NOC/oFQ contributes to hypoxic–ischemic impairment of N-methyl- d-aspartate-induced cerebral vasodilation

Abstract

Previous studies in piglets show that either hypoxia, ischemia–reperfusion (I+R) or combined hypoxia–ischemia–reperfusion (H+I+R) attenuated N-methyl- d-aspartate (NMDA)-induced pial artery dilation. This study was designed to determine the contribution of the newly described opioid nociceptin orphanin FQ (NOC/oFQ) to hypoxic–ischemic impairment of NMDA induced cerebral vasodilation in piglets equipped with a closed cranial window. Global cerebral ischemia was produced via elevated intracranial pressure. Hypoxia decreased P O 2 to 35±3 mmHg with unchanged P CO 2 . I+R elevated CSF NOC/oFQ from 67±4 to 266±29 pg/ml (≈10 −10 M) while H+I+R elevated CSF NOC/oFQ to 483±67 pg/ml within 1 h of reperfusion. Such elevated NOC/oFQ levels returned to control within 4 h in I+R animals and within 12 h in H+I+R animals. Topical NOC/oFQ (10 −10 M) had no effect on pial artery diameter by itself but attenuated NMDA (10 −8, 10 −6 M) induced pial dilation (control, 9±1 and 16±1; coadministered NOC/oFQ, 5±1 and 10±1%). NMDA induced pial artery dilation was attenuated by I+R or H+I+R; but such dilation was partially restored by pretreatment with the putative NOC/oFQ antagonist [F/G] NOC/oFQ (1–13) NH 2 (10 −6 M) (control, 9±1 and 16±1; I+R, 3±1 and 5±1; I+R+NOC/oFQ antagonist, 6±1 and 11±1%) Similar results were obtained for glutamate. These data suggest that NOC/oFQ release contributes to impaired NMDA and glutamate-induced cerebrovasodilation following I+R or H+I+R.