The neuropeptide orphanin FQ (also known as nociceptin; OFQ͞N) has been implicated in modulating stress-related behavior. OFQ͞N was demonstrated to reverse stress-induced analgesia and possess anxiolytic-like activity after central administration. To further study physiological functions of OFQ͞N, we have generated OFQ͞N-deficient mice by targeted disruption of the OFQ͞N gene. Homozygous mice display increased anxiety-like behavior when exposed to a novel and threatening environment. OFQ͞N-null mice show elevated basal pain threshold but develop normal stressinduced analgesia. Interestingly, these mice show impaired adaptation to repeated stress when compared with wild-type mice, whereas their performance in spatial learning remained unaffected. Basal and poststress plasma corticosterone levels were found to be elevated in OFQ͞N-deficient animals. Thus, OFQ͞N appears to be crucially involved in the neurobiological regulation of stress-coping behavior and fear.Physiological responses to stress include changes in behavior, sensory processing, and endocrine and metabolic homeostasis that are positively or negatively regulated by a multitude of neuronal pathways (1-7). An increased vulnerability to stress is discussed as a major contributing factor in human psychiatric disorders, such as anxiety and depression (8). At the hormonal level, these diseases often are accompanied by an overactivity of the hypothalamic-pituitary-adrenal (HPA) system (9, 10). However, the physiological basis for this dysregulation remains unclear. The recently discovered neuropeptide OFQ͞N (11, 12) appears to alleviate behavioral and sensory responses to stress, such as fear responses (13) or analgesia (14). Further studies on the functions of OFQ͞N in the neuronal processing of stress are hampered by the unavailability of a selective and high-affinity antagonist. Therefore, we took a genetic approach and generated OFQ͞N-deficient mice that were analyzed for phenotypical differences in stress-related responses. The absence of OFQ͞N increases stress-related variables of behavior and sensory processing, such as anxiety and nociceptive threshold, in genetically engineered mice. Mice lacking OFQ͞N show elevated glucocorticoid levels, indicating a chronic activation of the HPA system that might contribute to the observed phenotypic changes. In addition, an important function of OFQ͞N for stress adaptation was discovered, because OFQ͞N-deficient mice failed to habituate after repeated exposure to stressful stimuli. These results suggest that the OFQ͞N system may have important functions in the neural circuitry of stress processing.