Inhibition of the spinal astrocytic ERK/TNF-αpathway activation correlates with the analgesic effects of 8-O-acetyl-SM in rat model of neuropathic pain
Background:Neuropathic pain (NP) continues to be challenging to treat due to lack of effective drugs.Spinal astrocytes play a pivotal role in nerve injury-induced central sensitization.Accumulating studies indicated thatglia-mediated inflammatory reactions contribute to the introduction and development of neuropathic pain.Besides,the activation of the extracellular regulated protein kinases (ERK)/tumor necrosis α pathway in astrocytes has been reported to be critical for spinal astrocytic activation and neuropathic pain (NP) development after spinal nerve ligation (SNL).8-O-acetyl-SM (8-OaS), a major active component of a traditional Chinese drug, Lamiophlomisrotata, possesses potent immuno-suppressive activities.Methods:The effects of lidocaine, ketamineand 8-OaS on SNL-induced mechanical allodynia were investigated using behavioral tests.The activation of spinal glial fibrillary acidic protein (GFAP) , pERKand TNF-αwas observed by immunofluorescent histochemistry and Western blot.Results:In the present study, we observed that intrathecalinjection of lidocaine,ketamineand8-OaS significantly reduced SNL-induced mechanical hypersensitivity and the anti-nociception effect of 8-OaS in a dose dependent manner.Double immunostaining showed that ERK was highly expressed in astrocytes after SNL,indicatingthat ERK signaling pathway participates in the activation of astrocytes.We further observed that intrathecalinjection of ERK inhibitor (PD98059)significantly decreased spinal astrocytic activation and TNF-α expression.Finally, Western blot analysis revealed that intrathecal 8-OaS (ED50) could also reduce SNL-induced ERK phosphorylation and TNF-α expression.However, no significant increasesin mechanical hindpawwithdrawal threshold and TNF-αtexpression were observed compared with the 8-OaS-treated groupafter co-treatment with 8-OaS and PD98059.Conclusion: our results suggest thatthe analgesic effects of 8-OaS in NP are mainly mediatedby the down-regulation of SNL-induced astrocytic activation, which is via the inhibition of ERK/TNF-αpathway.
Wei Zhang Jian Wang Meng-Ying Li Jing-Wen Wang Yin Wu Yu-Wen Li Jia Cui Na Jia Lei Wang Yu-Lin Dong Yun-Qing Li Ai-Dong Wen
Department of Pharmacy,Xijing Hospital;The Fourth Military Medical University,Xi”an 710032,China Student of the Year 2012,The Fourth Military Medical University,Xi”an 710032,China Department of Endocrinology,Xijing Hospital;The Fourth Military Medical University,Xi”an 710032,Chin Department of Anatomy and K.K.Leung Brain Research Centre,The Fourth Military Medical University,Xi” Department of Anatomy and K.K.Leung Brain Research Centre,The Fourth Military Medical University,Xi”