Monoacylglycerol Lipase Inhibitors Reverse Paclitaxel-Induced Nociceptive Behavior and Proinflammatory Markers in a Mouse Model of Chemotherapy-Induced Neuropathy

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 366; no. 1; p. 169
• Main Authors: Curry, Zachary A, Wilkerson, Jenny L, Bagdas, Deniz, Kyte, S Lauren, Patel, Nipa, Donvito, Giulia, Mustafa, Mohammed A, Poklis, Justin L, Niphakis, Micah J, Hsu, Ku-Lung, Cravatt, Benjamin F, Gewirtz, David A, Damaj, M Imad, Lichtman, Aron H
• Format: Journal Article
• Language: English
• Published: United States 01-07-2018
• Subjects: Animals; Antineoplastic Agents - adverse effects; Apoptosis - drug effects; Benzodioxoles - pharmacology; Benzodioxoles - therapeutic use; Biomarkers - metabolism; Carbamates - pharmacology; Carbamates - therapeutic use; Cell Line, Tumor; Cell Proliferation - drug effects; Chemokine CCL2 - metabolism; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Humans; Hyperalgesia - chemically induced; Hyperalgesia - drug therapy; Hyperalgesia - metabolism; Hyperalgesia - physiopathology; Inflammation - metabolism; Male; Mice; Monoacylglycerol Lipases - antagonists & inhibitors; Nociception - drug effects; p38 Mitogen-Activated Protein Kinases - metabolism; Paclitaxel - adverse effects; Phosphoproteins - metabolism; Piperidines - pharmacology; Piperidines - therapeutic use; Receptor, Cannabinoid, CB1 - metabolism; Receptor, Cannabinoid, CB2 - metabolism; Succinimides - pharmacology; Succinimides - therapeutic use
• ISSN: 1521-0103
• DOI: 10.1124/jpet.117.245704

Although paclitaxel effectively treats various cancers, its debilitating peripheral neuropathic pain side effects often persist long after treatment has ended. Therefore, a compelling need exists for the identification of novel pharmacologic strategies to mitigate this condition. As inhibitors of monoacylglycerol lipase (MAGL), the primary hydrolytic enzyme of the endogenous cannabinoid, 2-arachidonyolglycerol, produces antinociceptive effects in numerous rodent models of pain, we investigated whether inhibitors of this enzyme (i.e., JZL184 and MJN110) would reverse paclitaxel-induced mechanical allodynia in mice. These drugs dose dependently reversed allodynia with respective ED
values (95% confidence limit) of 8.4 (5.2-13.6) and 1.8 (1.0-3.3) mg/kg. Complementary genetic and pharmacologic approaches revealed that the antiallodynic effects of each drug require both cannabinoid receptors, CB
and CB
MJN110 reduced paclitaxel-mediated increased expression of monocyte chemoattractant protein-1 (MCP-1, CCL2) and phospho-p38 MAPK in dorsal root ganglia as well as MCP-1 in spinal dorsal horn. Whereas the antinociceptive effects of high dose JZL184 (40 mg/kg) underwent tolerance following 6 days of repeated dosing, repeated administration of a threshold dose (i.e., 4 mg/kg) completely reversed paclitaxel-induced allodynia. In addition, we found that the administration of MJN110 to control mice lacked intrinsic rewarding effects in the conditioned place preference (CPP) paradigm. However, it produced a CPP in paclitaxel-treated animals, suggesting a reduced paclitaxel-induced aversive state. Importantly, JZL184 did not alter the antiproliferative and apoptotic effects of paclitaxel in A549 and H460 non-small cell lung cancer cells. Taken together, these data indicate that MAGL inhibitors reverse paclitaxel-induced neuropathic pain without interfering with chemotherapeutic efficacy.