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Spinal 5-HT3 receptors mediate descending facilitation and contribute to behavioral hypersensitivity via a reciprocal neuron-glial signaling cascade

Wei Guo1, Kan Miyoshi2, Ronald Dubner1, Ming Gu1, Man Li3, Jian Liu4, Jiale Yang1, Shiping Zou1, Ke Ren1, Koichi Noguchi2 and Feng Wei1*

Author Affiliations

1 Department of Neural and Pain Sciences, Dental School; Program in Neuroscience, University of Maryland, 650 W. Baltimore St, Baltimore, Maryland 21201, USA

2 Department of Anatomy and Neuroscience, Institute for Advanced Medical Sciences, Hyogo University, Hyogo 663-8501, Japan

3 Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China

4 Department of Anesthesiology, Jinling hospital, Nanjing University School of Medicine, Nanjing 210002, China

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Molecular Pain 2014, 10:35  doi:10.1186/1744-8069-10-35

Published: 9 June 2014

Abstract

Background

It has been recently recognized that the descending serotonin (5-HT) system from the rostral ventromedial medulla (RVM) in the brainstem and the 5-HT3 receptor subtype in the spinal dorsal horn are involved in enhanced descending pain facilitation after tissue and nerve injury. However, the mechanisms underlying the activation of the 5-HT3 receptor and its contribution to facilitation of pain remain unclear.

Results

In the present study, activation of spinal 5-HT3 receptors by intrathecal injection of a selective 5-HT3 receptor agonist SR 57227 induced spinal glial hyperactivity, neuronal hyperexcitability and pain hypersensitivity in rats. We found that there was neuron-to-microglia signaling via the chemokine fractalkine, microglia to astrocyte signaling via cytokine IL-18, astrocyte to neuronal signaling by IL-1β, and enhanced activation of NMDA receptors in the spinal dorsal horn. Glial hyperactivation in spinal dorsal horn after hindpaw inflammation was also attenuated by molecular depletion of the descending 5-HT system by intra-RVM Tph-2 shRNA interference.

Conclusions

These findings offer new insights into the cellular and molecular mechanisms at the spinal level responsible for descending 5-HT-mediated pain facilitation during the development of persistent pain after tissue and nerve injury. New pain therapies should focus on prime targets of descending facilitation-induced glial involvement, and in particular the blocking of intercellular signaling transduction between neurons and glia.

Keywords:
5-HT3 receptor; Glia; Proinflammatory cytokines; NMDA receptor; Pain