Only tyrosine-containing metabolites of [Leu]enkephalin impair active avoidance conditioning in mice

The effects of the enkephalin metabolites, Tyr, des-Tyr-[Leu]enkephalin (GGFL), and Tyr-Gly-Gly (YGG), on acquisition of an active avoidance task following their IP administration to mice were determined. Neither free Tyr (3.9-390.0 micrograms/kg) nor GGFL (7.1-710.0 micrograms/kg) altered acquisition of the avoidance response. In contrast, 53, but not 16 micrograms/kg, of YGG significantly impaired response acquisition. A 390.0, but not 39.0 micrograms/kg, dose of Tyr decreased locomotor activity levels measured in an open field. Together with previous findings that the enkephalin metabolites Tyr-Gly and Tyr-Gly-Gly-Phe also impair avoidance acquisition, these data indicate that the dipeptide Tyr-Gly is the minimum sequence needed to intefere with acquisition of an active avoidance response. Because the various enkephalin metabolites do not bind to opioid receptors, it is likely that their effects on avoidance acquisition represent a separate class of pharmacological agents whose effects are mediated by a nonopioid receptor mechanism. These results are important to the interpretation of behavioral studies involving peripheral administration of the opioid peptide, [Leu]enkephalin (LE).