Cannabinoid WIN-55,212-2 mesylate inhibits tumor necrosis factor-α-induced expression of nitric oxide synthase in dorsal root ganglion neurons

Tan,Rong; Cao,Lijun

doi:10.3892/ijmm.2018.3687

Cannabinoid WIN-55,212-2 mesylate inhibits tumor necrosis factor-α-induced expression of nitric oxide synthase in dorsal root ganglion neurons

Authors:
- Rong Tan
- Lijun Cao
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Affiliations: Department of Anesthesiology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
Published online on: May 17, 2018 https://doi.org/10.3892/ijmm.2018.3687
Pages: 919-925
Copyright: © Tan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Tumor necrosis factor-α (TNF-α) is an established pain modulator in the peripheral nervous system. Elevated levels of TNF-α in dorsal root ganglion (DRG) neurons reportedly is critical for neuropathic pain processing. It has been shown that the production of nitric oxide, a key player in the development and maintenance of nociception, depends on the expression of nitric oxide synthases (NOSs) and their activities. Accumulating evidence also supports an important role of cannabinoids in modulating neuropathic pain. In this study, we explored the effects and the underlying mechanisms of crosstalk between TNF-α and cannabinoid on the expression/activity of NOS in DRG neurons. With or without knockdown of p38 mitogen-activated protein kinase (MAPK), DRG neurons were treated with TNF-α in the presence or absence of synthetic cannabinoid WIN-55,212-2 mesylate (WIN-55) and selective cannabinoid receptor (CB) antagonists. TNF-α significantly increased the NOS activity as well as the mRNA stability and expression of neuronal NOS (nNOS) in DRG neurons; this was abolished by inhibiting p38 MAPK signaling. WIN-55 inhibited TNF-α-induced p38 MAPK activity as well as TNF-α-induced increase of mRNA stability and expression/activity of nNOS; the inhibitory effect of WIN-55 was blocked by a selective CB2 antagonist. Our findings suggest that TNF-α induces the expression/activity of nNOS in DRG neurons by increasing its mRNA stability by a p38 MAPK-dependent mechanism; WIN-55 inhibits this effect of TNF-α by inhibiting p38 MAPK via CB2. By linking the functions of TNF-α, NOS and cannabinoid in DRG neurons, this study adds new insights into the molecular mechanisms underlying the pharmacologic effects of cannabinoids on neuropathic pain as well as into the pathophysiology of neuropathic pain.

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