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Neurochemical Research

, Volume 40, Issue 5, pp 1000–1012 | Cite as

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

  • Yuya Yamamoto
  • Ryuji Terayama
  • Noriko Kishimoto
  • Kotaro Maruhama
  • Masahide Mizutani
  • Seiji Iida
  • Tomosada Sugimoto
Original Paper

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.

Keywords

Microglia Minocycline Nerve injury c-Fos ERK Spinal dorsal horn 

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

Notes

Acknowledgments

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

Conflict of interest

The authors do not have any conflict of interest.

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Yuya Yamamoto
    • 1
    • 2
  • Ryuji Terayama
    • 1
    • 3
  • Noriko Kishimoto
    • 1
    • 2
  • Kotaro Maruhama
    • 1
    • 3
  • Masahide Mizutani
    • 2
    • 3
  • Seiji Iida
    • 2
    • 3
  • Tomosada Sugimoto
    • 1
    • 3
  1. 1.Department of Oral Function and AnatomyOkayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOkayamaJapan
  2. 2.Department of Oral and Maxillofacial Reconstructive SurgeryOkayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOkayamaJapan
  3. 3.Advanced Research Center for Oral and Craniofacial SciencesOkayama University Dental SchoolOkayamaJapan

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