Superoxide Generation Links Nociceptin/Orphanin FQ (NOC/oFQ) Release to Impaired N -Methyl- d -Aspartate Cerebrovasodilation After Brain Injury

Abstract

Background and Purpose-Although activation of the N-methyl-D-aspartate (NMDA) receptor is thought to contribute to altered cerebrovascular regulation after traumatic brain injury, the effects of such injury on the vascular response to NMDA itself has been less well appreciated. The newly described opioid nociceptin/orphanin FQ (NOC/oFQ) elicits pial artery dilation, at least in part, in a prostaglandin-dependent manner and is released into cerebrospinal fluid after fluid percussion brain injury (FPI). Generation of superoxide anion (O 2 Ϫ ) occurs after FPI, and a byproduct of cyclooxygenase metabolism is the generation of O 2 Ϫ . This study was designed to determine whether NOC/oFQ generates O 2 Ϫ , which in turn could link NOC/oFQ release to impaired NMDA-induced pial artery dilation after FPI. Methods-Injury of moderate severity (1.9 to 2.1 atm) was produced by the lateral FPI technique in anesthetized newborn pigs equipped with a closed cranial window. Superoxide dismutase-inhibitable nitroblue tetrazolium (NBT) reduction was determined as an index of O 2 Ϫ generation. Results-Under non-brain injury conditions, topical NOC/oFQ (10 Ϫ10 mol/L, the concentration present in cerebrospinal fluid after FPI) increased superoxide dismutase-inhibitable NBT reduction from 1Ϯ1 to 20Ϯ3 pmol/mm 2 but had no effect itself on pial artery diameter. Indomethacin (5 mg/kg IV) blunted such NBT reduction (1Ϯ1 to 6Ϯ2 pmol/mm 2 ), whereas the NOC/oFQ receptor antagonist [F/G] NOC/oFQ (1-13) NH 2 (10 Ϫ6 mol/L) blocked NBT reduction. [F/G] NOC/oFQ (1-13) NH 2 and indomethacin also blunted the NBT reduction observed after FPI (1Ϯ1 to 15Ϯ1 versus 1Ϯ1 to 4Ϯ1 versus 1Ϯ1 to 4Ϯ1 pmol/mm 2 for sham, NOC/oFQ antagonist, and indomethacin-treated animals, respectively). NMDA (10 Ϫ8 and 10 Ϫ6 mol/L)-induced pial artery dilation was reversed to vasoconstriction after FPI, and [F/G] NOC/oFQ (1-13) NH 2 attenuated such vasoconstriction (sham 9Ϯ1% and 16Ϯ1% versus FPI Ϫ7Ϯ1% and Ϫ12Ϯ1% versus FPI-[F/G] NOC/oFQ (1-13) NH 2 -pretreated animals Ϫ2Ϯ1% and Ϫ3Ϯ1%). Indomethacin and the free radical scavengers polyethylene glycol superoxide dismutase and catalase also partially restored NMDA-induced vasodilation. Conclusions-These data show that NOC/oFQ, in concentrations present in cerebrospinal fluid after FPI, increased O 2

Vasopressin-Induced Protein Kinase C–Dependent Superoxide Generation Contributes to ATP-Sensitive Potassium Channel but Not Calcium-Sensitive Potassium Channel Function Impairment After Brain Injury

“…27,28 More recent studies have shown that the opioid nociceptin/orphanin FQ contributes to O 2 Ϫ generation after this insult in a mechanism dependent on the activation of cyclooxygenase. 29 Results of the present study extend the latter observations to indicate that several vasoactive substances released into CSF after brain injury have the ability to contribute to O 2 Ϫ generation after this insult via separate signal transduction pathways. In addition, because chelerythrine blocked the NBT reduction associated with topical administration of the PKC activator phorbol-12,13-dibutyrate, this probe appears to be an efficacious PKC inhibitor, strengthening the conclusions of the present study.…”

In-vivo effects of nociceptin and its structural analogue [Orn9] nociceptin on the antioxidant status of rat blood and liver after carrageenan-induced paw inflammation

“…Following fluid percussion brain injury (FPI), it has been demonstrated that N/OFQ at concentrations found in the cerebrospinal fluid increases superoxide anion radical (O 2 -) production in a cyclooxygenase-dependent manner [15,16]. The peptide also increases protein kinase C (PKC)-dependent O 2 -production after insult [17].…”

Study of the cytotoxicity and antioxidant capacity of N/OFQ(1–13)NH2 and its structural analogues

“…A dramatic increase in N/OFQ gene expression has also been demonstrated in astrocytes, in response to inflammatory mediators and OS [4]. It has been reported that N/OFQ, in concentrations that are observed in cerebrospinal fluid after fluid percussion brain injury (FPI), increases superoxide (O 2 -) production in a cyclooxygenase-dependent manner [2,22]; it also increases pyruvate kinase C (PKC)-dependent O 2 -production after insult [1]. According to Kulkarni and Armstead [22], superoxide generation links N/OFQ release to impaired Nmethyl-D-aspartate cerebral vasodilation after brain injury.…”

“…It has been reported that N/OFQ, in concentrations that are observed in cerebrospinal fluid after fluid percussion brain injury (FPI), increases superoxide (O 2 -) production in a cyclooxygenase-dependent manner [2,22]; it also increases pyruvate kinase C (PKC)-dependent O 2 -production after insult [1]. According to Kulkarni and Armstead [22], superoxide generation links N/OFQ release to impaired Nmethyl-D-aspartate cerebral vasodilation after brain injury. Using a battery of behavioral tests, Marti et al [27] showed that co-administration of the NOP receptor antagonist J-113397 and L-DOPA to 6-hydroxydopamine hemilesioned rats produces an additive attenuation of Parkinson's symptoms.…”