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Monoacylglycerol lipase inhibitors reverse paclitaxel-induced nociceptive behavior and proinflammatory markers in a mouse model of chemotherapy-induced neuropathy.

Monoacylglycerol lipase inhibitors reverse paclitaxel-induced nociceptive behavior and proinflammatory markers in a mouse model of chemotherapy-induced neuropathy.
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Curry Z, Wilkerson J, Bagdas D, Kyte S, Patel N, Donvito G, Mustafa MA, Poklis J, Niphakis M, Hsu KL, Cravatt BF, Gewirtz DA, Damaj MI, Lichtman AH,


Curry Z, Wilkerson J, Bagdas D, Kyte S, Patel N, Donvito G, Mustafa MA, Poklis J, Niphakis M, Hsu KL, Cravatt BF, Gewirtz DA, Damaj MI, Lichtman AH, (click to view)

Curry Z, Wilkerson J, Bagdas D, Kyte S, Patel N, Donvito G, Mustafa MA, Poklis J, Niphakis M, Hsu KL, Cravatt BF, Gewirtz DA, Damaj MI, Lichtman AH,

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The Journal of pharmacology and experimental therapeutics 2018 03 14() pii jpet.117.245704
Abstract

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, produce 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% C.L.) of 8.4 (5.2-13.6) and 1.8 (1.0-3.3) mg/kg. Complementary genetic and pharmacologic approaches revealed that the anti-allodynic 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 six 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.

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