The hypothalamo-pituitary-adrenal (HPA) axis activity of Lewis rats has been reported to be hyporesponsive to immune challenge, and nitric oxide (NO) has been demonstrated to be involved in the regulation of the HPA axis during the response to immune challenge. The present study investigates the effect of systemic injection of lipopolysaccharide (LPS) on NO production within the paraventricular nucleus (PVN) of immature female Fisher-344 (F344) and Lew/N rats (Lew/N), to clarify the pathophysiological role of NO in the dysregulation of the HPA axis in Lewis/N. Intraperitoneal injection of 25 mg/kg LPS significantly increased neuronal NO synthase (nNOS) mRNA expression in the PVN of F344 rats, but did not change nNOS mRNA levels in the PVN of Lew/N rats. CRF mRNA levels in the PVN significantly increased in response to LPS injection only in F344 rats. In contrast, inducible NOS (iNOS) mRNA increased similarly in both strains. These results demonstrated a defect of up-regulation of nNOS gene expression in the PVN of Lew/N rats following immune challenge. The defect appears to be associated with the dysfunction of the HPA axis in this strain. An increase in iNOS mRNA may partially restore NO production in the PVN.