A highly selective ligand for brain delta opiate receptors, a cyclopropyl(E)Phe(4)-enkephalin analog, suppresses mu receptor-mediated thermal analgesia by morphine.

[D-Ala(2)(2R,3S)-delta(E)Phe(4)Leu(5)]enkephalin (CP-OH) [delta denoting cyclopropyl; superscript E indicating the E-configuration about the cyclopropane ring], a highly selective opioid ligand for delta receptors in rat brain, but not for those in the mouse vas deferens, was examined for in vivo biological activities by intracerebroventricular administration. CP-OH (5-20 micrograms) showed no analgesic activity in the hot plate (51 degrees C) test using rats. However, it suppressed completely the analgesic effects of intraperitoneally administered morphine (3 mg/kg rat) in a dose-dependent manner. CP-OH showed no binding affinity for brain kappa receptors to which dynorphin, an opioid peptide that inhibits morphine analgesia, binds predominantly. These results suggest that, besides the conventional delta receptors which mediate analgesia, the rat brain contains another delta-like receptor which has a modulatory role to attenuate morphine-induced analgesia mediated through the mu receptors, and that this modulatory receptor does not exist in the mouse vas deferens.