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.