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Activated Microglia Contribute to Convergent Nociceptive Inputs to Spinal Dorsal Horn Neurons and the Development of Neuropathic Pain

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Abstract

The activation of microglia in the spinal dorsal horn following peripheral nerve injury has been reported previously, and this change has been proposed to contribute to the development of a neuropathic pain state. We recently demonstrated that peripheral nerve injury activated convergent nociceptive inputs to spinal dorsal horn neurons. The present study was designed to further examine the role of microglia in the activation of convergent nociceptive inputs as well as development of a neuropathic pain state after peripheral nerve injury. Tibial nerve injury initially induced hyposensitivity at 3 days post-injury, and this was followed by hypersensitivity to tactile and thermal stimuli at 14 days. The intraperitoneal administration of minocycline (30 mg/kg), an inhibitor of microglial activation, for 8 days starting on the day of surgery prevented increases in OX-42 immunofluorescence labeling in the spinal dorsal horn and the development of tactile and thermal hypersensitivity at 14 days post-injury. The same minocycline treatment (day 0–7) also reduced the nerve injury-induced convergence of nociceptive inputs to spinal dorsal horn neurons, as revealed by double immunofluorescence labeling for c-Fos induced by noxious heat stimulation of the hindpaw and phosphorylated extracellular signal-regulated kinase induced by electrical stimulation of the injured tibial nerve. However, the administration of minocycline for 8 days starting 7 days after surgery did not prevent nerve injury-induced microglial activation, convergent nociceptive inputs, or tactile and thermal hypersensitivity. These results suggest that microglial activation in the early stage following peripheral nerve injury plays an important role in the anomalous convergence of nociceptive signals to spinal dorsal horn neurons and the development of neuropathic pain.

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Abbreviations

ANOVA:

Analysis of variance

BDNF:

Brain-derived neurotrophic factor

c-Fos-IR:

c-Fos protein-like immunoreactive

CNS:

Central nervous system

ES:

Electrical stimulation

iNOS:

Inducible nitric oxide synthase

i.p.:

Intraperitoneal

MAPK:

Mitogen-activated protein kinase

p-ERK:

Phosphorylated extracellular signal-regulated kinase

p-ERK-IR:

p-ERK immunoreactive

PB:

Phosphate buffer

PBS:

Phosphate-buffered saline

PWL:

Paw withdrawal latency

PWT:

Paw withdrawal threshold

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Acknowledgments

This study was supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (24592764).

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The authors do not have any conflict of interest.

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Authors and Affiliations

  1. Department of Oral Function and Anatomy, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8525, Japan

    Yuya Yamamoto, Ryuji Terayama, Noriko Kishimoto, Kotaro Maruhama & Tomosada Sugimoto

  2. Department of Oral and Maxillofacial Reconstructive Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8525, Japan

    Yuya Yamamoto, Noriko Kishimoto, Masahide Mizutani & Seiji Iida

  3. Advanced Research Center for Oral and Craniofacial Sciences, Okayama University Dental School, Okayama, 700-8525, Japan

    Ryuji Terayama, Kotaro Maruhama, Masahide Mizutani, Seiji Iida & Tomosada Sugimoto

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  1. Yuya Yamamoto
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  2. Ryuji Terayama
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  3. Noriko Kishimoto
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  4. Kotaro Maruhama
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  5. Masahide Mizutani
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Correspondence to Ryuji Terayama.

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Yamamoto, Y., Terayama, R., Kishimoto, N. et al. Activated Microglia Contribute to Convergent Nociceptive Inputs to Spinal Dorsal Horn Neurons and the Development of Neuropathic Pain. Neurochem Res 40, 1000–1012 (2015). https://doi.org/10.1007/s11064-015-1555-8

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  • DOI: https://doi.org/10.1007/s11064-015-1555-8

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