title: Remifentanil-induced cerebral blood flow effects in normal humans: dose and ApoE genotype.
abstract: BACKGROUND
  Opioids have been linked to limbic system activation and, in animals, to neurotoxicity. Limbic system nonpharmacologic activation patterns have been linked to the Apolipoprotein E (ApoE) allelic distribution. We tested the hypothesis that, in the absence of surgery, small doses of remifentanil produce limbic system activation in humans which varies with dose and ApoE genotype.
  
  
  METHODS
  Twenty-seven ASA I-II volunteers received a remifentanil (Ultiva) infusion at four sequentially increasing doses: 0, 0.05, 0.1, and 0.2 microg x kg(-1) x min(-1) while receiving 100% oxygen. Cerebral blood flow (CBF) was measured at each dose globally and in the amygdala, cingulate, hippocampus, insula, and thalamus regions by pulsed arterial spin labeling magnetic resonance imaging. ApoE single nucleotide polymorphisms were determined in each subject.
  
  
  RESULTS
  Significant dose-related CBF increases, without correction for Paco(2), were detected in all areas. After normalizing for global CBF to correct for Paco(2) effects, the remifentanil-mediated increased CBF in the cingulate persisted, with decreased flow occurring in the hippocampus and amygdala. All these Paco(2)-corrected effects were reversed in the presence of the ApoE4 polymorphism.
  
  
  CONCLUSIONS
  Remifentanil at sedative doses produces both activating and depressing effects in various limbic system structures. The cingulate cortex seems to have the most susceptibility to remifentanil activation, and ApoE4 seems to produce relative activation of the hippocampus and amygdala.
authors.affiliation: Department of Anesthesiology and Critical Care, Hospital of the University of Pennsylvania, Philadelphia, PA 19104-4283, USA. kofkea@uphs.upenn.edu
authors.forename: W Andrew
authors.initials: WA
authors.lastname: Kofke
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Blissitt
authors.forename: Hengyi
authors.initials: H
authors.lastname: Rao
authors.forename: Jiongjiong
authors.initials: J
authors.lastname: Wang
authors.forename: Kathakali
authors.initials: K
authors.lastname: Addya
authors.forename: John
authors.initials: J
authors.lastname: Detre
mesh_terms: D000328:Adult; D053327:Apolipoprotein E4 / Q000235:genetics*; D002560:Cerebrovascular Circulation / Q000187:drug effects* / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D006801:Humans; D008032:Limbic System / Q000098:blood supply / Q000187:drug effects; D008297:Male; D010880:Piperidines / Q000008:administration & dosage*; D012039:Regional Blood Flow / Q000187:drug effects / Q000235:genetics; D000077208:Remifentanil
chemical_list: D053327:Apolipoprotein E4; D010880:Piperidines; D000077208:Remifentanil