PROLYL-LEUCYL-GLYCINAMIDE, CYCLO(LEUCYLGLYCINE), AND DERIVATIVES BLOCK DEVELOPMENT OF PHYSICAL-DEPENDENCE ON MORPHINE IN MICE

Pro-Leu-Gly-NH2 (MIF) and several structural analogues, all injected in 50-μg doses daily in mice receiving morphine chronically, were found to prevent development of physical dependence as measured by changes in body temperature associated with naloxone-induced withdrawal. Dose-response studies, using again a protocol of daily injections of peptide at 50, 5, 0.5, 0.05, or 0.005 μg per mouse revealed MIF and cyclo(Leu-Gly) to be the most potent peptides and to be effective in blocking physical dependence to morphine at a dose as low as 0.5 and 0.05 μg per mouse, respectively. The benzyloxycarbonyl derivatives of MIF, Pro-Leu, and Pro-D-Leu exhibited significant activities down to a dose of 5 μg of peptide per mouse.