Nociceptin and its NOP receptor may play an important role in neuronal systems that process stress-related stimuli. Their importance in the regulation of basal activity of the hypothalamo-pituitary-adrenal (HPA) axis has recently been demonstrated (Leggett et al. 2006,). However the effect of stress on the endogenous nociceptin/NOP system is poorly understood, as is the significance of the NOP receptor in the context of acute stress. We investigated the effects of restraint stress or an inflammatory stimulus (lipopolysaccharide, LPS) on pre-pro-nociceptin (ppNOFQ) and NOP mRNA expression in the rat hypothalamus and hippocampus using RT-PCR. Conscious male Sprague-Dawley rats (200-225 g) were exposed to acute restraint (60 min or homecage control) or an intraperitonneal injection of LPS (250 μg in 0.5 ml/rat or sterile 0.9% saline vehicle). Rats were killed 2 and 4 h following the onset of restraint or 4 h following LPS injection. Total RNA was extracted from hypothalamus and hippocampus using standard protocols. In semi-quantitative RT-PCR assays glyceraldehyde-3-phosphate dehydrogenase (G3PDH) mRNA was an internal control. Data for ppNOFQ and NOP mRNA were normalised by reference to G3PDH mRNA, determined in the same sample (n=6-8 rats/group). A Mann-Whitney U test showed a significant decrease in hippocampal ppNOFQ mRNA in rats killed 2 h after restraint (79 ± 2.4% of homecage control level, *P<0.05). Restraint also caused a significant decrease in expression of hippocampal NOP mRNA 4 h after stress onset (78 ± 5.2% of homecage control level, *P<0.05). In the hypothalamus restraint had little effect on ppNOFQ mRNA level; however, NOP mRNA level was significantly reduced 2 h following stress onset (71 ± 5.3% of homecage control level, *P<0.05). In a separate study, LPS treatment caused a pronounced increase in ppNOFQ mRNA in the hypothalamus 4 h after injection (150 ± 11.1% of saline control level, **p<0.01)), but had no effect on hippocampal ppNOFQ mRNA. Unlike following restraint, NOP mRNA level was not significantly changed in either brain region 4 h after LPS injection. These results suggest that changes in ppNOFQ and NOP receptor gene plasticity may reflect adaptive responses to HPA axis activation. Furthermore, the apparent differential effect of psychological or inflammatory stressors warrants further investigation of the interaction between the limbic nociceptin system and the stress response.