title: Relationship between NOC/oFQ, dynorphin, and COX-2 activation in impaired NMDA cerebrovasodilation after brain injury.
abstract: Previous studies have observed that the recently described endogenous opioid, nociceptin/orphanin FQ (NOC/oFQ), contributes to impairment of N-methyl-D-aspartate (NMDA)-induced cerebrovasodilation following fluid percussion brain injury (FPI) via a cyclooxygenase (COX)-dependent generation of superoxide anion (O(2)(-)). This study was designed to investigate the relationship between NOC/oFQ, another opioid, dynorphin, and activation of the COX-2 isoform of the enzyme in such impaired dilation to NMDA after FPI in piglets equipped with a closed cranial window. Superoxide dismutase (SOD)-inhibitable nitroblue tetrazolium (NBT) reduction was determined as an index of O(-)(2) generation. Under non-brain injury conditions, NOC/oFQ (10(-10) M), the CSF concentration observed after FPI, increased CSF dynorphin, while the NOC/oFQ antagonist [F/G] NOC/oFQ (1-13) NH(2) attenuated the stimulated release of dynorphin following FPI (34 +/- 3 and 97 +/- 6 vs. 36 +/- 3 and 68 +/- 8 pg/mol for CSF dynorphin before and after FPI in untreated and NOC/oFQ antagonist-pretreated animals). FPI increased SOD-inhibitable NBT reduction, but pretreatment with norbinaltorphimine, a dynorphin antagonist, or NS398, a COX-2 inhibitor, blunted such reduction (1 +/- 1 vs. 19 +/- 3 vs. 4 +/- 1 vs. 4 +/- 1 pmol/mm(2) for control, FPI, FPI-norbinaltorphimine and FPI-NS398, respectively). Under non-brain injury conditions, dynorphin, in a concentration observed in CSF after FPI, also increased SOD-inhibitable NBT reduction, which was blunted by NS398. NMDA-induced pial artery dilation was reversed to vasoconstriction following FPI, but pretreatment with norbinaltorphimine or NS398 partially protected such responses (9 +/- 1 and 16 +/- 1, control; - 8 +/- 1 and - 13 +/- 2, FPI; 6 +/- 1 and 12 +/- 1% FPI-norbinaltorphimine for NMDA 10(-8), 10(-6) M, respectively). These data show that NOC/oFQ modulates the CSF release of dynorphin after FPI. These data also show that dynorphin contributes to O(2)(-) generation after FPI via COX-2 activation. These data additionally indicate that dynorphin and COX-2 activation contribute to impairment of NMDA pial artery dilation after FPI. Finally, these data suggest that NOC/oFQ impairs NMDA dilation postinsult via the sequential release of dynorphin, activation of COX-2, and generation of O(2)(-).
authors.affiliation: Department of Anesthesia, University of Pennsylvania, Philadelphia, Pennsylvania, 19104, USA.
authors.forename: Miriam
authors.initials: M
authors.lastname: Kulkarni
authors.forename: William M
authors.initials: WM
authors.lastname: Armstead
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001930:Brain Injuries / Q000201:enzymology / Q000503:physiopathology*; D051546:Cyclooxygenase 2; D004399:Dynorphins / Q000037:antagonists & inhibitors / Q000134:cerebrospinal fluid / Q000378:metabolism* / Q000494:pharmacology; D004789:Enzyme Activation; D005260:Female; D018698:Glutamic Acid / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology; D009578:Nitrobenzenes / Q000494:pharmacology; D018847:Opioid Peptides / Q000134:cerebrospinal fluid / Q000378:metabolism*; D010841:Pia Mater / Q000098:blood supply; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism; D013552:Swine; D014664:Vasodilation / Q000187:drug effects*; D000097629:Nociceptin
chemical_list: D051546:Cyclooxygenase 2; D004399:Dynorphins; D018698:Glutamic Acid; D007213:Indomethacin; D007527:Isoenzymes; D016202:N-Methylaspartate; D009271:Naltrexone; D009578:Nitrobenzenes; D018847:Opioid Peptides; D011451:Prostaglandin-Endoperoxide Synthases; D013449:Sulfonamides; D013481:Superoxides; D000097629:Nociceptin; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; C051844:norbinaltorphimine