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Serotonergic transmission after spinal cord injury

  • Neurology and Preclinical Neurological Studies - Review Article
  • Published:
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Abstract

Changes in descending serotonergic innervation of spinal neural activity have been implicated in symptoms of paralysis, spasticity, sensory disturbances and pain following spinal cord injury (SCI). Serotonergic neurons possess an enhanced ability to regenerate or sprout after many types of injury, including SCI. Current research suggests that serotonine (5-HT) release within the ventral horn of the spinal cord plays a critical role in motor function, and activation of 5-HT receptors mediates locomotor control. 5-HT originating from the brain stem inhibits sensory afferent transmission and associated spinal reflexes; by abolishing 5-HT innervation SCI leads to a disinhibition of sensory transmission. 5-HT denervation supersensitivity is one of the key mechanisms underlying the increased motoneuron excitability that occurs after SCI, and this hyperexcitability has been demonstrated to underlie the pathogenesis of spasticity after SCI. Moreover, emerging evidence implicates serotonergic descending facilitatory pathways from the brainstem to the spinal cord in the maintenance of pathologic pain. There are functional relevant connections between the descending serotonergic system from the rostral ventromedial medulla in the brainstem, the 5-HT receptors in the spinal dorsal horn, and the descending pain facilitation after tissue and nerve injury. This narrative review focussed on the most important studies that have investigated the above-mentioned effects of impaired 5-HT-transmission in humans after SCI. We also briefly discussed the promising therapeutical approaches with serotonergic drugs, monoclonal antibodies and intraspinal cell transplantation.

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References

  • Ahn AH, Basbaum AI (2006) Tissue injury regulates serotonin 1D receptor expression: implications for the control of migraine and inflammatory pain. J Neurosci 26:8332–8338

    CAS  PubMed Central  PubMed  Google Scholar 

  • Aira Z, Buesa I, Gallego M, García Del Caño G, Mendiable N, Mingo J, Rada D, Bilbao J, Zimmermann M, Azkue JJ (2012) Time-dependent cross talk between spinal serotonin 5-HT2A receptor and mGluR1 subserves spinal hyperexcitability and neuropathic pain after nerve injury. J Neurosci 32(39):13568–13581

    CAS  PubMed  Google Scholar 

  • Alilain WJ, Horn KP, Hu H, Dick TE, Silver J (2011) Functional regeneration of respiratory pathways after spinal cord injury. Nature 475(7355):196–200

    CAS  PubMed Central  PubMed  Google Scholar 

  • Antri M, Mouffle C, Orsal D, Barthe JY (2003) 5-HT1A receptors are involved in short- and long-term processes responsible for 5-HT-induced locomotor function recovery in chronic spinal rat. Eur J Neurosci 18:1963–1972

    CAS  PubMed  Google Scholar 

  • Antri M, Barthe JY, Mouffle C, Orsal D (2005) Long-lasting recovery of locomotor function in chronic spinal rat following chronic combined pharmacological stimulation of serotonergic receptors with 8-OHDPAT and quipazine. Neurosci Lett 384:162–167

    CAS  PubMed  Google Scholar 

  • Ashby P, McCrea DA (1987) Neurophysiology of spinal spasticity. In: Davidoff RA (ed) Handbook of the spinal cord. Dekker, New York, pp 119–143

    Google Scholar 

  • Baker LL, Chandler SH (1987) Characterization of postsynaptic potentials evoked by sural nerve stimulation in hindlimb motoneurons from acute and chronic spinal cats. Brain Res 420:340–350

    CAS  PubMed  Google Scholar 

  • Ballermann M, Fouad K (2006) Spontaneous locomotor recovery in spinal cord injured rats is accompanied by anatomical plasticity of reticulospinal fibers. Eur J Neurosci 23:1988–1996

    PubMed  Google Scholar 

  • Barbeau H, Rossignol S (1991) Initiation and modulation of the locomotor pattern in the adult chronic spinal cat by noradrenergic, serotonergic and dopaminergic drugs. Brain Res 546:250–260

    CAS  PubMed  Google Scholar 

  • Barbeau H, Fung J, Leroux A, Ladouceur M (2002) A review of the adaptability and recovery of locomotion after spinal cord injury. Prog Brain Res 137:9–25

    CAS  PubMed  Google Scholar 

  • Bardin L, Tarayre JP, Malfetes N, Koek W, Colpaert FC (2003) Profound, non-opioid analgesia produced by the high-efficacy 5-HT(1A) agonist F 13640 in the formalin model of tonic nociceptive pain. Pharmacology 67:182–194

    CAS  PubMed  Google Scholar 

  • Bareyre FM, Kerschensteiner M, Raineteau O, Mettenleiter TC, Weinmann O, Schwab ME (2004) The injured spinal cord spontaneously forms a new intraspinal circuit in adult rats. Nat Neurosci 7:269–277

    CAS  PubMed  Google Scholar 

  • Basbaum AI, Zahs K, Lord B (1988) The fiber caliber of 5-HT immunoreactive axons in the dorsolateral funiculus of the spinal cord of the rat and cat. Somatosens Res 5:177–185

