title: Spinal 5-HT(3) receptor activation induces behavioral hypersensitivity via a neuronal-glial-neuronal signaling cascade.
abstract: Recent studies indicate that the descending serotonin (5-HT) system from the rostral ventromedial medulla (RVM) in the brainstem and the 5-HT(3) 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-HT(3) receptor and its contribution to facilitation of pain remain unclear. In the present study, activation of spinal 5-HT(3) receptor by intrathecal injection of a selective 5-HT(3) receptor agonist, SR57227, induced spinal glial hyperactivity, neuronal hyperexcitability, and pain hypersensitivity in rats. We found that there was neuron-to-microglia signaling via chemokine fractalkine, microglia to astrocyte signaling via the cytokine IL-18, astrocyte to neuronal signaling by IL-1β, and enhanced activation of GluN (NMDA) receptors in the spinal dorsal horn. In addition, exogenous brain-derived neurotrophic factor-induced descending pain facilitation was accompanied by upregulation of CD11b and GFAP expression in the spinal dorsal horn after microinjection in the RVM, and these events were significantly prevented by functional blockade of spinal 5-HT(3) receptors. Enhanced expression of spinal CD11b and GFAP after hindpaw inflammation was also attenuated by molecular depletion of the descending 5-HT system by intra-RVM Tph-2 shRNA interference. Thus, 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 neuron and glia.
authors: Department of Neural and Pain Sciences, Program in Neuroscience, Dental School, University of Maryland, Baltimore, Maryland 21201, USA.
authors: Ming
authors: M
authors: Gu
authors: Kan
authors: K
authors: Miyoshi
authors: Ronald
authors: R
authors: Dubner
authors: Wei
authors: W
authors: Guo
authors: Shiping
authors: S
authors: Zou
authors: Ke
authors: K
authors: Ren
authors: Koichi
authors: K
authors: Noguchi
authors: Feng
authors: F
authors: Wei
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D015153:Blotting, Western; D000073883:CX3C Chemokine Receptor 1; D018925:Chemokines / Q000502:physiology; D016207:Cytokines / Q000502:physiology; D004558:Electric Stimulation; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018014:Gene Transfer Techniques; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006930:Hyperalgesia / Q000139:chemically induced* / Q000523:psychology; D007150:Immunohistochemistry; D007278:Injections, Spinal; D020382:Interleukin-18 / Q000502:physiology; D053583:Interleukin-1beta / Q000502:physiology; D008297:Male; D008845:Microinjections; D009457:Neuroglia / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009475:Neurons, Afferent / Q000187:drug effects; D009619:Nociceptors / Q000187:drug effects / Q000502:physiology; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D019707:Receptors, Chemokine / Q000096:biosynthesis; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects; D044406:Receptors, Serotonin, 5-HT3 / Q000187:drug effects*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013116:Spinal Cord / Q000187:drug effects / Q000502:physiology*
chemical_list: D000073883:CX3C Chemokine Receptor 1; C516305:CX3CR1 protein, rat; D018925:Chemokines; D016207:Cytokines; D018690:Excitatory Amino Acid Agonists; D005904:Glial Fibrillary Acidic Protein; D020382:Interleukin-18; D053583:Interleukin-1beta; D010880:Piperidines; D019707:Receptors, Chemokine; D016194:Receptors, N-Methyl-D-Aspartate; D044406:Receptors, Serotonin, 5-HT3; D017366:Serotonin Receptor Agonists; C083009:4-amino-1-(6-chloro-2-pyridyl)piperidine hydrochloride