title: Changes of blood endocannabinoids during anaesthesia: a special case for fatty acid amide hydrolase inhibition by propofol?
abstract: BACKGROUND
  • Available data from animal studies suggest that the narcotic drug propofol interacts with the endocannabinoid system. Inhibition of enzymatic degradation of anandamide could explain some of the characteristics of propofol. Direct measurements have not been reported yet in humans.
  
  
  CONCLUSIONS
  • Propofol does not change the time course of anandamide plasma concentrations during anaesthesia. Furthermore, propofol does not inhibit fatty acid amide hydrolase activity ex vivo or in vitro. Thus, specific characteristics of the narcotic drug propofol cannot be explained by peripheral inhibition of anandamide degradation in humans.
  
  
  OBJECTIVE
  The aim of our study was to describe the time course of endocannabinoids during different anaesthesia protocols in more detail, and to challenge the hypothesis that propofol acts as a FAAH inhibitor.
  
  
  METHODS
  Endocannabinoids were measured during the first hour of anaesthesia in 14 women and 14 men undergoing general anaesthesia with propofol and in 14 women and 14 men receiving thiopental/sevoflurane. We also incubated whole human blood samples ex vivo with propofol and the known FAAH inhibitor oloxa and determined FAAH enzyme kinetics.
  
  
  RESULTS
  Plasma anandamide decreased similarly with propofol and thiopental/sevoflurane anaesthesia, and reached a nadir after 10 min. Areas under the curve for anandamide (mean and 95% CI) were 53.3 (47.4, 59.2) nmol l(-1) 60 min with propofol and 48.5 (43.1, 53.8) nmol l(-1) 60 min with thiopental/sevoflurane (P= NS). Anandamide and propofol plasma concentrations were not correlated at any time point. Ex vivo FAAH activity was not inhibited by propofol. Enzyme kinetics (mean ± SD) of recombinant human FAAH were K(m) = 16.9 ± 8.8 µmol l(-1) and V(max) = 44.6 ± 15.8 nmol mg(-1) min(-1) FAAH without, and K(m) = 16.6 ± 4.0 µmol l(-1) and V(max) = 44.0 ± 7.6 nmol mg( 1 ) min(-1) FAAH with 50 µmol l(-1) propofol (P= NS for both).
  
  
  CONCLUSIONS
  Our findings challenge the idea that propofol anaesthesia and also propofol addiction are directly mediated by FAAH inhibition, but we cannot exclude other indirect actions on cannabinoid receptors.
authors.affiliation: Institute of Clinical Pharmacology, Hannover Medical School, Hannover, Germany.
authors.forename: Carina
authors.initials: C
authors.lastname: Jarzimski
authors.forename: Matthias
authors.initials: M
authors.lastname: Karst
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Zoerner
authors.forename: Christin
authors.initials: C
authors.lastname: Rakers
authors.forename: Marcus
authors.initials: M
authors.lastname: May
authors.forename: Maria T
authors.initials: MT
authors.lastname: Suchy
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Tsikas
authors.forename: Joachim K
authors.initials: JK
authors.lastname: Krauss
authors.forename: Dirk
authors.initials: D
authors.lastname: Scheinichen
authors.forename: Jens
authors.initials: J
authors.lastname: Jordan
authors.forename: Stefan
authors.initials: S
authors.lastname: Engeli
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000758:Anesthesia / Q000379:methods*; D018686:Anesthetics, Intravenous / Q000493:pharmacokinetics / Q000494:pharmacology*; D001095:Arachidonic Acids / Q000097:blood / Q000378:metabolism; D019540:Area Under Curve; D063388:Endocannabinoids / Q000097:blood* / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008738:Methyl Ethers / Q000493:pharmacokinetics / Q000494:pharmacology; D008875:Middle Aged; D053284:Polyunsaturated Alkamides / Q000097:blood / Q000378:metabolism; D015742:Propofol / Q000493:pharmacokinetics / Q000494:pharmacology*; D043882:Receptors, Cannabinoid / Q000097:blood* / Q000378:metabolism; D000077149:Sevoflurane; D013874:Thiopental / Q000493:pharmacokinetics / Q000494:pharmacology; D013997:Time Factors; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D018686:Anesthetics, Intravenous; D001095:Arachidonic Acids; D063388:Endocannabinoids; D008738:Methyl Ethers; D053284:Polyunsaturated Alkamides; D015742:Propofol; D043882:Receptors, Cannabinoid; D000077149:Sevoflurane; D013874:Thiopental; D000099252:Fatty Acid Amide Hydrolases; C078814:anandamide