Theranostics 2017; 7(7):2015-2032. doi:10.7150/thno.19500

Research Paper

Melatonin Suppresses Neuropathic Pain via MT2-Dependent and -Independent Pathways in Dorsal Root Ganglia Neurons of Mice

Jia-Ji Lin1, 2*, Ye Lin1*, Tian-Zhi Zhao3*, Chun-Kui Zhang2, Ting Zhang2, Xiao-Li Chen1, Jia-Qi Ding1, Ting Chang1, Zhuo Zhang1, Chao Sun1, Dai-Di Zhao1, Jun-Lin Zhu3, Zhu-Yi Li1✉, Jin-Lian Li2✉

1. Department of Neurology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shannxi, 710004, China;
2. Department of Anatomy, Fourth Military Medical University, Xi'an, Shannxi, 710032, China;
3. Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shannxi, 710004, China.
* Jia-Ji Lin, Ye Lin and Tian-Zhi Zhao contributed equally to this work.

Abstract

Melatonin (Mel) and its receptors (MT1 and MT2) have a well-documented efficacy in treating different pain conditions. However, the anti-nociceptive effects of Mel and Mel receptors in neuropathic pain (NP) are poorly understood. To elucidate this process, pain behaviors were measured in a dorsal root ganglia (DRG)-friendly sciatic nerve cuffing model. We detected up-regulation of MT2 expression in the DRGs of cuff-implanted mice and its activation by the agonist 8-M-PDOT (8MP). Also, Mel attenuated the mechanical and thermal allodynia induced by cuff implantation. Immunohistochemical analysis demonstrated the expression of MT2 in the DRG neurons, while MT1 was expressed in the satellite cells. In cultured primary neurons, microarray analysis and gene knockdown experiments demonstrated that MT2 activation by 8MP or Mel suppressed calcium signaling pathways via MAPK1, which were blocked by RAR-related orphan receptor alpha (RORα) activation with a high dose of Mel. Furthermore, expression of nitric oxide synthase 1 (NOS1) was down-regulated upon Mel treatment regardless of MT2 or RORα. Application of Mel or 8MP in cuff-implanted models inhibited the activation of peptidergic neurons and neuro-inflammation in the DRGs by down-regulating c-fos, calcitonin gene-related peptide [CGRP], and tumor necrosis factor-1α [TNF-1α] and interleukin-1β [IL-1β]. Addition of the MT2 antagonist luzindole blocked the effects of 8MP but not those of Mel. In conclusion, only MT2 was expressed in the DRG neurons and up-regulated upon cuff implantation. The analgesic effects of Mel in cuff-implanted mice were closely associated with both MT2-dependent (MAPK-calcium channels) and MT2-independent (NOS1) pathways in the DRG.

Keywords: melatonin, neuropathic pain, melatonin receptor, dorsal root ganglia, neuron.

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How to cite this article:
Lin JJ, Lin Y, Zhao TZ, Zhang CK, Zhang T, Chen XL, Ding JQ, Chang T, Zhang Z, Sun C, Zhao DD, Zhu JL, Li ZY, Li JL. Melatonin Suppresses Neuropathic Pain via MT2-Dependent and -Independent Pathways in Dorsal Root Ganglia Neurons of Mice. Theranostics 2017; 7(7):2015-2032. doi:10.7150/thno.19500. Available from http://www.thno.org/v07p2015.htm