Altered release of prostaglandins by opioids contributes to impaired cerebral hemodynamics following brain injury

Objectives: After fluid percussion brain injury (FPI) in the newborn pig, pial arteries constrict and responses to dilator stimuli, including opioids, are blunted. This study was designed to determine if altered release of prostaglandins contributes to blunted opioid dilation of cerebral arteries in newborn piglets following brain injury. Design: Prospective, in vivo, cerebral hemodynamic animal study. Setting: University research laboratory. Subjects: Newborn (1- to 5-days old) piglets of either gender. Interventions: In anesthetized, newborn, 1- to 5-day-old pigs, a closed cranial window was used to measure pial artery diameter and to collect cortial periarachnoid cerebrospinal fluid (CSF) for determination of 6-keto-PGF 1α , the stable metabolite of prostaglandin I 2 (PGI 2 ) and thromboxane B 2 (TXB 2 ), the stable metabolite 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 Results: Methionine enkephalin (Met) vasodilation was blunted after FPI but was partially restored with indomethacin pretreatment (5 mglkg 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, restoration of Met dilation after FPI was observed with SO 29,548, a TXA 2 antagonist. Met-induced 6-keto-PGF 1α 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 before and after FPI, respectively, n = 6). In contrast, Met-induced TX 2 release was enhanced after FPI (340 ± 20, 423 ± 25, and 473 ± 30 pg/mL vs. 518 ± 30, 726 ± 90, and 901 ± 35 pglmL for control, 10 -10 , and 10 -6 M Met before and after FPI, respectively, n = 6). Leucine enkephalin- and dynorphin-induced dilation and associated prostaglandin release were similarly altered following FPI. β endorphin-induced constriction was enhanced following FPI, and these potentiated responses were blunted after indomethacin or SO 29,548 pretreatment. Conclusions: These data show that FPI increases CSF 6-keto-PGF 1α and TXB 2 concentrations. These data suggest that altered release of prostaglandins by opioids contribute to impaired cerebral hemodynamics following FPI in piglets.