Ketamine induces central antinociception mediated by endogenous cannabinoids and activation of CB1 receptors

Neurosci Lett. 2019 Apr 23:699:140-144. doi: 10.1016/j.neulet.2019.01.059. Epub 2019 Feb 1.


The participation of endocannabinoids in central and peripheral antinociception induced by several compounds has been shown by our group. In this study, we investigated the effect of endocannabinoids on the central antinociception induced by ketamine. The nociceptive threshold for thermal stimulation was measured using the tail-flick test in Swiss mice. The drugs were administered intracerebroventricularly. Probabilities less than 5% (p < 0.05) were considered to be statistically significant (Two-way ANOVA/Bonferroni's test). The CB1-selective cannabinoid receptor antagonist AM251 (2 and 4 μg) completely reversed the central antinociception induced by ketamine (4 μg) in a dose-dependent manner. In contrast, the CB2-selective cannabinoid receptor antagonist AM630 (2 and 4 μg) did not antagonize this effect. Additionally, the administration of the anandamide amidase inhibitor MAFP (0.2 μg) and anandamide uptake inhibitor VDM11 (4 μg) significantly enhanced the antinociception induced by a low dose of ketamine (2 μg). It was concluded that central antinociception induced by ketamine involves the activation of CB1 cannabinoid receptors. Mobilization of cannabinoids might be required for the activation of those receptors, since inhibitors of the endogenous cannabinoids potentiate the effect of Ketamine.

Keywords: CB(1) receptor; Cannabinoids; Central antinociception; Ketamine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics / pharmacology*
  • Animals
  • Arachidonic Acids / pharmacology
  • Cannabinoids / metabolism*
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • Indoles / pharmacology
  • Infusions, Intraventricular
  • Ketamine / administration & dosage
  • Ketamine / antagonists & inhibitors
  • Ketamine / pharmacology*
  • Male
  • Mice
  • Organophosphonates / pharmacology
  • Pain Measurement / drug effects
  • Piperidines / pharmacology
  • Pyrazoles / pharmacology
  • Receptor, Cannabinoid, CB1 / agonists*
  • Receptor, Cannabinoid, CB1 / antagonists & inhibitors
  • Receptor, Cannabinoid, CB2 / antagonists & inhibitors


  • Analgesics
  • Arachidonic Acids
  • Cannabinoids
  • Indoles
  • N-(2-methyl-3-hydroxyphenyl)-5,8,11,14-eicosatetraenamide
  • Organophosphonates
  • Piperidines
  • Pyrazoles
  • Receptor, Cannabinoid, CB1
  • Receptor, Cannabinoid, CB2
  • methyl arachidonylfluorophosphonate
  • AM 251
  • Ketamine
  • iodopravadoline