Previous work reveals that orphanin FQ/nociceptin (OFQ/N) administered supraspinally produces an initial hyperalgesic response followed by analgesia. Spinally, OFQ/N elicits a rapidly appearing, naltrexone-reversible, dose-dependent analgesia in the tailflick assay without any indication of hyperalgesia. Two OFQ/N fragments, OFQ/N (1-7) and OFQ/N (1-11), are active, but far weaker. Blockade of sigma receptors with haloperidol enhances the analgesic potency of spinal OFQ/N, OFQ/N (1-7) and OFQ/N (1-11), but not as dramatically as supraspinal OFQ. Antisense probes targeting the second and third coding exons, but not the first exon, of the cloned mouse OFQ/N receptor (KOR-3) partially block OFQ/N analgesia.