It has been hypothesized that morphine tolerance and dependence in mice following chronic exposure may reflect increased compensatory activity of antiopioid systems. The endogenous peptide nociceptin/orphanin FQ has been shown to have anti-opioid effects, for example antagonizing morphine analgesia. Moreover, chronic morphine administration increases synthesis of the peptide, and morphine tolerance and dependence can be attenuated or reversed by antagonists and agonists of the nociceptin/orphanin FQ receptor, respectively. The present study seeks to confirm a role for nociceptin/orphanin FQ in opioid tolerance and dependence by comparing morphine ED₅₀ values and naloxone-precipitated withdrawal jumping in mice homozygous (knock-out) and heterozygous for a null mutation of the Npnc1 gene encoding the nociceptin/orphanin FQ propeptide, and their wild type littermates, following chronic morphine exposure. Relative to morphine-naive control mice, significant rightward shifts in the morphine dose-response curve, resulting in increased morphine ED₅₀ values (approximately two to three-fold), was observed for all genotypes following three days of repeated systemic morphine injections. However, no differences between genotypes in the magnitude of tolerance were observed. In contrast, knock-out mice displayed significantly increased naloxone-precipitated withdrawal jumping relative to heterozygous and wild-type mice following implantation with a morphine pellet (25mg) for 72h. Use of nociception/orphaninFQ transgenic knock-out mice thus demonstrate the differential involvement of nociceptin/orphanin FQ in morphine tolerance and dependence.