Nociceptin/Orphanin FQ Alters Prostaglandin Cerebrovascular Action following Brain Injury

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Abstract
Previous studies have observed that fluid percussion brain injury (FPI) elevated the CSF concentration of the opioid nociceptin/orphanin FQ (NOC/oFQ). In separate studies, FPI impaired pial artery dilation to the prostaglandins PGI2 and PGE2. This study was designed to investigate the following: (1) role of NOC/oFQ in impaired dilation to PGI2 and PGE2, (2) the effects of FPI on vasoconstriction to the TXA2 mimic U46619 and PGF2α, and (3) the role of NOC/oFQ in such FPI induced effects on U46619 and PGF2α. Lateral FPI was induced in newborn pigs equipped with a closed cranial window. PGI2 (1, 10, 100 ng/ml) vasodilation was blunted by FPI and fully restored by the NOC/oFQ antagonist, [F/G] NOC/oFQ (1-13) NH2 (10-6M) (9 ± 1, 13 ± 1, and 19 ± 1 vs. 2 ± 1, 4 ± 1, and 5 + 1 vs 7 ± 1, 12 ± 2, and 17 ± 3% for control, FPI, and FPI + [F/G] NOC/oFQ (1-13) NH2, respectively). Similar effects were observed for PGE2. In contrast, U46619 (1, 10 ng/ml) induced vasoconstriction was potentiated by FPI but returned to the response observed prior to FPI by [F/G] NOC/oFQ (1-13) NH2 ( -8 ± 1 and -14 ± 1 vs. -15 ± 1 and -25 ± 1 vs. -7 ± 1 and -12 ± 2% for control, FPI, and FPI + [F/G] NOC/oFQ (1-13) NH2, respectively). Similar effects were observed for PGF2α. Coadministration of NOC/oFQ (10-10M), the CSF concentration observed after FPI, with agonists under nonbrain injury conditions blunted PGI2 and PGE2 vasodilation, but potentiated U46619 and PGF2α vasoconstriction similarly to that observed after FPI. These data show that FPI blunted PGI2 and PGE2 vasodilation but potentiated U46619 and PGF2α vasoconstriction. Additionally, these data show that administration of a NOC/oFQ receptor antagonist prevented such FPI associated events. NOC/oFQ administrated in a concentration observed after FPI produced blunted dilator prostaglandin and potentiated vasoconstriction prostaglandin vascular responses under nonbrain injury conditions. Finally, these data suggest that NOC/oFQ alters prostaglandin cerebrovascular action following brain injury.