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Melatonin Attenuates Pain Hypersensitivity and Decreases Astrocyte-Mediated Spinal Neuroinflammation in a Rat Model of Oxaliplatin-Induced Pain

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Abstract

Neuroinflammatory response in spinal dorsal horn has been demonstrated to be a critical factor in oxaliplatin-induced pain. Melatonin has been shown to have anti-inflammatory and anti-allodynia effects in both preclinical and clinical studies. In the present study, we investigated the role of systemic administration of melatonin on oxaliplatin-induced pain. Intraperitoneal (i.p.) injection with oxaliplatin induced significantly mechanical allodynia and thermal hyperalgesia. Melatonin (i.p.) significantly alleviated mechanical allodynia and thermal hyperalgesia in the oxaliplatin but not sham-treated rats. The attenuation of nociceptive response persisted at least to 3 days after melatonin injection, throughout the entire observing window. Immunohistochemistry showed that oxaliplatin induced a significant increase of glial fibrillary acidic protein (GFAP) immunodensities, which could be suppressed by melatonin. Western blotting showed that GFAP protein levels were significantly elevated in the oxaliplatin-vehicle group. Melatonin significantly decreased oxaliplatin-induced upregulation of GFAP expressions. Oxaliplatin injection also enhanced the messenger RNA (mRNA) expressions of cytokines including interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) and chemokines including monocyte chemoattractant protein-1 (MCP-1) and monocyte inflammatory protein-1 (MIP-1α) in the spinal dorsal horn, which could be significantly repressed by melatonin. In vitro study showed that mRNA levels of TNF-α, IL-1β, MCP-1, and MIP-1α in primarily astrocytes were significantly increased after lipopolysaccharide (LPS, 1 μg/ml) stimulation. Melatonin (10 and 100 μM) greatly inhibited synthesis of these inflammatory mediators, in a dose-related manner. Conclusively, our data provide a novel implication of anti-nociceptive mechanism of melatonin in chemotherapy-related pain.

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Abbreviations

cDNA:

Complementary DNA

GAPDH:

Glyceraldehyde-3-phosphate-dehydrogenase

GFAP:

Glial fibrillary acidic protein

IL-1β:

Interleukin-1β

i.p. :

Intraperitoneal

LPS:

Lipopolysaccharide

MCP-1:

Monocyte chemoattractant protein-1

MIP-1α:

Monocyte inflammatory protein-1

NFκB:

Nuclear factor kappa B

PB:

Phosphate buffer

PCR:

Polymerase chain reaction

PWL:

Paw withdrawal latency

PWT:

Paw withdrawal threshold

TLRs:

Toll-like receptors

TNF-α:

Tumor necrosis factor-α

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Acknowledgments

This study was supported by the grants from Medicine Health Science and Technology Program of Zhejiang Province (No. 2017200948) and National Natural Science Foundation of China (No. 81471889).

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Authors and Affiliations

  1. Department of Intensive Care Unit, Second Affiliated Hospital, School of Medicine, Zhejiang University, No. 88 Jiefang Road, Hangzhou, Zhejiang, 310009, China

    Ye-song Wang, Wei Cui, Li-bin Li, Zhao-cai Zhang, Bao-ping Tian & Gen-sheng Zhang

  2. Department of Neurointensive Care Unit, Second Affiliated Hospital, School of Medicine, Zhejiang University, No. 88 Jiefang Road, Hangzhou, Zhejiang, 310009, China

    Yuan-yuan Li

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  1. Ye-song Wang
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Ye-song Wang and Yuan-yuan Li contributed equally to this study.

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Sup Fig. 1

Immunostaining of primary cultured astrocytes with the astrocytic marker glial fibrillary acidic protein (GFAP). (JPEG 402 kb)

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Wang, Ys., Li, Yy., Cui, W. et al. Melatonin Attenuates Pain Hypersensitivity and Decreases Astrocyte-Mediated Spinal Neuroinflammation in a Rat Model of Oxaliplatin-Induced Pain. Inflammation 40, 2052–2061 (2017). https://doi.org/10.1007/s10753-017-0645-y

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