Role of Nociceptin/Orphanin FQ in Age-Dependent Cerebral Hemodynamic Effects of Brain Injury

Abstract

This study was designed to compare the role of the newly described endogenous opioid nociceptin/orphanin FQ (NOC/oFQ) in the reductions of cerebral blood flow (CBF) and pial artery diameter observed following fluid percussion brain injury (FPI) in chloralose anesthetized newborn and juvenile pigs as a function of time postinsult. FPI elevated CSF NOC/oFQ concentration from 70 ± 3 to 444 ± 51 within 1 h and to 1,931 ± 112 pg/mL (n = 7) within 8 h, whereas concentrations returned to control value within 168 h in the newborn. In contrast, FPI elevated CSF NOC/oFQ from 77 ± 4 to 202 ± 16 pg/mL (n = 7) within 1 h, while values returned to control value within 8 h in the juvenile. Topical NOC/oFQ (10⁻⁸, 10⁻⁶ M) induced vasodilation was reversed to vasoconstriction by FPI in the newborn while such responses were only attenuated in the juvenile at 1 h post insult (control, 9 ± 1 and 16 ± 1%; FPI newborn, −8 ± 1 and −14 ± 1%; FPI juvenile, 2 ± 1 and 5 ± 1 %, n = 7). Such altered dilation returned to control value within 168 h in newborns and 8 h in juveniles. Blood flow in the cerebrum was reduced from 57 ± 4 to 23 ± 3 mL · min⁻¹ · 100 g⁻¹ (n = 7) within 1 h and returned to control value with 168 h post FPI in newborns. In animals pretreated with [F/G] NOC/oFQ (1–13) NH₂ (1 mg/kg, i.V.), a NOC/oFQ antagonist, however, CBF only fell to 39 ± 4 mL · min⁻¹ · 100 g⁻¹ (n = 7) at 1 h post insult in newborns. In contrast, CBF was only reduced from 57 ± 6 to 32 ± 2 in untreated and to 39 ± 3 mL/min⁻¹ · 100 g⁻¹ (n = 7) in treated juveniles within 1 h post FPI. Similar observations for reductions in pial artery diameter were made in untreated and treated newborns and juveniles. These data suggest that an elevated CSF NOC/oFQ concentration and altered vascular responsiveness to this opioid contribute to reductions in CBF and pial artery diameter observed following FPI. Because such NOC/oFQ changes were greater in newborns versus juveniles, these data further suggest that NOC/oFQ contributes to age-related cerebral hemodynamic differences in the effects of FPI.