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

Lin, Jia-Ji; Lin, Ye; Zhao, Tian-Zhi; Zhang, Chun-Kui; Zhang, Ting; Chen, Xiao-Li; Ding, Jia-Qi; Chang, Ting; Zhang, Zhuo; Sun, Chao; Zhao, Dai-Di; Zhu, Jun-Lin; Li, Zhu-Yi; Li, Jin-Lian

doi:10.7150/thno.19500

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

Research Paper

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

Jia-Ji Lin^{1, 2*}, Ye Lin^1*, Tian-Zhi Zhao^3*, 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 Li^1✉, Jin-Lian Li^2✉

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.

Citation:

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. https://www.thno.org/v07p2015.htm

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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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APA

Lin, J.J., Lin, Y., Zhao, T.Z., Zhang, C.K., Zhang, T., Chen, X.L., Ding, J.Q., Chang, T., Zhang, Z., Sun, C., Zhao, D.D., Zhu, J.L., Li, Z.Y., Li, J.L. (2017). Melatonin Suppresses Neuropathic Pain via MT2-Dependent and -Independent Pathways in Dorsal Root Ganglia Neurons of Mice. Theranostics, 7(7), 2015-2032. https://doi.org/10.7150/thno.19500.

ACS

Lin, J.J.; Lin, Y.; Zhao, T.Z.; Zhang, C.K.; Zhang, T.; Chen, X.L.; Ding, J.Q.; Chang, T.; Zhang, Z.; Sun, C.; Zhao, D.D.; Zhu, J.L.; Li, Z.Y.; Li, J.L. 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.

NLM

CSE

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. 2017. Melatonin Suppresses Neuropathic Pain via MT2-Dependent and -Independent Pathways in Dorsal Root Ganglia Neurons of Mice. Theranostics. 7(7):2015-2032.

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