Rationale: Orphanin FQ/nociceptin (OFQ/N), the endogenous ligand of the opioid receptor-like (ORL-1) receptor, shows similarities to dynorphin A (1-17) in structure and functions. Dynorphin and other kappa opioid receptor agonists have been shown to block cocaine sensitization. Objective: The present study was designed to examine the ability of OFQ/N to block cocaine-induced behavioral sensitization. Methods: Rats were habituated to testing chambers for 1 h, injected with artificial cerebrospinal fluid (aCSF) or OFQ/N (15 nmol) followed by saline or cocaine (20 mg/kg) and locomotor activity was measured for a further 1 h. Rats were treated similarly for the next 2 days except the dose of OFQ/N was doubled on each subsequent day. Rats were then challenged with cocaine (7.5 mg/kg) in the absence of OFQ/N on day 8. The specificity of OFQ/N's action was examined in the presence of J-113397 (30 nmol), an ORL-1 receptor antagonist. The ability of OFQ/N to block the context-independent component of cocaine sensitization was also tested wherein rats were treated in their home cages on days 1-3. Finally, the effect of intra-VTA OFQ/N administration on cocaine sensitization was examined. Results: Sensitization did not develop in rats repeatedly treated with OFQ/N, via either route of administration, prior to cocaine administration on days 1-3. The inhibitory effect of OFQ/N was not dependent on context and was blocked by pretreatment with J-113397. Conclusion: Our results indicate that OFQ/N blocks cocaine-induced behavioral sensitization through activation of the ORL-1 receptor and that the VTA may be one of the substrates for this action of OFQ/N.