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PAIN MECHANISMS

The Antinociceptive Effects of Local Injections of Propofol in Rats Are Mediated in Part by Cannabinoid CB₁ and CB₂ Receptors

Josée Guindon, DVM, PhD^*, Jesse LoVerme, PhD, Daniele Piomelli, PhD, and Pierre Beaulieu, MD, PhD, FRCA^*

From the *Department of Pharmacology, Faculty of Medicine, Université de Montréal–CHUM, Montréal, Québec, Canada; Departments of Psychiatry and Pharmacology, University of California, Irvine, California; and Department of Anesthesiology, Faculty of Medicine, Université de Montréal–CHUM, Montréal, Québec, Canada.

Address correspondence and reprint requests to Pierre Beaulieu, Department of Anesthesiology, CHUM–Hôtel-Dieu, 3840 rue St-Urbain, Montréal, H2W 1T8, Québec, Canada. Address e-mail to pierre.beaulieu{at}umontreal.ca.

Abstract

BACKGROUND: Propofol can inhibit fatty acid amidohydrolase, the enzyme responsible for the metabolism of anandamide (an endocannabinoid). To study the potential antinociceptive effect of propofol, we administered different doses (0.005, 0.05, 0.5, 5, and 500 µg) of the anesthetic in the hind paw of animals to determine an ED₅₀. To further investigate the mechanisms by which propofol produced its antinociceptive effect, we used specific antagonists for the cannabinoid CB₁ (AM251) and CB₂ (AM630) receptors and measured fatty-acid amide/endocannabinoid (anandamide, 2-arachidonylglycerol, and palmitoylethanolamide) concentrations in skin paw tissues.

METHODS: Formalin tests were performed on 65 Wistar rats allocated to six different groups: 1) control (Intralipid^TM 10%); 2) propofol (ED₅₀ dose); 3) AM251; 4) AM251 + propofol; 5) AM630; 6) AM630 + propofol. Drugs were injected subcutaneously in the dorsal surface of the hind paw (50 µL) 15 min before 2.5% formalin injection into the same paw. Fatty-acid amide/endocannabinoid levels were measured by high performance liquid chromatography/mass spectrometry analysis.

RESULTS: Propofol produced a dose-dependent antinociceptive effect for the early and late phases of the formalin test with an ED₅₀ of 0.08 ± 0.061 µg for the latter phase. This effect was antagonized by AM251 and AM630. It was locally mediated, since a higher dose of propofol given in the contralateral paw was not antinociceptive. Finally, only paw concentrations of palmitoylethanolamide were significantly increased.

CONCLUSION: In a test of inflammatory pain, locally injected propofol decreased pain behavior in a dose-dependent manner. This antinociceptive effect was mediated, in part, by CB₁ and CB₂ receptors.

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