JZL184 is anti-hyperalgesic in a murine model of cisplatin-induced peripheral neuropathy

Abstract

Cisplatin has been used effectively to treat a variety of cancers but its use is limited by the development of painful peripheral neuropathy. Because the endocannabinoid 2-arachidonoyl-sn-glycerol (2-AG) is anti-hyperalgesic in several preclinical models of chronic pain, the anti-hyperalgesic effect of JZL184, an inhibitor of 2-AG hydrolysis, was tested in a murine model of cisplatin-induced hyperalgesia. Systemic injection of cisplatin (1 mg/kg) produced mechanical hyperalgesia when administered daily for 7 days. Daily peripheral administration of a low dose of JZL184 in conjunction with cisplatin blocked the expression of mechanical hyperalgesia. Acute injection of a cannabinoid (CB)-1 but not a CB2 receptor antagonist reversed the anti-hyperalgesic effect of JZL184 indicating that downstream activation of CB1 receptors suppressed the expression of mechanical hyperalgesia. Components of endocannabinoid signaling in plantar hind paw skin and lumbar dorsal root ganglia (DRGs) were altered by treatments with cisplatin and JZL184. Treatment with cisplatin alone reduced levels of 2-AG and AEA in skin and DRGs as well as CB2 receptor protein in skin. Combining treatment of JZL184 with cisplatin increased 2-AG in DRGs compared to cisplatin alone but had no effect on the amount of 2-AG in skin. Evidence that JZL184 decreased the uptake of [3H]AEA into primary cultures of DRGs at a concentration that also inhibited the enzyme fatty acid amide hydrolase, in conjunction with data that 2-AG mimicked the effect of JZL184 on [3H]AEA uptake support the conclusion that AEA most likely mediates the anti-hyperalgesic effect of JZL184 in this model.

The Endogenous Cannabinoid System: A Budding Source of Targets for Treating Inflammatory and Neuropathic Pain

“…Conversely, AM1710 suppressed the maintenance of mechanical and cold allodynia in the cisplatin model through a CB 2 receptor mechanism of action, with no evidence of CB 1 receptor involvement (Deng et al, 2012). Finally, FAAH and MAGL inhibitors reduced cisplatin-induced mechanical and cold allodynia, which are CB 1 and CB 2 receptors-mediated (Guindon et al, 2013;Khasabova et al, 2014).…”

Peripherally Restricted Cannabinoids for the Treatment of Pain

“…This is reproduced by the administration of anandamide . Similarly, in a model of chemotherapy‐induced painful neuropathy, systemic administration of JZL184, an inhibitor of monoacylglycerol lipase (the enzyme that degrades 2‐AG), reduces pain‐related behaviors in mice via CB 1 receptors at the dorsal root ganglia (periphery) level …”

“…33 Similarly, in a model of chemotherapy-induced painful neuropathy, systemic administration of JZL184, an inhibitor of monoacylglycerol lipase (the enzyme that degrades 2-AG), reduces painrelated behaviors in mice via CB 1 receptors at the dorsal root ganglia (periphery) level. 34 The ex vivo activation of CB 1 receptors using arachidonoyl-2 0 -chloroethylamide (ACEA) reduces the nerve growth factor-induced transient receptor potential vanilloid type-1 (TRPV1) sensitization in peripheral nociceptors. 35 Accordingly, ACEA or methanandamide reduces peripheral nociceptor sensitization in rats, and their individual administration into the hind paw of rats attenuates mechanical allodynia and hyperalgesia via peripheral CB 1 (but not CB 2 ) activation in a model of chronic inflammatory pain.…”

Targeting Peripherally Restricted Cannabinoid Receptor 1, Cannabinoid Receptor 2, and Endocannabinoid-Degrading Enzymes for the Treatment of Neuropathic Pain Including Neuropathic Orofacial Pain

“…Repeated systemic administration of a threshold dose of this compound completely reversed paclitaxel-induced allodynia without development of tolerance, while a high dose induced tolerance to its anti-nociceptive effect [227]. Chronic local intra-plantar injection of JZL184 was also effective in reducing mechanical hyperalgesia in a cisplatin-induced neuropathic pain model [228].…”