Morphine tolerance and dependence in nociceptin/orphanin FQ transgenic knock-out mice

It has been hypothesized that morphine tolerance and dependence in mice fol lowing chronic exposure may reflect increased compensatory activity of anti opioid systems. The endogenous peptide nociceptin/orphanin FQ has been show n to have anti-opioid effects, for example antagonizing morphine analgesia. Moreover, chronic morphine administration increases synthesis of the pepti de, and morphine tolerance and dependence can be attenuated or reversed by antagonists and agonists of the nociceptin/orphanin FQ receptor, respective ly. The present study seeks to confirm a role for nociceptin/orphanin FQ in opioid tolerance and dependence by comparing morphine ED50, values and nal oxone-precipitated withdrawal jumping in mice homozygous (knock-out) and he terozygous for a null mutation of the Npnc1 gene encoding the nociceptin/or phanin FQ propeptide, and their wild type littermates, following chronic mo rphine exposure. Relative to morphine-naive control mice, significant rightward shifts in th e morphine dose-response curve, resulting in increased morphine ED50 values (approximately two to three-fold), was observed Tot all genotypes followin g three days of repeated systemic morphine injections. However, no differen ces between genotypes in the magnitude of tolerance were observed. In contr ast, knock-out mice displayed significantly increased naloxone-precipitated withdrawal jumping relative to heterozygous and wild-type mice following i mplantation with a morphine pellet (25 mg) for 72 h. Use of nociception/orphaninFQ transgenic knock-out mice thus demonstrate th e differential involvement of nociceptin/orphanin FQ in morphine tolerance and dependence. (C) 2001 IBRO. Published by Elsevier Science Ltd. All right s reserved.