PHARMACOLOGICAL CHARACTERIZATION OF ORPHANIN FQ NOCICEPTIN AND ITS FRAGMENTS/

The cloning of a fourth member of the opioid receptor family has led t o 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 anta gonists. This is followed in the next 30 min by loss of hyperalgesia a nd the appearance of analgesia in the tailflick assay which is readily reversed by opioid antagonists. However, the very poor affinity of OF Q/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 med iated through typical opioid receptors. Blockade of the antiopioid sig ma system by haloperidol enhances the analgesic potency of OFQ/N of mo re than 100-fold. This effect is pronounced in BALB-C and Swiss-Webste r mice. Although OFQ/N alone has little analgesic activity in these mi ce, the blockade of sigma systems with haloperidol uncovers a robust a nalgesic 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 action s are reversed by the opioid antagonist diprenorphine despite very poo r affinities of both peptides against [I-125]OFQ/N binding and all the opioid receptors. In antisense studies, a probe targeting the first c oding exon of KOR-3 eliminates OFQ/N hyperalgesia, but not OFQ/N analg esia. Conversely, antisense probes based on the second and third codin g exons are inactive against OFQ/N hyperalgesia but readily reverse ka ppa(3) opioid analgesia. These results suggest that OFQ/N elicits both analgesia and hyperalgesia through pharmacologically distinct recepto rs that do not correspond to traditional opioid receptors.