Inhibitors of monoacylglycerol lipase, fatty-acid amide hydrolase and endocannabinoid transport differentially suppress capsaicin-induced behavioral sensitization through peripheral endocannabinoid mechanisms

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 may elucidate the role of endocannabinoids in controlling nociceptive transmission. We compared effects of the MGL inhibitor JZL184, the FAAH inhibitor URB597, and the endocannabinoid uptake inhibitor VDM11, administered locally in the paw, on behavioral hypersensitivities produced by capsaicin, the pungent ingredient in hot chili peppers. Intradermal capsaicin (10 μg i.pl.) produced nocifensive behavior, thermal hyperalgesia, and mechanical allodynia in rats. JZL184 (100 μg i.pl.) suppressed capsaicin-induced nocifensive behavior and thermal hyperalgesia without altering capsaicin-evoked mechanical allodynia. Effects of JZL184 were blocked by either the CB1 antagonist AM251 (80 μg i.pl.) or the CB2 antagonist AM630 (25 μg i.pl.). URB597 (75 μg i.pl.) suppressed capsaicin-induced mechanical allodynia without altering capsaicin-evoked thermal hyperalgesia or nocifensive behavior. Effects of URB597 were blocked by AM251 (80 μg i.pl.), but not by AM630 (25 μg i.pl.). VDM11 (100 μg i.pl.) suppressed capsaicin-evoked hypersensitivity for all three dependent measures (nocifensive behavior, thermal hyperalgesia, and mechanical allodynia), suggesting an additive effect following putative elevation of both AEA and 2-AG. The VDM11-induced suppression of capsaicin-evoked nocifensive behavior and thermal hyperalgesia was blocked by either AM251 (80 μg i.pl.) or AM630 (25 μg i.pl.), as observed with JZL184. The VDM11-induced suppression of capsaicin-evoked mechanical allodynia was blocked by AM251 (25 μg i.pl.) only, as observed with URB597. Thus, peripheral inhibition of enzymes hydrolyzing 2-AG and AEA suppresses capsaicin-evoked behavioral sensitization with distinct patterns of pharmacological specificity and in a non-overlapping and modality-specific manner. Modulation of endocannabinoids in the periphery suppressed capsaicin-evoked nocifensive behavior and thermal hyperalgesia through either CB1 or CB2 receptor mechanisms but suppressed capsaicin-evoked mechanical allodynia through CB1 mechanisms only. Inhibition of endocannabinoid transport was more effective in suppressing capsaicin-induced sensitization 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. Our data suggest that 2-AG, the putative product of MGL inhibition, and AEA, the putative product of FAAH inhibition, differentially suppress capsaicin-induced nociception through peripheral cannabinoid mechanisms.

Chemical Probes of Endocannabinoid Metabolism

“…or MAGL (JZL184, 100 mg i.p.l.) (Spradley et al, 2010). JZL184 attenuated the thermal hyperalgesia and nocifensive behavior caused by capsaicin injection, while URB597 reduced capsaicin- Fig.…”

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology

“…Inhibitors of AEA and 2-AG inactivation via FAAH, MAGL, or the putative EMT, administered locally at injury sites, produce antinociception, e.g., by differentially suppressing nociception provoked by intraplantar injections of capsaicin through peripheral cannabinoid mechanisms (813). The antinociceptive effects of systemic FAAH inhibitors were suggested to be mediated only by peripheral CB1 (813), and, indeed, a peripherally restricted FAAH inhibitor produced antinociception in models of nerve injury and inflammation (149).…”

“…The antinociceptive effects of systemic FAAH inhibitors were suggested to be mediated only by peripheral CB1 (813), and, indeed, a peripherally restricted FAAH inhibitor produced antinociception in models of nerve injury and inflammation (149). However, intrathecal injection of intermediate-high doses of a FAAH inhibitor also produce analgesia, and this is mediated by TRPV1 activation/desensitization due to either stronger elevation of spinal AEA or its enzymatic oxidation to compounds that still fully activate the channel (817).…”

Full Fatty Acid Amide Hydrolase Inhibition Combined with Partial Monoacylglycerol Lipase Inhibition: Augmented and Sustained Antinociceptive Effects with Reduced Cannabimimetic Side Effects in Mice

“…Pharmacologic inhibition or genetic deletion of FAAH (Cravatt et al, 2001;Kathuria et al, 2003) and MAGL (Long et al, 2009a;Chanda et al, 2010;Schlosburg et al, 2010) elevates respective AEA and 2-AG levels in the brain. Blockade of either enzyme produces antinociceptive effects in a variety of acute and chronic preclinical models of pain (Kathuria et al, 2003;Chang et al, 2006;Jhaveri et al, 2007;Russo et al, 2007;Kinsey et al, 2009;Spradley et al, 2010;Guindon et al, 2011Guindon et al, , 2013Ghosh et al, 2013). Inhibitors of these enzymes often lack full efficacy in neuropathic and inflammatory pain models, which reflects a potential limitation for their clinical development.…”