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

Mol Pain. 2014 Jun 9;10:35. doi: 10.1186/1744-8069-10-35.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

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

Substances

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