Melissa Jones
Jie Wen
Uniformed Services University, USA
Biography
Interest in the medical use of cannabinoids has greatly increased in the last few years. Our previous studies have shown that inhibition of the minor endocannabinoid 2-AG hydrolytic enzyme alpha, beta-hydrolase domain 6 (ABHD6) significantly reduces neuroinflammation and exerts neuroprotection in animal models of traumatic brain injury and multiple sclerosis. Unlike inhibition of the principle 2-AG hydrolytic enzyme, monoacylglycerol lipase (MAGL), which leads to 2-AG overload and cannabinoid receptor desensitization, selective inhibition of ABHD6 is thought to provide therapeutic benefits without producing cannabimimetic side effects. Accumulating evidence suggests that neuroinflammation is a major contributing factor to the pathogenesis of neuropathic pain. In this study we sought to determine the potential therapeutic effect of a selective ABHD6 inhibitor WWL70 in the management of neuropathic pain. In the murine model of neuropathic pain induced by chronic constriction (CCI) of the sciatic nerve, we found that WWL70 treatment significantly alleviated CCI-induced thermal hyperalgesia and mechanical allodynia in the ipsilateral paw at 3 and 7 days post-injury. Treatment with WWL70 also significantly attenuated the increased inflammatory response characterized by the downregulation of TNF-α, IL-6, IL-1β, MCP-1 in the ipsilateral sciatic nerve, DRG and spinal cord of CCI mice. Co-administration of cannabinoid receptor antagonists did not affect the effect of WWL70, suggesting that WWL70’s anti-nociceptive effect is independent on cannabinoid signaling pathways. Treatment with WWL70 reduced the expression of COX-2 and PGES2 and the production of PGE2 in the injured sciatic nerve. This result suggested that interference with the eicosanoid signaling pathway contributes, at least in part, to the therapeutic mechanisms of WWL70 on CCI induced neuropathic pain.