FUNCTIONAL ANTAGONISM OF MU-OPIOID, DELTA-OPIOID AND KAPPA-OPIOID ANTINOCICEPTION BY ORPHANIN FQ

Orphanin FQ (OFQ) is the recently isolated endogenous ligand for the o rphan opioid-like receptor, LC132. Initial reports suggested that OFQ increased pain sensitivity when injected intracerebroventricularly (i. c.v.) in mice. However, we have recently demonstrated that OFQ is inst ead an anti-opioid peptide that reverses morphine- and opioid-mediated stress-induced antinociception. Morphine binds to multiple opioid rec eptor types (mu delta, and kappa). The present study was designed to e xamine specific interactions of OFQ with antinociception mediated by e ach receptor type. To this end, mice were administered i.c.v. cocktail s containing either vehicle or OFQ (10 nmol) and a mu-specific ([D-Ala (2), N-Me-Phe(4)-Gly-ol]enkephalin; DAMGO; 0-0.1 nmol), delta-specific ([D-Pen(2), D-Pen(5)]enkephalin; DPDPE; 0-50 nmol), or kappa-specific (U-50,488H; 0-1000 nmol) agonist. As we have shown previously, OFQ al one had no effect on nociceptive sensitivity. OFQ was, however, able t o completely block supraspinal antinociception produced by all three r eceptor type-selective agonists. We conclude, therefore, that OFQ func tionally antagonizes mu (and (opioid receptors, and may play a general role in opioid modulation.