PHARMACOLOGICAL CHARACTERIZATION OF ENDOMORPHIN-1 AND ENDOMORPHIN-2 IN MOUSE-BRAIN

The recently isolated peptides endomorphin-1 and endomorphin-2 have be en suggested to be the endogenous ligands for the mu receptor. In trad itional opioid receptor binding assays in mouse brain homogenates, bot h endomorphin-1 and endomorphin-2 competed both mu(1) and mu(2) recept or sites quite potently. Neither compound had appreciable affinity for either delta or kappa, receptors, confirming an earlier report. Howev er, the two endomorphins displayed reasonable affinities for kappa, bi nding sites, with K-i values between 20 and 30 nM. Both endomorphins c ompeted H-3-[D-Ala(2),MePhe(4),Gly(ol)(5)] enkephalin binding to MOR-I receptors expressed in CHO cells with high affinity. In mouse brain h omogenates I-125-endomorphin-1 and I-125-endomorphin-2 binding was sel ectively competed by mu ligands, I-125-Endomorphin-1 and I-125-endomor phin-2 also labeled MOR-I receptors expressed in CHO cells with high a ffinity. Autoradiography of the two I-125-labeled endomorphins demonst rated regional patterns in the brain similar to those previously obser ved for mu drugs. Pharmacologically, the endomorphins were potent anal gesics. Although they were equipotent supraspinally, endomorphin-1 was more potent spinally. Endomorphin analgesia was effectively blocked b y naloxone, as well as the mu-selective antagonists beta-funaltrexamin e and naloxonazine. In CXBK mice, which are insensitive to supraspinal morphine, neither endomorphin was active, consistent with a mu mechan ism of action. Finally, the endomorphins inhibited gastrointestinal tr ansit. In conclusion, these results support the mu selectivity of thes e agents.