Wistar Ottawa Karlsburg W (WOKW) rats and their controls, dark agouti (DA), present different features: in particular, DA rats are lean, while the WOKW are obese and present symptoms of hypertension, dyslipidemia, hyperinsulinemia, and impaired glucose tolerance. The present study tested the hypothesis that these two strains would demonstrate different sensitivity to nociceptin/orphanin FQ (N/OFQ). N/OFQ was injected into the lateral brain ventricle (LBV) of sated DA and WOKW rats, and corticosterone levels in both strains were measured after LBV injection of N/OFQ. LBV N/OFQ injections dose-dependently produced a significant increase in food intake (4 h) in DA rats, but not in WOKW. However, corticosterone levels were increased by N/OFQ to a greater degree in WOKW than in DA rats. Gene sequencing and gene expression of ORL1 receptor and cocaine-amphetamine regulated transcript (Cart) peptide were evaluated to study the difference in N/OFQ-induced feeding behavior in the two strains. WOKW rats had a different amino acid sequence of Cart peptide and a significantly higher expression of Cart in the hypothalamus. The present data show that DA and WOKW rats demonstrate different sensitivity to N/OFQ, and suggest that Cart peptide might be the underlying mechanism of this difference.