Nociceptin/orphanin FQ metabolism and bioactive metabolites.
The endogenous ligand for the orphan NOR receptor (earlier named ORL1) was recently discovered. This ligand, nociceptin/orphanin FQ is involved in a number of pharmacological actions in the CNS, including modulation of pain and cognition. However, its specific physiological role remains to be determined. Two major pathways of metabolism have been identified; the action of aminopeptidase(s) that prominently occurs in plasma, and endopeptidase activity that successively generates the N-terminal 1-13 and 1-9 fragments. Both pathways result in fragments that are inactive at the NOR receptor. However, short N-terminal fragments appear to be active in blocking the release of substance P from primary afferent C-fiber terminals in the dorsal spinal cord. The same endopeptidase(s) may also be involved in the fragmentation of dynorphin A since the inhibitor profile is similar. Enzyme activity is upregulated by morphine using either peptide as substrate that may lead to pharmacological interactions.
Terenius
L
L
Department of Clinical Neuroscience, Experimental Alcohol and Drug Addiction Research, Karolinska Institutet, CMM L8:01, Karolinska Hospital, S-171 76, Stockholm, Sweden. lars.terenius@cmm.ki.se
Sandin
J
J
Sakurada
T
T
D000595:Amino Acid Sequence; D000626:Aminopeptidases / Q000097:blood; D000818:Animals; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D004399:Dynorphins / Q000378:metabolism; D006801:Humans; D008024:Ligands; D051379:Mice; D008969:Molecular Sequence Data; D018847:Opioid Peptides / Q000097:blood / Q000737:chemistry / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism; D011498:Protein Precursors / Q000378:metabolism; D051381:Rats; D011957:Receptors, Opioid / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014665:Vasodilator Agents / Q000097:blood / Q000737:chemistry / Q000378:metabolism; D000094942:Nociceptin Receptor; D000097629:Nociceptin
D000626:Aminopeptidases; D004399:Dynorphins; D008024:Ligands; D018847:Opioid Peptides; D010455:Peptides; D011498:Protein Precursors; D011957:Receptors, Opioid; D014665:Vasodilator Agents; D000094942:Nociceptin Receptor; D000097629:Nociceptin; C119224:pronociceptin