Abstract
BackgroundTargeting the endocannabinoid system has emerged as an effective strategy for the treatment of inflammatory and neurological diseases. Unlike the inhibition of the principal 2-arachidonyl glycerol (2-AG) hydrolytic enzyme monoacylglycerol lipase (MAGL), which leads to 2-AG overload and cannabinoid receptor desensitization, selective inhibition of the minor 2-AG hydrolytic enzyme alpha, beta-hydrolase domain 6 (ABHD6) can provide therapeutic benefits without producing cannabimimetic side effects. We have shown that inhibition of ABHD6 significantly reduces neuroinflammation and exerts neuroprotection in animal models of traumatic brain injury and multiple sclerosis. However, the role of ABHD6 inhibition on neuropathic pain has not been explored.MethodsNeuropathic pain was induced by chronic constriction injury (CCI) of the mouse sciatic nerve and examined by Hargreaves and Von Frey tests. Activation of inflammatory cells and the production of cytokines and chemokines in the spinal cord dorsal horn, dorsal root ganglion (DRG), and sciatic nerve were assessed by qRT-PCR, enzyme-linked immunosorbent assay (ELISA), and immunohistochemistry. The levels of 2-AG and arachidonic acid (AA) in sciatic nerve were quantified by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS).ResultsTreatment with the selective ABHD6 inhibitor WWL70 significantly alleviated CCI-induced thermal hyperalgesia and mechanical allodynia. Microglia activation, macrophage infiltration, and the production of nociceptive mediators were reduced in the ipsilateral lumbar spinal cord dorsal horn, DRG, and sciatic nerve of WWL70-treated animals. The diminished cytokine and chemokine production is likely due to the inhibitory effect of WWL70 on NF-κB phosphorylation. Surprisingly, the anti-nociceptive and anti-inflammatory effects of WWL70 were not reversed by addition of the cannabinoid receptor antagonists. Treatment with WWL70 did not alter the levels of 2-AG, AA, and the phosphorylation of cytosolic phospholipase A2 (cPLA2), but significantly reduced the production of prostaglandin E2 (PGE2) and the expression of cyclooxygenase-2 (COX-2) and prostaglandin E synthase-2 (PGES2) in the injured sciatic nerve.ConclusionsThis study reveals a novel mechanism for the antinociceptive effect of the 2-AG catabolic enzyme ABHD6 inhibitor WWL70. Understanding the interaction between endocannabinoid and eicosanoid pathways might provide a new avenue for the treatment of inflammatory and neuropathic pain.
Highlights
Targeting the endocannabinoid system has emerged as an effective strategy for the treatment of inflammatory and neurological diseases
constriction injury (CCI)-induced mechanical allodynia and thermal hyperalgesia were attenuated by administration of WWL70 Eight to 10-week-old male C57BL/6 mice were subjected to CCI surgery and treated with various doses of WWL70 (1, 5, and 10 mg/kg)
We have shown that the ABHD6 inhibitor WWL70 can significantly reduce thermal hyperalgesia and mechanical allodynia
Summary
Targeting the endocannabinoid system has emerged as an effective strategy for the treatment of inflammatory and neurological diseases. Targeting the neuron-glial interaction or the neuroimmune interface is a suitable strategy for developing therapeutics to treat neuropathic pain. Targeting the endocananbinoid system in both neurons and glial cells can alleviate inflammatory and neuropathic pain [4]. This system is composed of cannabinoid type 1 (CB1) and type 2 (CB2) receptors, the endogenous ligands anandamide (AEA) and 2-arachidonyl glycerol (2-AG), and enzymes for their synthesis and hydrolysis [5]. Following the induction of inflammatory and neuropathic pain, the levels of AEA, 2-AG, and the cannabinoid receptors are increased in spinal cord and DRG [9, 10], suggesting endocannabinoid signaling might modulate the initiation and propagation of pain. Blockage of 2-AG and AEA degradation attenuates mechanical allodynia and thermal hyperalgesia in several inflammatory and neuropathic pain animal models [11,12,13,14,15]
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