Pharmacological characterization of orphanin FQ/nociceptin and its fragments

The cloning of a fourth member of the opioid receptor family has led to the discovery of a new neuropeptide termed orphanin FQ or nociceptin (OFQ/N). Studies in CD-I mice confirm the ability of OFQ/N to rapidly induce hyperalgesia within 15 min which is insensitive to opioid antagonists. This is followed in the next 30 min by loss of hyperalgesia and the appearance of analgesia in the tailflick assay which is readily reversed by opioid antagonists. However, the very poor affinity of OFQ/N for all the traditional opioid receptors and the insensitivity of OFQ/N analgesia to antisense oligodeoxynucleotides active against MOR-I, DOR-I or KOR-1 sequences that selectively block mu, delta or kappa, analgesia, respectively, make it unlikely that OFQ/N analgesia is mediated through typical opioid receptors. Blockade of the antiopioid sigma system by haloperidol enhances the analgesic potency of OFQ/N of more than 100-fold. This effect is pronounced in BALB-C and Swiss-Webster mice. Although OFQ/N alone has little analgesic activity in these mice, the blockade of sigma systems with haloperidol uncovers a robust analgesic response in both strains. Two shorter OFQ/N fragments, OFQ/N(1-7) and OFQ/N(I-II), also are analgesic in CD-1 mice and their actions are reversed by the opioid antagonist diprenorphine despite very poor affinities of both peptides against [I-125]OFQ/N binding and all the opioid receptors. In antisense studies, a probe targeting the first coding exon of KOR-3 eliminates OFQ/N hyperalgesia, but not OFQ/N analgesia. Conversely, antisense probes based on the second and third coding exons are inactive against OFQ/N hyperalgesia but readily reverse kappa(3) opioid analgesia. These results suggest that OFQ/N elicits both analgesia and hyperalgesia through pharmacologically distinct receptors that do not correspond to traditional opioid receptors.