The general anesthetic propofol increases brain N-arachidonylethanolamine (anandamide) content and inhibits fatty acid amide hydrolase

Sachin Patel, Eric R. Wohlfeil, David J. Rademacher, Erica J. Carrier, LaToya J. Perry, Abhijit Kundu, J R Falck, Kasem Nithipatikom, William B. Campbell, Cecilia J. Hillard

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111 Scopus citations

Abstract

1. Propofol (2,6-diisopropylphenol) is widely used as a general anesthetic and for the maintenance of long-term sedation. We have tested the hypothesis that propofol alters endocannabinoid brain content and that this effect contributes to its sedative properties. 2. A sedating dose of propofol in mice produced a significant increase in the whole-brain content of the endocannabinoid, N-arachidonylethanolamine (anandamide), when administered intraperitoneally in either Intralipid or emulphor-ethanol vehicles. 3. In vitro, propofol is a competitive inhibitor (IC 50 52 μM; 95% confidence interval 31, 87) of fatty acid amide hydrolase (FAAH), which catalyzes the degradation of anandamide. Within a series of propofol analogs, the critical structural determinants of FAAH inhibition and sedation were found to overlap. Other intravenous general anesthetics, including midazolam, ketamine, etomidate, and thiopental, do not affect FAAH activity at sedative-relevant concentrations. Thiopental, however, is a noncompetitive inhibitor of FAAH at a concentration of 2 mM. 4. Pretreatment of mice with the CB 1 receptor antagonist SR141716 (1 mg kg -1, i.p.) significantly reduced the number of mice that lost their righting reflex in response to propofol. Pretreatment of mice with the CB 1 receptor agonist, Win 55212-2 (1 mg kg -1, i.p.), significantly potentiated the loss of righting reflex produced by propofol. These data indicate that CB 1 receptor activity contributes to the sedative properties of propofol. 5. These data suggest that propofol activation of the endocannabinoid system, possibly via inhibition of anandamide catabolism, contributes to the sedative properties of propofol and that FAAH could be a novel target for anesthetic development.

Original languageEnglish (US)
Pages (from-to)1005-1013
Number of pages9
JournalBritish Journal of Pharmacology
Volume139
Issue number5
DOIs
StatePublished - Jul 1 2003

Keywords

  • 2,6-diisopropylphenol
  • 2-arachidonylglycerol
  • Endocannabinoid
  • Marijuana
  • SR141716
  • Win 55212-2

ASJC Scopus subject areas

  • Pharmacology

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    Patel, S., Wohlfeil, E. R., Rademacher, D. J., Carrier, E. J., Perry, L. J., Kundu, A., Falck, J. R., Nithipatikom, K., Campbell, W. B., & Hillard, C. J. (2003). The general anesthetic propofol increases brain N-arachidonylethanolamine (anandamide) content and inhibits fatty acid amide hydrolase. British Journal of Pharmacology, 139(5), 1005-1013. https://doi.org/10.1038/sj.bjp.0705334