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

J Pharmacol Exp Ther. 2018 Jul;366(1):169-183. doi: 10.1124/jpet.117.245704. Epub 2018 Mar 14.

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, 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*
  • Paclitaxel / adverse effects*
  • Phosphoproteins / metabolism
  • Piperidines / pharmacology
  • Piperidines / therapeutic use
  • Receptor, Cannabinoid, CB1 / metabolism
  • Receptor, Cannabinoid, CB2 / metabolism
  • Succinimides / pharmacology
  • Succinimides / therapeutic use
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Antineoplastic Agents
  • Benzodioxoles
  • Biomarkers
  • Carbamates
  • Ccl2 protein, mouse
  • Chemokine CCL2
  • Enzyme Inhibitors
  • JZL 184
  • MJN110
  • Phosphoproteins
  • Piperidines
  • Receptor, Cannabinoid, CB1
  • Receptor, Cannabinoid, CB2
  • Succinimides
  • p38 Mitogen-Activated Protein Kinases
  • Monoacylglycerol Lipases
  • Paclitaxel