Cyclo(Gly-Gln) inhibits the cardiorespiratory depression produced by beta-endorphin and morphine

Glycyl-L-glutamine (Gly-Gln; beta-endorphin 30-31) is an endogenous dipeptide that is synthesized through the post-translational processing of beta-endorphin. Previously, we showed that Gly-Gln inhibits the hypotension and respiratory depression produced by central beta-endorphin administration. In this study, we tested whether cyclo(Gly-Gln), a non-polar, cyclic Gly-Gln derivative, was similarly effective following intracerebro-ventricular (i.c.v.) or intra-arterial (i.a.) administration to pentobarbital-anesthetized rats pretreated with beta-endorphin (0.5 nmol i.c.v.). Intracerebroventricular cyclo(Gly-Gln) (0.3, 0.6 or 1.0 nmol) injection produced a dose-dependent inhibition of beta-endorphin-induced hypotension, but not bradycardia, with a potency similar to that of Gly-Gln. Cyclo(Gly-Gln) (5 mg/kg) was also effective following i.a. injection and significantly attenuated the fall in arterial pressure elicited by i.c.v. beta-endorphin, consistent with evidence that cyclic dipeptides permeate the blood-brain barrier; i.a. Gly-Gln was ineffective. Intra-arterial cyclo(Gly-Gln) (5 mg/kg) and i.c.v. Gly-Gln (10 nmol) also attenuated the hypotension and respiratory depression induced by morphine (50 or 100 nmol i.c.v.). Cyclo(Gly-Gln) (0.5, 5.0 or 50.0 mg/kg i.a.) had no effect on arterial pressure or heart rate when given alone. These findings indicate that cyclo(Gly-Gln) is a biologically active peptide capable of reversing the cardiorespiratory depression produced by beta-endorphin or morphine.