The neuropeptide orphanin FQ/nociceptin (OFQ/N) has been shown to counteract several effects of endogenous and exogenous opioids, and it has been proposed as an opioid-modulating agent involved in the development of morphine tolerance and dependence. However, conflicting results have been obtained from animal models using different protocols to induce morphine tolerance. Here, we report that both genetic and pharmacological blockade of OFQ/N signaling can effectively prevent development of morphine tolerance. OFQ/N knockout mice injected daily with low doses of morphine (10 mg/kg) fail to develop tolerance even after 3 weeks of treatment, whereas their wild-type litter mates show profound tolerance starting after 10 days. Likewise, coadministration of morphine together with the synthetic N/OFQ peptide antagonist, J-113397 (1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one), is able to block tolerance development in normal mice. These data indicate that release of endogenous OFQ/N after morphine administration might produce a gradual decline of analgesic potency, i.e., tolerance. Interestingly, tolerant and nontolerant groups of mice receiving repeated daily low morphine doses did not differ in their withdrawal behavior after naloxone injection. In contrast, mice receiving escalating doses of morphine developed analgesic tolerance independent of their OFQ/N genotype, whereas withdrawal symptoms were attenuated in OFQ/N-deficient animals. These results indicate that the endogenous OFQ/N system is differentially involved in morphine tolerance development and establishment of opiate dependence, depending on the specific morphine dosage regimen. Furthermore, it suggests that OFQ/N antagonists could provide a novel therapeutic strategy to attenuate morphine tolerance development.Morphine and related opioids are still the most powerful and widely used drugs in the clinical management of severe pain. However, long-term use of opioids is limited by the development of tolerance and dependence. Tolerance is a gradual loss in drug effect upon repeated administration, requiring increasing doses to maintain analgesia. Dependence reflects a change in neuronal homeostasis that results in withdrawal symptoms upon cessation of drug administration. Studies on knockout mice have shown that activation of -opioid (MOP) receptors is responsible for morphine-induced analgesia, tolerance, and dependence (Matthes et al., 1996). However, the mechanisms of adaptive changes downstream of MOP activation are still poorly understood. Therefore, elucidating the molecular and neurobiological mechanisms of opioid tolerance has been compared with the "search for the Holy Grail" (Kieffer and Evans, 2002).The search for physiological correlates of opioid tolerance has indicated a number of protein kinases, ion channels, second messenger-synthesizing enzymes, glutamate receptors, cytoskeletal proteins, and neurotrophic factors to be involved (Nestler, 1997;Williams et al., 2001). In addition,...

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