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

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.

• Authors: Wei Guo, Kan Miyoshi, Ronald Dubner, Ming Gu, Man Li, Jian Liu, Jiale Yang, Shiping Zou, Ke Ren, Koichi Noguchi, Feng Wei
• Journal: Molecular pain (Mol Pain) Vol. 10 Pg. 35 (Jun 09 2014) ISSN: 1744-8069 [Electronic] United States
• PMID: 24913307 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Glial Fibrillary Acidic Protein
• Piperidines
• Serotonin Antagonists
• Serotonin Receptor Agonists
• 4-amino-1-(6-chloro-2-pyridyl)piperidine hydrochloride

Topics

• Animals
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Gene Expression Regulation (drug effects)
• Glial Fibrillary Acidic Protein (metabolism)
• Hyperalgesia (chemically induced, pathology)
• Inflammation (chemically induced, complications)
• Male
• Neuralgia (drug therapy, etiology)
• Neuroglia (drug effects, physiology)
• Neurons (drug effects, physiology)
• Pain Perception (drug effects, physiology)
• Piperidines (toxicity)
• Rats
• Rats, Sprague-Dawley
• Serotonin Antagonists (therapeutic use)
• Serotonin Receptor Agonists (toxicity)
• Signal Transduction (drug effects, physiology)
• Spinal Cord (cytology, drug effects, metabolism)
• Spinal Nerves (injuries)