1. Spinal 5-HT3 receptors mediate descending facilitation and contribute to behavioral hypersensitivity via a reciprocal neuron-glial signaling cascade
- Author
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Koichi Noguchi, Kan Miyoshi, Wei Guo, Jian Liu, Feng Wei, Man Li, Ming Gu, Shiping Zou, Ke Ren, Ronald Dubner, and Jia-Le Yang
- Subjects
Male ,Pain ,5-HT3 receptor ,Rats, Sprague-Dawley ,Cellular and Molecular Neuroscience ,Piperidines ,Glia ,Glial Fibrillary Acidic Protein ,Medicine ,Animals ,Receptor ,Proinflammatory cytokines ,Inflammation ,Neurons ,biology ,Dose-Response Relationship, Drug ,business.industry ,Research ,Pain Perception ,Nerve injury ,NMDA receptor ,Rats ,Serotonin Receptor Agonists ,Disease Models, Animal ,medicine.anatomical_structure ,Anesthesiology and Pain Medicine ,Spinal Nerves ,nervous system ,Gene Expression Regulation ,Spinal Cord ,Hyperalgesia ,biology.protein ,Molecular Medicine ,Neuralgia ,Serotonin ,Rostral ventromedial medulla ,Neuron ,Brainstem ,Serotonin Antagonists ,medicine.symptom ,business ,Neuroscience ,Neuroglia ,Astrocyte ,Signal Transduction - 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.
- Published
- 2014