Antagonism of ethanol narcosis by histidyl-proline diketopiperazine

Abstract

THYROTROPIN-RELEASING hormone, pyroglutamyl-histidyl-prolineamide (TRH, Fig. 1) belongs to the class of hypothalamic peptides termed releasing factors¹. Although TRH was originally described as the hormone which stimulates the release of thyrotropin, it has subsequently been shown to be involved in many other biological processes¹. The mechanism by which TRH exhibits this broad range of activities is not clear; it might involve the action of TRH at multiple recognition sites or TRH might serve as a precursor for compounds which are biologically active. Previous studies on TRH metabolism have demonstrated the formation of pyroglutamyl-histidyl-proline (acid TRH, Fig. 1)¹. Attempts to associate biological activity with this compound have been uniformly negative, providing no support for the precursor hypothesis^2,3. We show here that, in addition to acid TRH, TRH is also metabolised to histidylproline diketopiperazine (His-Pro, Fig. 1)^4,5. This cyclic dipeptide is substantially more potent than TRH in reducing ethanol-induced sleep in rats⁶. These data indicate that TRH metabolism plays a part in its biological effects.