Superoxide generation links nociceptin/orphanin FQ (NOC/oFQ) release to impaired N-methyl-D-aspartate cerebrovasodilation after brain injury.
OBJECTIVE
Although activation of the N-methyl-D-aspartate (NMDA) receptor is thought to contribute to altered cerebrovascular regulation after traumatic brain injury, the effects of such injury on the vascular response to NMDA itself has been less well appreciated. The newly described opioid nociceptin/orphanin FQ (NOC/oFQ) elicits pial artery dilation, at least in part, in a prostaglandin-dependent manner and is released into cerebrospinal fluid after fluid percussion brain injury (FPI). Generation of superoxide anion (O(2)(-)) occurs after FPI, and a byproduct of cyclooxygenase metabolism is the generation of O(2)(-). This study was designed to determine whether NOC/oFQ generates O(2)(-), which in turn could link NOC/oFQ release to impaired NMDA-induced pial artery dilation after FPI.


METHODS
Injury of moderate severity (1.9 to 2.1 atm) was produced by the lateral FPI technique in anesthetized newborn pigs equipped with a closed cranial window. Superoxide dismutase-inhibitable nitroblue tetrazolium (NBT) reduction was determined as an index of O(2)(-) generation.


RESULTS
Under non-brain injury conditions, topical NOC/oFQ (10(-)(10) mol/L, the concentration present in cerebrospinal fluid after FPI) increased superoxide dismutase-inhibitable NBT reduction from 1+/-1 to 20+/-3 pmol/mm(2) but had no effect itself on pial artery diameter. Indomethacin (5 mg/kg IV) blunted such NBT reduction (1+/-1 to 6+/-2 pmol/mm(2)), whereas the NOC/oFQ receptor antagonist [F/G] NOC/oFQ (1-13) NH(2) (10(-)(6) mol/L) blocked NBT reduction. [F/G] NOC/oFQ (1-13) NH(2) and indomethacin also blunted the NBT reduction observed after FPI (1+/-1 to 15+/-1 versus 1+/-1 to 4+/-1 versus 1+/-1 to 4+/-1 pmol/mm(2) for sham, NOC/oFQ antagonist, and indomethacin-treated animals, respectively). NMDA (10(-)(8) and 10(-)(6) mol/L)-induced pial artery dilation was reversed to vasoconstriction after FPI, and [F/G] NOC/oFQ (1-13) NH(2) attenuated such vasoconstriction (sham 9+/-1% and 16+/-1% versus FPI -7+/-1% and -12+/-1% versus FPI-[F/G] NOC/oFQ (1-13) NH(2)-pretreated animals -2+/-1% and -3+/-1%). Indomethacin and the free radical scavengers polyethylene glycol superoxide dismutase and catalase also partially restored NMDA-induced vasodilation.


CONCLUSIONS
These data show that NOC/oFQ, in concentrations present in cerebrospinal fluid after FPI, increased O(2)(-) production in a cyclooxygenase-dependent manner and contributes to such production after FPI. These data show that NOC/oFQ contributes to impaired NMDA-induced pial artery dilation after FPI. Therefore, these data suggest that cyclooxygenase-dependent O(2)(-) generation links NOC/oFQ release to impaired NMDA-induced cerebrovasodilation after brain injury.
Departments of Anesthesia and Pharmacology, University of Pennsylvania, Philadelphia 19104, USA.
M
M
Kulkarni
W M
WM
Armstead
D000818:Animals; D000831:Animals, Newborn; D002536:Cerebral Arteries / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology; D002561:Cerebrovascular Disorders / Q000134:cerebrospinal fluid* / Q000188:drug therapy / Q000503:physiopathology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018846:Excitatory Amino Acids / Q000819:agonists*; D005260:Female; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology*; D009580:Nitroblue Tetrazolium / Q000494:pharmacology; D018847:Opioid Peptides / Q000134:cerebrospinal fluid*; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects / Q000378:metabolism; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors / Q000134:cerebrospinal fluid*; D014664:Vasodilation / Q000187:drug effects*; D000097629:Nociceptin
D016861:Cyclooxygenase Inhibitors; D018690:Excitatory Amino Acid Agonists; D018846:Excitatory Amino Acids; D007213:Indomethacin; D016202:N-Methylaspartate; D009580:Nitroblue Tetrazolium; D018847:Opioid Peptides; D011451:Prostaglandin-Endoperoxide Synthases; D013482:Superoxide Dismutase; D000097629:Nociceptin