Identification and characterization of novel mammalian neuropeptide FF-like peptides that attenuate morphine-induced antinociception

The two mammalian neuropeptides NPFF and NPAF have been shown to have impor tant roles in nociception, anxiety, learning and memory, and cardiovascular reflex. Two receptors (FF1 and FF2) have been molecularly identified for N PFF and NPAF. We have now characterized a novel gene designated NPVF that e ncodes two neuropeptides highly similar to NPFF. NPVF mRNA was detected spe cifically in a region between the dorsomedial and ventromedial hypothalamic nuclei. NPVF-derived peptides displayed higher affinity for FF1 than NPFF- derived peptides, but showed poor agonist activity for FF2. Following intra cerebral ventricular administration, a NPVF-derived peptide blocked morphin e-induced analgesia more potently than NPFF in both acute and inflammatory models of pain. In situ hybridization analysis revealed distinct expression patterns of FF1 and FF2 in the rat central nervous system. FF1 was broadly distributed, with the highest levels found in specific regions of the limb ic system and the brainstem where NPVF-producing neurons were shown to proj ect. FF2, in contrast, was mostly expressed in the spinal cord and some reg ions of the thalamus. These results indicate that the endogenous ligands fo r FF1 and FF2 are NPVF- and NPFF-derived peptides, respectively, and sugges t that the NPVF/FF1 system may be an important part of endogenous anti-opio id mechanism.