The opioid peptide nociceptin (orphanin FQ) has been implicated in reward, reinforcement and addiction. The current study sought evidence of a role of endogenous nociceptin in nicotine responses by studying nociceptin receptor (NOP) knockout mice. The results were: (1) NOP receptor knockout mice showed enhanced anxiety-like behavior on an elevated plus maze. Whereas nicotine (0.05-0.5 mg/kg) tended to be anxiogenic in wild-type mice, NOP receptor KO mice were resistant to this effect, though interpretation was confounded by their stronger anxiety-like behavior. (2) When presented increasing nicotine concentrations (3-50 microg/ml) in a bottle choice drinking paradigm, there were no genotype-dependent differences in nicotine preference. However, NOP receptor knockout mice consumed more 3 microg/ml nicotine solution when considered in absolute terms. (3) NOP receptor knockout mice showed stronger hypothermic responses to nicotine (1 or 2 mg/kg) administration. (4) There was modest evidence that NOP receptor KO mice showed attenuated behavioral sensitization to a low dose of nicotine (0.05 mg/kg) during repeated daily treatment. (5) NOP receptor knockout mice more rapidly tolerated the sedative effect of nicotine (1 mg/kg), due partially to slightly lower locomotion on first treatment. (6) NOP receptor knockout mice, unlike wild-type mice, showed a significant mecamylamine (2.5 mg/kg) induced conditioned place aversion to nicotine (24 mg/kg/day) withdrawal. These results show that mice lacking the influence of endogenous N/OFQ mice are hypersensitive to nicotine in most measures, showing a role of endogenous nociceptin in modulating or mediating the acute effects of nicotine, and possibly nicotine addiction.