Endocannabinoids decrease neuropathic pain-related behavior in mice through the activation of one or both peripheral CB1 and CB2 receptors

• Published in: Neuropharmacology 2014-02, Vol.77, p.441-452
• Main Authors: Desroches, Julie, Charron, Sophie, Bouchard, Jean-François, Beaulieu, Pierre
• Format: Article
• Language: English
• Subjects: 2-Arachidonoyl glycerol; Anandamide; Animals; Arachidonic Acids - pharmacology; Arachidonic Acids - therapeutic use; Behavior, Animal - drug effects; Cannabinoid receptors; Endocannabinoids - pharmacology; Endocannabinoids - therapeutic use; Fatty-acid amide hydrolase; Glycerides - pharmacology; Glycerides - therapeutic use; Hyperalgesia - drug therapy; Hyperalgesia - metabolism; Male; Mice; Mice, Knockout; Monoacylglycerol lipase; Neuralgia - drug therapy; Neuralgia - metabolism; Neuropathic pain; Pain Measurement; Pain Threshold - drug effects; Piperidines - pharmacology; Polyunsaturated Alkamides - pharmacology; Polyunsaturated Alkamides - therapeutic use; Pyrazoles - pharmacology; Receptor, Cannabinoid, CB1 - agonists; Receptor, Cannabinoid, CB1 - antagonists & inhibitors; Receptor, Cannabinoid, CB1 - metabolism; Receptor, Cannabinoid, CB2 - agonists; Receptor, Cannabinoid, CB2 - antagonists & inhibitors; Receptor, Cannabinoid, CB2 - metabolism
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2013.10.006

The two most studied endocannabinoids are anandamide (AEA), principally catalyzed by fatty-acid amide hydrolase (FAAH), and 2-arachidonoyl glycerol (2-AG), mainly hydrolyzed by monoacylglycerol lipase (MGL). Inhibitors targeting these two enzymes have been described, including URB597 and URB602, respectively. Several recent studies examining the contribution of CB1 and/or CB2 receptors on the peripheral antinociceptive effects of AEA, 2-AG, URB597 and URB602 in neuropathic pain conditions using either pharmacological tools or transgenic mice separately have been reported, but the exact mechanism is still uncertain. Mechanical allodynia and thermal hyperalgesia were evaluated in 436 male C57BL/6, cnr1KO and cnr2KO mice in the presence or absence of cannabinoid CB1 (AM251) or CB2 (AM630) receptor antagonists in a mouse model of neuropathic pain. Peripheral subcutaneous injections of AEA, 2-AG, WIN55,212-2 (WIN; a CB1/CB2 synthetic agonist), URB597 and URB602 significantly decreased mechanical allodynia and thermal hyperalgesia. These effects were inhibited by both cannabinoid antagonists AM251 and AM630 for treatments with 2-AG, WIN and URB602 but only by AM251 for treatments with AEA and URB597 in C57BL/6 mice. Furthermore, the antinociceptive effects for AEA and URB597 were observed in cnr2KO mice but absent in cnr1KO mice, whereas the effects of 2-AG, WIN and URB602 were altered in both of these transgenic mice. Complementary genetic and pharmacological approaches revealed that the anti-hyperalgesic effects of 2-AG and URB602 required both CB1 and CB2 receptors, but only CB2 receptors mediated its anti-allodynic actions. The antinociceptive properties of AEA and URB597 were mediated only by CB1 receptors. •AEA, 2-AG, WIN55,212-2, URB597 and URB602 induced local antinociceptive effects.•Cannabinoid receptors contribute to local effects under neuropathic pain conditions.•2-AG and URB602 require both CB1 and CB2 receptors to induce antinociception.•AEA and URB597 require only CB1 receptors to produce their analgesic effects.•Complementary genetic/pharmacological approaches have resolved this issue.