Cross-tolerance studies distinguish morphine- and metkephamid-induced analgesia

In vitro data demonstrate that metkephamid (LY127623), an analog of methionine enkephalin, has a high affinity for the delta opioid receptor, as well as the mu-receptor. Data generated utilizing two in vivo measures of receptor selectivity, furthermore, indicate that metkephamid's analgesic activity is in part mediated by delta opioid receptors. The analgesic activity of metkephamid was investigated in the mouse writhing assay following chronic treatment with morphine, the prototypic mu agonist. Mice were treated chronically with increasing doses of morphine or saline and the inhibition of writhing measured in response to an acute injection of morphine or metkephamid. The dose response curve for morphine was shifted to the right 3- to 4-fold following chronic administration of morphine. In contrast, no such shift in the dose response curve for metkephamid was observed in these morphine-tolerant mice. In a further series of tests, a 50 mg/kg dose of naloxazone 20 hr prior to the assessment of morphine or metkephamid analgesia in the mouse hot plate test substantially shifted the dose-response curve for morphine to the right, while leaving the dose-response curve for metkephamid unchanged. These results suggest that delta-receptor activation contributes to the analgesia produced by metkephamid.