The general anesthetic propofol increases brain N-arachidonylethanolamine (anandamide) content and inhibits fatty acid amide hydrolase.
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 micro M; 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.
Patel
Sachin
S
Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
Wohlfeil
Eric R
ER
Rademacher
David J
DJ
Carrier
Erica J
EJ
Perry
LaToya J
LJ
Kundu
Abhijit
A
Falck
J R
JR
Nithipatikom
Kasem
K
Campbell
William B
WB
Hillard
Cecilia J
CJ
D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018681:Anesthetics, General; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D053284:Polyunsaturated Alkamides; D015742:Propofol; D051381:Rats; D017207:Rats, Sprague-Dawley; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D018681:Anesthetics, General; D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D053284:Polyunsaturated Alkamides; D015742:Propofol; D000099252:Fatty Acid Amide Hydrolases; C078814:anandamide