Kaneko Takeru

Physical dependence liability of dynorphin A analogs in rodents

Abstract 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-Tyr 1 ,N-methyl-Arg 7 ,D-Leu 8 ] dy-norphin-A-(1–8) ethylamide (E-2078) twice daily for up to 7 weeks. Mice that had received repeated [D-Cys 2 ,Cys 5 ,N-methyl-Arg 7 , D-Leu 8 ]dynorphin-A-(1–9) amide displayed jumping behavior after subcutaneous injection of naloxonc. an opioid receptor antagonist. In contrast, the animals that had received repeated E-2078 or [N-methyl-Tyr 1 .Phe 4 (p-NO 2 ),N-methyl-Arg 7 , D-Leu 8 ]dynorphin-A-(1–8) ethylamide displayed very few jumps after naloxonc 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-Tyr 1 ,Phe 4 (p-NO 2 ),N-methyl-Arg 7 ,D-Leu 8 ]dynorphin-A-(1–8) ethylamidc may have little dependence liability and that [D-Cys 2 ,Cys 5 ,N-methyl-Arg 7 ,D-Leu 8 ]dynorphin-A-(1–9) amide can cause physical dependence.