Targeting monoacylglycerol lipase for the reversal and prevention of paclitaxel-induced allodynia in mice

Chemotherapy-induced peripheral neuropathy (CIPN) is a side-effect of chemotherapy causing pain in the hands and feet. In particular, paclitaxel causes CIPN lasting for years without effective treatment. There is a strong need for analgesics to both treat and prevent CIPN. One system containing multiple targets to treat CIPN is the endogenous cannabinoid system. This system consists of cannabinoid type 1 (CB1) and type 2 (CB2) receptors primarily expressed on presynaptic neurons and cells of the immune system, respectively. Inhibition of monoacylglycerol lipase (MAGL), which hydrolyzes the endogenous cannabinoid 2- arachidonoylglycerol (2-AG), with JZL184 or MJN110 produces antinociceptive and anti- inflammatory effects in rodent pain models. In this dissertation, we test the hypothesis that MAGL inhibitors will both reverse and prevent mouse paclitaxel-induced mechanical allodynia. JZL184 and MJN110 reversed paclitaxel allodynia in dose-dependent manners with ED50 values (95% C.L.) of 8.4 (5.2-13.6) and 1.8 (1.0-3.3) mg/kg. Using genetic and pharmacologic approaches, we demonstrate that the anti-allodynic effects of both inhibitors require both cannabinoid receptors. As CIPN treatment could require repeated dosing, we demonstrate that repeated administration of 4 mg/kg JZL184 for six days produces anti-allodynic effects in contrast to tolerance development after repeated treatment with 40 mg/kg. We also show that MJN110 attenuates paclitaxel-induced inflammation in the spinal cord and dorsal root ganglia (DRG), namely monocyte chemoattractant protein-1 (MCP-1, CCL2) and phosphorylated p38 MAPK (phospho-p38) expression. Using the conditioned place preference (CPP) paradigm, we demonstrate that MJN110 produces a CPP in paclitaxel-treated, but not in control mice. As CIPN develops during chemotherapy, we also show that JZL184 does not interfere with the anti- proliferative and anti-apoptotic effects of paclitaxel in A549 or H460 lung cancer cell lines. Lastly, we show that co-administration of MAGL inhibitors with paclitaxel prevents the development of allodynia. Co-treatment with 5 mg/kg MJN110 or 40 mg/kg JZL184 prevents allodynia up to one or two week(s), respectively, after paclitaxel cessation. Treatment with 40 mg/kg JZL184 prevents allodynia in both CB1 (+/+) and (-/-) mice, suggesting that prevention is CB1-independent. Taken together, these results suggest that MAGL is a viable target for both the treatment and prevention of paclitaxel-induced allodynia in mice