Regulation of nociceptin/orphanin FQ neurotransmission in conjunction with peripheral inflammation and hyperalgesia was explored, using receptor autoradiography. Binding of [3H]nociceptin was quantified in spinal segment L4 of rats at 2, 4 and 8 days following injection of complete Freund's adjuvant (CFA) into one hind-paw. Densitometric analysis of autoradiograms showed that [3H]nociceptin binding increased in medial and lateral laminae I-II bilaterally 4 days following injection of CFA compared to untreated rats; no change in binding occurred in lamina X at the times examined. Biochemical studies confirmed that the specific binding of [3H]nociceptin to sections of rat brain was consistent with the binding characteristics of the nociceptin receptor. These results suggest that spinal nociceptin receptors are upregulated during hyperalgesia. This response may enhance endogenous mechanisms of antinociception to attenuate the hyperalgesia induced by CFA.