NOC/oFQ activates ERK and JNK but not p38 MAPK to impair prostaglandin cerebrovasodilation after brain injury

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.