Age-Dependent NOC/oFQ Contribution to Impaired Hypotensive Cerebral Hemodynamics after Brain Injury

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Abstract
Previous studies have observed that the newly described opioid, nociceptin/orphanin FQ (NOC/oFQ), contributed to age dependent reductions in cerebral blood flow (CBF) and pial artery diameter after fluid percussion brain injury (FPI). Unrelated studies have noted a similar age dependency in impaired hypotensive cerebral autoregulation after FPI. This study was designed to compare the role of NOC/oFQ in impaired hypotensive cerebral autoregulation after FPI in newborn and juvenile pigs equipped with a closed cranial window. Ten minutes of hemorrhagic hypotension (10-15 mL blood/kg) decreased mean arterial blood pressure uniformly in both groups (≈44%). In the newborn, hypotensive pial artery dilation was blunted within 1 h of FPI but partially protected by pretreatment with the NOC/oFQ antagonist, [F/G] NOC/oFQ (1-13) NH2 (1 mg/kg, i.v.) (34 ± 1 vs. 8 ± 1 vs. 20 ± 2% for sham control, FPI, and FPI-[F/G] NOC/oFQ (1-13) NH2, respectively). CBF was reduced during normotension by FPI, further reduced by hypotension, but both were partially protected by this antagonist in the newborn (63 ± 4, 34 ± 2, and 20 ± 2 vs. 65 ± 4, 47 ± 2, and 29 ± 2 mL/min·100 g for normotension, normotension-FPI and hypotension-FPI in the absence and presence of [F/G] NOC/oFQ (1-13) NH2, respectively). In contrast, blunted hypotensive pial artery dilation was protected significantly less by this NOC/oFQ antagonist in the juvenile (32 ± 2 vs. 7 ± 2 vs. 13 ± 2% for sham control, FPI and FPI-NOC/oFQ antagonist, respectively). Similarly, [F/G] NOC/oFQ (1-13) NH2 had less protective effect on normotensive and hypotensive CBF values post FPI in the juvenile. These data indicate that NOC/oFQ contributes to impaired hypotensive cerebral hemodynamics following brain injury in an age-dependent manner.