Modulation of the anti‐nociceptive effects of 2‐arachidonoyl glycerol by peripherally administered FAAH and MGL inhibitors in a neuropathic pain model

Background and purpose: There are limited options for the treatment of neuropathic pain. Endocannabinoids, such as anandamide and 2‐arachidonoyl glycerol (2‐AG), are promising pain modulators and there is recent evidence of interactions between anandamide and 2‐AG biosynthesis and metabolism. It has been clearly demonstrated that 2‐AG degradation is mainly catalysed not only by monoacylglycerol lipase (MGL) but also by a fatty acid amide hydrolase (FAAH). Inhibitors specifically targeting these two enzymes have also been described: URB602 and URB597, respectively. However, the anti‐nociceptive effects of the combination of peripherally injected 2‐AG, URB602 and URB597 in a neuropathic pain model have not yet been determined. This was performed in the presence or absence of cannabinoid CB 1 (AM251) and CB 2 (AM630) receptor antagonists. Experimental approach: Mechanical allodynia and thermal hyperalgesia were evaluated in 213 male Wistar rats allocated to 32 different groups. Drugs were injected subcutaneously in the dorsal surface of the hind paw (50 μL) 15 min before pain tests. Key results: 2‐AG, URB602 and URB597 significantly decreased mechanical allodynia and thermal hyperalgesia with ED50 of 1.6±1.5 and 127±83 μg for 2‐AG and URB602, respectively. These effects were mediated locally and were mostly inhibited by the two cannabinoid antagonists. Conclusions and implications: The combination of the three compounds did not produce any greater anti‐allodynic or anti‐hyperalgesic effects, suggesting that FAAH inhibition could reduce or limit the anti‐nociceptive effects of 2‐AG. Peripheral administration of endocannabinoids or MGL/FAAH inhibitors is a promising analgesic approach requiring further investigation. British Journal of Pharmacology (2008) 155 , 913–924; doi: 10.1038/bjp.2008.322 ; published online 11 August 2008