Retention of heroin and morphine-6 beta-glucuronide analgesia in a new line of mice lacking exon 1 of MOR-1

Morphine produces analgesia by activating mu opioid receptors encoded by th e MOR-1 gene. Although morphine-6 beta-glucuronide (M6G), heroin and 6-acet ylmorphine also are considered mu opioids, recent evidence suggests that th ey act through a distinct receptor mechanism. We examined this question in knockout mice containing disruptions of either the first or second coding e xon of MOR-1. Mice homozygous for either MOR-1 mutation were insensitive to morphine. Heroin, 6-acetylmorphine and M6G still elicited analgesia in the exon-l MOR-1 mutant, which also showed specific M6G binding, whereas M6G a nd 6-acetylmorphine were inactive in the exon-2 MOR-1 mutant. These results provide genetic evidence for a unique receptor site for M6G and heroin ana lgesia.