Plasma uptake and in vivo metabolism of [Leu]enkephalin following its intraperitoneal administration to rats

To understand better how Leu]enkephalin (LE) acts to modulate learning and memory in rats, the plasma uptake, disappearance, and metabolism of LE were investigated following its intraperitoneal administration. Concentrations of 3H]-LE and its radioactive metabolites were determined by thin layer chromatography in plasma samples withdrawn from rats at various times after injection of peptide. As measured in rats receiving an IP injection of a dose of LE (3 micrograms/kg) that impairs active avoidance conditioning, the LE was very rapidly metabolized, with greater than 95% of plasma 3H] in the form of metabolites by 1 min after injection. Despite this rapid metabolism, low but measurable quantities of intact LE were detectable in plasma at all sampling times. Consistent with a greater potency of D-Ala2-D-Leu5]enkephalin (DADLE) than of LE in modulating avoidance conditioning, DADLE was less rapidly metabolized than was LE following its IP administration. The metabolism of DADLE and LE in vivo was more rapid than it was in plasma in vitro, suggesting a role for membrane bound enzymes in the metabolism of IP-administered enkephalins. The data demonstrate that, despite a rapid hydrolysis of LE in vivo, sufficient LE is present in plasma following IP administration of a behaviorally active dose to support a role of circulating intact LE in the modulation of avoidance conditioning.