-A-(1-8) ethylamide may have little dependence liability and that [D-Cys2,Cys5,N-methyl-Arg7,D-Leu8]dynorphin-A-(1-9) amide can cause physical dependence.
Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan.
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T
Nakazawa
T
T
Kaneko
H
H
Yoshino
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S
Tachibana
M
M
Goto
T
T
Taki
K
K
Yamatsu
D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D004399:Dynorphins / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology*; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009270:Naloxone / Q000494:pharmacology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013375:Substance Withdrawal Syndrome / Q000523:psychology; D019966:Substance-Related Disorders / Q000523:psychology*
D000700:Analgesics; D010446:Peptide Fragments; C061285:E 2078; C067204:dynorphin A amide (1-9), Cys(2)-Cys(5)-MeArg(7)-Leu(8)-; C073463:dynorphin A ethylamide (1-8), N-methyl-Tyr(1)-4-nitro-Phe(4)-N-methyl-Arg(7)-Leu(8)-; D009270:Naloxone; D004399:Dynorphins