PT  - JOURNAL ARTICLE
AU  - Zachary A. Curry
AU  - Jenny L. Wilkerson
AU  - Deniz Bagdas
AU  - S. Lauren Kyte
AU  - Nipa Patel
AU  - Giulia Donvito
AU  - Mohammed A. Mustafa
AU  - Justin L. Poklis
AU  - Micah J. Niphakis
AU  - Ku-Lung Hsu
AU  - Benjamin F. Cravatt
AU  - David A. Gewirtz
AU  - M. Imad Damaj
AU  - Aron H. Lichtman
TI  - Monoacylglycerol Lipase Inhibitors Reverse Paclitaxel-Induced Nociceptive Behavior and Proinflammatory Markers in a Mouse Model of Chemotherapy-Induced Neuropathy
AID  - 10.1124/jpet.117.245704
DP  - 2018 Jul 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 169--183
VI  - 366
IP  - 1
4099  - http://jpet.aspetjournals.org/content/366/1/169.short
4100  - http://jpet.aspetjournals.org/content/366/1/169.full
SO  - J Pharmacol Exp Ther2018 Jul 01; 366
AB  - 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 ED50 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, CB1 and CB2. 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.