title: 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.forename: Wei
authors.initials: W
authors.lastname: Guo
authors.forename: Kan
authors.initials: K
authors.lastname: Miyoshi
authors.forename: Ronald
authors.initials: R
authors.lastname: Dubner
authors.forename: Ming
authors.initials: M
authors.lastname: Gu
authors.forename: Man
authors.initials: M
authors.lastname: Li
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.forename: Jiale
authors.initials: J
authors.lastname: Yang
authors.forename: Shiping
authors.initials: S
authors.lastname: Zou
authors.forename: Ke
authors.initials: K
authors.lastname: Ren
authors.forename: Koichi
authors.initials: K
authors.lastname: Noguchi
authors.affiliation: Department of Neural and Pain Sciences, Dental School; Program in Neuroscience, University of Maryland, 650 W, Baltimore St, Baltimore, Maryland 21201, USA. fwei@umaryland.edu.
authors.forename: Feng
authors.initials: F
authors.lastname: Wei
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006930:Hyperalgesia / Q000139:chemically induced / Q000473:pathology*; D007249:Inflammation / Q000139:chemically induced / Q000150:complications; D008297:Male; D009437:Neuralgia / Q000188:drug therapy / Q000209:etiology; D009457:Neuroglia / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D058748:Pain Perception / Q000187:drug effects / Q000502:physiology*; D010880:Piperidines / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D012702:Serotonin Antagonists / Q000627:therapeutic use; D017366:Serotonin Receptor Agonists / Q000633:toxicity; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013116:Spinal Cord / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D013127:Spinal Nerves / Q000293:injuries
chemical_list: D005904:Glial Fibrillary Acidic Protein; D010880:Piperidines; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C083009:4-amino-1-(6-chloro-2-pyridyl)piperidine hydrochloride