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.