ALTERED RELEASE OF PROSTAGLANDINS BY OPIOIDS CONTRIBUTES TO IMPAIRED CEREBRAL HEMODYNAMICS FOLLOWING BRAIN INJURY

Objectives: After fluid percussion brain injury (FPI) in the newborn p ig, pial arteries constrict and responses to dilator stimuli, includin g opioids, are blunted. This study was designed to determine if altere d release of prostaglandins contributes to blunted opioid dilation of cerebral arteries in newborn piglets following brain injury. Design: P rospective, in vivo, cerebral hemodynamic animal study. Setting: Unive rsity research laboratory. Subjects: Newborn (1- to 5-days old) piglet s of either gender. Interventions: In anesthetized, newborn, 1- to 5-d ay-old pigs, a closed cranial window was used to measure pial artery d iameter and to collect cortial periarachnoid cerebrospinal fluid (CSF) for determination of 6-keto-PGF(1 alpha), the stable metabolite of pr ostaglandin I-2 (PGI(2)) and thromboxane B-2 (TXB2), the stable metabo lite of TXA(2), via radioimmunoassay. FPI of moderate severity (1.9 to 2.3 atmospheres) was produced by using a pendulum to strike a piston on a saline-filled cylinder that was fluid coupled to the brain via a hollow screw inserted through the cranium. Measurements and Main Resul ts: Methionine enkephalin (Met) vasodilation was blunted after FPI but was partially restored with indomethacin pretreatment (5 mg/kg iv) (8 +/- 1 [SEM] %, 13 +/- 1%, and 20 +/- 1% vs. 1 +/- 1%, 3 +/- 1%, and 5 +/- 1% vs. 7 +/- 1%, 10 +/- 1%, and 15 +/- 1%, respectively, for 10(- 10), 10(-8),and 10(-6) M Met during control conditions, after FPI, and after FPI pretreated with indomethacin, n = 6). Similarly, restoratio n of Met dilation after FPI was observed with SQ 29,548, a TXA(2) anta gonist. Met-induced 6-keto-PGF(1 alpha) release was blunted following FPI (889 +/- 20, 1130 +/- 33, and 1886 +/- 59 vs. 2630 +/- 36, 2775 +/ - 30, and 2825 +/- 36 pg/mL for control, 10(-10), and 10(-6) M Met bef ore and after FPI, respectively, n = 6). In contrast, Met-induced TXB2 release was enhanced after FPI (340 +/- 20, 423 +/- 25, and 473 +/- 3 0 pg/mL vs. 518 +/- 30, 726 +/- 90, and 901 +/- 35 pg/mL for control, 10(-10), and 10(-6) M Met before and after FPI, respectively, n = 6). Leucine enkephalin-and dynorphin-induced dilation and associated prost aglandin release were similarly altered following FPI. beta endorphin- induced constriction was enhanced following FPI, and these potentiated responses were blunted after indomethacin or SQ 29,548 pretreatment. Conclusions: These data show that FPI increases CSF 6-keto-PGF(1 alpha ) and TXB2 concentrations. These data suggest that altered release of prostaglandins by opioids contribute to impaired cerebral hemodynamics following FPI in piglets.