Pharmacological characterization of Endomorphin-1 and Endomorphin-2 in Mouse Brain

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 286; no. 2; pp. 1007 - 1013
• Main Authors: Goldberg, I E, Rossi, G C, Letchworth, S R, Mathis, J P, Ryan-Moro, J, Leventhal, L, Su, W, Emmel, D, Bolan, E A, Pasternak, G W
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics 01.08.1998
• Subjects: Analgesics, Opioid - pharmacokinetics; Analgesics, Opioid - pharmacology; Animals; Autoradiography; Brain - drug effects; CHO Cells; Cricetinae; Gastrointestinal Transit; Injections, Intraventricular; Iodine Radioisotopes; Male; Membranes - drug effects; Membranes - metabolism; Mice; Mice, Inbred Strains; Oligopeptides - pharmacokinetics; Oligopeptides - pharmacology; Pain Measurement - drug effects; Receptors, Opioid, mu - agonists; Receptors, Opioid, mu - drug effects
• ISSN: 0022-3565; 1521-0103

The recently isolated peptides endomorphin-1 and endomorphin-2 have been suggested to be the endogenous ligands for the mu receptor. In traditional opioid receptor binding assays in mouse brain homogenates, both endomorphin-1 and endomorphin-2 competed both mu 1 and mu 2 receptor sites quite potently. Neither compound had appreciable affinity for either delta or kappa 1 receptors, confirming an earlier report. However, the two endomorphins displayed reasonable affinities for kappa 3 binding sites, with K i values between 20 and 30 nM. Both endomorphins competed 3 H-[ d -Ala 2 ,MePhe 4 ,Gly(ol) 5 ] enkephalin binding to MOR-1 receptors expressed in CHO cells with high affinity. In mouse brain homogenates 125 I-endomorphin-1 and 125 I-endomorphin-2 binding was selectively competed by mu ligands. 125 I-Endomorphin-1 and 125 I-endomorphin-2 also labeled MOR-1 receptors expressed in CHO cells with high affinity. Autoradiography of the two 125 I-labeled endomorphins demonstrated regional patterns in the brain similar to those previously observed for mu drugs. Pharmacologically, the endomorphins were potent analgesics. Although they were equipotent supraspinally, endomorphin-1 was more potent spinally. Endomorphin analgesia was effectively blocked by naloxone, as well as the mu -selective antagonists β-funaltrexamine and naloxonazine. In CXBK mice, which are insensitive to supraspinal morphine, neither endomorphin was active, consistent with a mu mechanism of action. Finally, the endomorphins inhibited gastrointestinal transit. In conclusion, these results support the mu selectivity of these agents.