title: Role of altered cyclooxygenase metabolism in impaired cerebrovasodilation to nociceptin/orphanin FQ following brain injury.
abstract: This study was designed to determine the role of altered cyclooxygenase metabolism in impaired pial artery dilation to the newly described opioid, nociceptin orphanin FQ (NOC/oFQ), following fluid percussion brain injury (FPI) in newborn pigs equipped with a closed cranial window. Recent studies show that NOC/oFQ contributes to oxygen free radical generation observed post FPI in a cyclooxygenase dependent manner. FPI was produced by using a pendulum to strike a piston on a saline filled cylinder that was fluid coupled to the brain via a hollow screw inserted through the cranium. NOC/oFQ (10(-8), 10(-6) M) modestly increased cerebrospinal fluid (CSF) 6-keto-PGF(1alpha), and thromboxane B(2) (TXB(2)), the stable breakdown products of PGI(2) and TXA(2), in sham animals (1148 +/- 83 to 1681 +/- 114 and 308 +/- 16 to 424 +/- 21 pg/ml for control and 10(-6) M NOC/oFQ 6-keto-PGF(1alpha), and TXB(2), respectively). In 1-h post FPI animals, basal levels of 6-keto-PGF(1alpha), and TXB(2) were elevated. NOC/oFQ stimulated release of 6-keto-PGF(1alpha), was blocked while such release of TXB(2) was enhanced (720 +/- 63 to 1446 +/- 117 pg/ml for control and 10(-6) M NOC/oFQ CSF TXB(2)). NOC/oFQ (10(-8), 10(-6) M) induced pial artery dilation that was reversed to vasoconstriction by FPI while the cyclooxygenase inhibitor indomethacin (5 mg/kg, intravenous) partially restored such vascular responses (8 +/- 1 and 15 +/- 1 vs. -7 +/- 1 and -12 +/- 1 vs. 7 +/- 1 and 12 +/- 1% for 10(-8), 10(-6) M NOC/oFQ in sham, FPI and FPI-Indo pretreated animals). Similar observations were made in FPI animals pretreated with the thromboxane receptor antagonist SQ 29,548 or the free radical scavenger polyethylene glycol superoxide dismutase and catalase. These data indicate that altered NOC/oFQ induced cyclooxygenase metabolism contributes to impairment of dilation to this opioid following FPI.
authors.affiliation: Department of Anesthesia, University of Pennsylvania, Philadelphia, PA, USA. armsteaw@mail.med.upenn.edu
authors.forename: W M
authors.initials: WM
authors.lastname: Armstead
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001769:Blood / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D001930:Brain Injuries / Q000201:enzymology* / Q000503:physiopathology; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002536:Cerebral Arteries / Q000187:drug effects* / Q000201:enzymology; D002560:Cerebrovascular Circulation / Q000187:drug effects* / Q000502:physiology; D004195:Disease Models, Animal; D005231:Fatty Acids, Unsaturated; D005260:Female; D006834:Hydrazines; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D018847:Opioid Peptides / Q000378:metabolism / Q000494:pharmacology*; D010841:Pia Mater / Q000098:blood supply / Q000187:drug effects / Q000201:enzymology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011453:Prostaglandins / Q000378:metabolism; D013482:Superoxide Dismutase / Q000494:pharmacology; D013552:Swine; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology; D000097629:Nociceptin
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D019086:Bridged Bicyclo Compounds, Heterocyclic; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D007213:Indomethacin; D018847:Opioid Peptides; D011451:Prostaglandin-Endoperoxide Synthases; D011453:Prostaglandins; D013482:Superoxide Dismutase; D000097629:Nociceptin; C045749:SQ 29548