AN ANTISENSE OLIGODEOXYNUCLEOTIDE TO THE DELTA-OPIOID RECEPTOR (DOR-1) INHIBITS MORPHINE-TOLERANCE AND ACUTE DEPENDENCE IN MICE

Pharmacological data from several laboratories support a modulatory ro le for the delta opioid receptor in morphine analgesia, tolerance, and physical dependence. We examined the role of the delta opioid recepto r in these processes using an in vivo antisense strategy in mice. Intr acerebroventricular administration of a 20mer antisense or a mismatch control oligodeoxynucleotide (ODN) targeting the mRNA of the cloned de lta opioid receptor (DOR-1) for 3 days did not affect baseline nocicep tive thresholds or morphine analgesia compared to untreated or saline- treated mice, However, dose-response studies indicate that the inducti on of morphine tolerance following 3 days of chronic morphine administ ration was blocked in antisense but not mismatch ODN or saline-treated mice. Antisense ODN treatment also blocked the development of acute m orphine dependence, whereas similar protection was not afforded to mic e treated with saline or mismatch ODN. This study demonstrates the rel evance of the cloned DOR-1 in morphine tolerance and dependence and pr ovides new evidence for a modulatory role of the delta opioid receptor using this novel approach.