Antagonists of the NOP receptor have antidepressant effects in rodent models, suggesting that the N/OFQ-NOP system may play an important role in affective disorders. Furthermore, multiple lines of experimental evidence link N/OFQ neurotransmission with physiological and behavioral responses to stress. One possibility is that disregulated expression of the N/OFQ peptide neurotransmitter and/or the NOP receptor may participate in the etiology of stress-induced psychopathology. In the present set of experiments, we compared gene expression for prepro-N/OFQ and NOP receptor in groups of rats that were exposed to differing regimens of social defeat stress. Male Long-Evans rats were exposed to no social defeat, a single, acute social defeat or to repeated social defeats with or without an acute defeat on the final day. In situ hybridization was conducted with (35)S-labelled riboprobes aimed at prepro-N/OFQ mRNA or NOP receptor mRNA. Expression was analyzed by quantification of optical density in limbic and extra-limbic forebrain regions. There were no statistically significant changes in prepro-N/OFQ mRNA expression after stress exposure in any of the brain regions analyzed. However, the rats that were exposed to acute social defeat displayed elevations in NOP receptor mRNA expression in the central and basomedial nuclei of the amygdala and in the paraventricular nucleus of the hypothalamus. Additionally, the rats that were acutely stressed after a history of repeated social defeat also displayed elevated levels of NOP receptor mRNA expression in the paraventricular nucleus of the hypothalamus. These results suggest that the N/OFQ-NOP receptor system is affected by acute stress exposure, particularly in limbic regions. This stress-induced upregulation of NOP receptor gene expression further supports the possibility that disregulation of the N/OFQ-NOP system may contribute to behavioral and hormonal disregulation following stress.