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Abstract
Monoacylglycerol lipase (MGL) and fatty acid amide hydrolase (FAAH) degrade the endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide (AEA), respectively. Pharmacological inhibition of these enzymes in the periphery holds promise for suppressing persistent pain in the absence of centrally-mediated psychotropic side-effects. We compared effects of intraplantar injection of the MGL inhibitor JZL184, the FAAH inhibitor URB597, and the endocannabinoid uptake inhibitor VDM11 on behavioral hypersensitivities produced by capsaicin, the pungent ingredient in hot chili peppers. Intradermal administration of capsaicin (10 g i.pl.) produced nocifensive behavior, thermal hyperalgesia, and mechanical allodynia in rats. JZL184 (100 g i.pl.) suppressed capsaicin-induced nocifensive behavior and thermal hyperalgesia without altering capsaicin-evoked mechanical allodynia. URB597 (75 g i.pl.) suppressed capsaicin-induced mechanical allodynia without altering capsaicin-evoked thermal hyperalgesia or nocifensive behavior. VDM11 (100 g i.pl.) suppressed capsaicin-evoked hypersensitivity for all three dependent measures (nocifensive behavior, thermal hyperalgesia, and mechanical allodynia), suggesting an additive effect following elevation of both AEA and 2- AG. Pharmacological inhibition of MGL and FAAH also activates specific cannabinoid receptor subtypes. Both the CB1 antagonist AM251 (80 g i.pl.) and the CB2 antagonist AM630 (25 g i.pl.) blocked the JZL184-induced suppressions of nocifensive behavior and thermal hyperalgesia. By contrast, AM251 (80 g i.pl.), but not AM630 (25 g i.pl.), blocked the anti-allodynic effects of URB597. The VDM11-induced suppression of capsaicin-evoked nocifensive behavior and thermal hyperalgesia was blocked by either AM251 (80 g i.pl.) or AM630 (25 g i.pl.), as observed with JZL184. The VDM11-induced suppression of capsaicin-evoked mechanical allodynia was blocked by AM251 (25 g i.pl.) only, as observed with URB597. In summary, peripheral inhibition of enzymes hydrolyzing 2-AG and AEA suppresses capsaicin-evoked behavioral hypersensitivities in a modality-specific manner. Modulation of endocannabinoids in the periphery suppresses capsaicin-evoked nocifensive behavior and thermal hyperalgesia through either CB1 or CB2 receptor mechanisms. By contrast, modulation of endocannabinoids suppresses capsaicin-evoked mechanical allodynia through CB1 mechanisms only. Inhibition of endocannabinoid transport was more effective in suppressing capsaicin-induced hypersensitivities compared to inhibition of either FAAH or MGL alone. These studies are the first to unveil the effects of pharmacologically increasing peripheral endocannabinoid levels on capsaicin-induced behavioral hypersensitivities.