title: Altered release of prostaglandins by opioids contributes to impaired cerebral hemodynamics following brain injury.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  Prospective, in vivo, cerebral hemodynamic animal study.
  
  
  METHODS
  University research laboratory.
  
  
  METHODS
  Newborn (1- to 5-days old) piglets of either gender.
  
  
  METHODS
  In anesthetized, newborn, 1- to 5-day-old pigs, a closed cranial window was used to measure pial artery diameter and to collect cortical periarachnoid cerebrospinal fluid (CSF) for determination of 6-keto-PGF1alpha, the stable metabolite of prostaglandin I2 (PGI2) and thromboxane B2 (TXB2), the stable metabolite of TXA2, 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.
  
  
  RESULTS
  Methionine enkephalin (Met) vasodilation was blunted after FPI but was partially restored with indomethacin pretreatment (5 mg/kg i.v.) (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 SQ 29,548, a TXA2 antagonist. Met-induced 6-keto-PGF1alpha 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 TXB2 release was enhanced after FPI (340 +/- 20, 423 +/- 25, and 473 +/- 30 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 prostaglandin 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-PGF1alpha and TXB2 concentrations. These data suggest that altered release of prostaglandins by opioids contribute to impaired cerebral hemodynamics following FPI in piglets.
authors.affiliation: Department of Anesthesia, University of Pennsylvania and the Children's Hospital of Philadelphia, 19104, USA.
authors.forename: A
authors.initials: A
authors.lastname: Al-Turki
authors.forename: W M
authors.initials: WM
authors.lastname: Armstead
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001930:Brain Injuries / Q000378:metabolism*; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D004347:Drug Interactions; D005260:Female; D006439:Hemodynamics; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D018847:Opioid Peptides / Q000494:pharmacology*; D011453:Prostaglandins / Q000134:cerebrospinal fluid / Q000378:metabolism*; D011863:Radioimmunoassay; D013552:Swine; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D018847:Opioid Peptides; D011453:Prostaglandins; D007213:Indomethacin