title: NOC/oFQ activates ERK and JNK but not p38 MAPK to impair prostaglandin cerebrovasodilation after brain injury.
abstract: Fluid percussion brain injury (FPI) elevates the CSF concentration of the opioid nociceptin/orphanin FQ (NOC/oFQ), which contributes to impairment of pial artery dilation to the prostaglandins (PG) PGE2 and PGI2. This study investigated the role of the ERK, p38, and JNK isoforms of mitogen-activated protein kinase (MAPK) in impaired PG cerebrovasodilation after FPI, and the relationship of brain injury induced release of NOC/oFQ to MAPK in such vascular impairment in newborn pigs equipped with a closed cranial window. FPI blunted PGE2 pial artery dilation, but U 0126 and SP 600125 (10(-6) M) (ERK and JNK MAPK inhibitors, respectively) partially prevented such impairment (7 +/- 1, 12 +/- 1, and 17 +/- 1 vs. 2 +/- 1, 3 +/- 1, and 5 +/- 1 vs. 4 +/- 1, 7 +/- 1, and 12 +/- 1% for 1, 10, and 100 ng/ml PGE2 in control, FPI, and FPI + U 0126 pretreated animals, respectively). In contrast, administration of SB 203580 (10(-5) M) (p38 MAPK inhibitor) did not prevent FPI impairment of PGE2 dilation. Co-administration of NOC/oFQ at the dose of 10(-10) M, the cerebrospinal fluid concentration observed after FPI, with PGE2 under non-brain injury conditions blunted PG dilation, but U 0126 or SP 600125 partially prevented such impairment (7 +/- 1, 11 +/- 1, and 16 +/- 2 vs. 0 +/- 1, 1 +/- 1, and 2 +/- 1, vs. 5 +/- 1, 9 +/- 1, and 13 +/- 2 for responses to PGE2 in control, NOC/oFQ, and NOC/oFQ + U 0126 treated animals, respectively). Administration of SB 203580 did not prevent impairment of PG pial artery dilation by NOC/oFQ. These data show that activation of ERK and JNK but not p38 MAPK contributes to impairment of PG cerebrovasodilation after FPI. These data suggest that NOC/oFQ induced ERK and JNK but not p38 MAPK activation contributes to impaired cerebrovasodilation to PG after FPI.
authors.affiliation: Department of Anesthesia, University of Pennsylvania, 3620 Hamilton Walk, John Morgan 305, Philadelphia, PA 19104, USA.
authors.forename: John
authors.initials: J
authors.lastname: Ross
authors.forename: William M
authors.initials: WM
authors.lastname: Armstead
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001930:Brain Injuries / Q000378:metabolism*; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D015232:Dinoprostone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000145:classification / Q000378:metabolism*; D018847:Opioid Peptides / Q000494:pharmacology*; D011453:Prostaglandins / Q000494:pharmacology*; D013552:Swine; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*; D000097629:Nociceptin
chemical_list: D015232:Dinoprostone; D004791:Enzyme Inhibitors; D020928:Mitogen-Activated Protein Kinases; D018847:Opioid Peptides; D011453:Prostaglandins; D014665:Vasodilator Agents; D000097629:Nociceptin