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Experimental Brain Research

, Volume 236, Issue 12, pp 3203–3213 | Cite as

A3 adenosine receptor agonist attenuates neuropathic pain by suppressing activation of microglia and convergence of nociceptive inputs in the spinal dorsal horn

  • Ryuji TerayamaEmail author
  • Mitsuyasu Tabata
  • Kotaro Maruhama
  • Seiji Iida
Research Article
  • 146 Downloads

Abstract

Peripheral nerve injuries cause glial activation and neuronal hyperactivity in the spinal dorsal horn. These changes have been considered to be involved in the underlying mechanisms for the development and maintenance of neuropathic pain. Using double immunofluorescence labeling, we previously demonstrated that spinal microglial activation induced by nerve injury enhanced convergence of nociceptive inputs in the spinal dorsal horn from uninjured afferents. The adenosine A3 receptor (A3AR) agonists have been shown to have antinociceptive activities in several experimental neuropathic pain models. However, the mechanisms underlying these antinociceptive actions of the A3AR agonist are still not fully explored. In this study, the effects of the A3AR agonist (i.e., IB-MECA) on microglial activation, enhancement of convergent nociceptive inputs, and nocifensive behaviors were examined after tibial nerve injury. Injury to the tibial nerve initially caused hyposensitivity to touch stimulus at 3 days, and then resulted in tactile allodynia at 14-day post-injury. The daily systemic administration of IB-MECA (0.1 mg/kg/day) for 8 days in a row starting on the day of nerve injury or 7 days after nerve injury prevented the development of behaviorally assessed hypersensitivities, and spinal microglial activation induced by nerve injury. These treatments also suppressed anomalous convergence of nociceptive primary inputs in the spinal dorsal horn. The present findings indicate that the A3AR agonist attenuates neuropathic pain states by suppressing enhanced microglial activation, and anomalous convergence of nociceptive inputs in the spinal dorsal horn from uninjured afferents after injury to the peripheral nerve.

Keywords

Adenosine A3AR Microglia Nerve injury Spinal dorsal horn 

Abbreviations

A3AR

Adenosine A3 receptor

ANOVA

Analysis of variance

BDNF

Brain-derived neurotrophic factor

CCD

Charge-coupled device

c-Fos-IR

c-Fos protein-like immunoreactive

CNS

Central nervous system

COX-2

Cyclooxygenase-2

DMSO

Dimethyl sulfoxide

ES

Electrical stimulation

IB-MECA

1-Deoxy-1-[6-[[(3-iodophenyl)methyl]amino]-9H-purin-9-yl]-N-methyl-β-d-ribofuranuronamide

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

PWT

Paw withdrawal threshold

TNF-α

Tissue necrosis factor-α

Notes

Acknowledgements

This study was supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (16K11440).

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  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.Department of Maxillofacial Anatomy and NeuroscienceHiroshima University Graduate School of Biomedical and Health SciencesHiroshimaJapan

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