ANTISENSE OLIGONUCLEOTIDES TO HUMAN SQA-NEUROPEPTIDE FF DECREASE MORPHINE-TOLERANCE AND DEPENDENCE IN MICE

Neuropeptide FF (Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-NH2) is able to modul ate opioid analgesia. Intracerebroventricular treatment for 5 days wit h antisense-oligodeoxynucleotides complementary to the sequence of hum an SQA-neuropeptide FF (Ser-Gln-Ala-Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-NH 2) precursor gene or by mismatch-oligodeoxynucleotides did not change the antinociceptive activity of morphine in the mouse tail flick test. In contrast, antisense- but not mismatch-oligodeoxynucleotides attenu ated significantly the tolerance to the analgesic activity of morphine and the withdrawal syndrome precipitated by naloxone in morphine-trea ted mice. These treatments with oligodeoxynucleotides did not modify n europeptide FF-immunoreactivity content in whole brain but repeated in jections of an agonist of neuropeptide FF receptors increased the inte nsity of morphine tolerance. These results demonstrate the important r ole of neuropeptide FF in opioid pharmacodependence. (C) 1998 Elsevier Science B.V. All rights reserved.