    CAS  PubMed  Google Scholar 

  • Bennett DJ, Hultborn H, Fedirchuk B, Gorassini M (1998) Synaptic activation of plateaus in hindlimb motoneurons of decerebrate cats. J Neurophysiol 80:2023–2037

    CAS  PubMed  Google Scholar 

  • Bennett DJ, Gorassini M, Fouad K, Sanelli L, Han Y, Cheng J (1999) Spasticity in rats with sacral spinal cord injury. J Neurotrauma 16:69–84

    CAS  PubMed  Google Scholar 

  • Bennett DJ, Sanelli L, Cooke C, Harvey PJ, Gorassini MA (2004) Spastic long-lasting reflexes in the awake rat after sacral spinal cord injury. J Neurophysiol 91:2247–2258

    CAS  PubMed  Google Scholar 

  • Bharne AP, Upadhya MA, Kokare DM, Subhedar NK (2011) Effects of alpha-melanocyte stimulating hormone on locomotor recovery following spinal cord injury in mice: role of serotoninergc system. Neuropeptides 45(1):25–31

    CAS  PubMed  Google Scholar 

  • Boulenguez P, Liabeuf S, Bos R, Bras H, Jean-Xavier C, Brocard C, Stil A, Darbon P, Cattaert D, Delpire E, Marsala M, Vinay L (2010) Down-regulation of the potassium-chloride cotransporter KCC2 contributes to spasticity after spinal cord injury. Nat Med 16:302–307

    CAS  PubMed  Google Scholar 

  • Bregman BS (1987) Development of serotonin immunoreactivity in the rat spinal cord and its plasticity after neonatal spinal cord lesions. Brain Res 431:245–263

    CAS  PubMed  Google Scholar 

  • Brenchat A, Zamanillo D, Hamon M, Romero L, Vela JM (2012) Role of peripheral vesus spinal 5-HT(7) receptors in the modulation of pain undersensitizing conditions. Eur J Pain 16(1):72–81

    CAS  PubMed  Google Scholar 

  • Brustein E, Rossignol S (1999) Recovery of locomotion after ventral and ventrolateral spinal lesions in the cat. II. Effects of noradrenergic and serotoninergic drugs. J Neurophysiol 81:1513–1530

    CAS  PubMed  Google Scholar 

  • Buchanan JT, Grillner S (1987) Newly identified ‘glutamate interneurons’ and their role in locomotion in the lamprey spinal cord. Science 236:312–314

    CAS  PubMed  Google Scholar 

  • Butt SJ, Harris-Warrick RM, Kiehn O (2002) Firing properties of identified interneuron populations in the mammalian hindlimb central pattern generator. J Neurosci 22:9961–9971

    CAS  PubMed  Google Scholar 

  • Carlsson A, Magnusson T, Rosengren E (1963) 5-Hydroxytryptamine of the spinal cord normally and after transection. Experientia 19:359

    CAS  PubMed  Google Scholar 

  • Chanrion B, Mannoury la Cour C, Gavarini S, Seimandi M, Vincent L, Pujol JF, Bockaert J, Marin P, Millan MJ (2008) Inverse agonist and neutral antagonist actions of antidepressants at recombinant and native 5-hydroxytryptamine2C receptors: differential modulation of cell surface expression and signal transduction. Mol Pharmacol 73:748–757

    CAS  PubMed  Google Scholar 

  • Chau C, Barbeau H, Rossignol S (1998) Effects of intrathecal alpha1- and alpha2-noradrenergic agonists and norepinephrine on locomotion in chronic spinal cats. J Neurophysiol 79:2941–2963

    CAS  PubMed  Google Scholar 

  • Clarke RW, Harris J, Houghton AK (1996) Spinal 5-HT-receptors and tonic modulation of transmission through a withdrawal reflex pathway in the decerebrated rabbit. Br J Pharmacol 119:1167–1176

    CAS  PubMed Central  PubMed  Google Scholar 

  • Clarke RW, Eves S, Harris J, Peachey JE, Stuart E (2002) Interactions between cutaneous afferent inputs to a withdrawal reflex in the decerebrated rabbit and their control by descending and segmental systems. Neuroscience 112:555–571

    CAS  PubMed  Google Scholar 

  • Colado MI, Arnedo A, Peralta E, Del Rio J (1988) Unilateral dorsal rhizotomy decreases monoamine levels in the rat spinal cord. Neurosci Lett 87:302–306

    Google Scholar 

  • Colpaert FC (2006) 5-HT1A receptor activation: new molecular and neuroadaptive mechanisms of pain relief. Curr Opin Investig Drugs 7:40–47

    CAS  PubMed  Google Scholar 

  • Cormier CM, Mukhida K, Walker G, Marsh DR (2010) Development of aurtonomic dysreflexia is associated with a lack of serotoninergic axons in the intermediolatweral cell column. J Neurotrauma 27(10):1805–1818

    PubMed  Google Scholar 

  • Courtine G, Song B, Roy RR, Zhong H, Herrmann JE, Ao Y, Qi J, Edgerton VR, Sofroniew MV (2008) Recovery of supraspinal control of stepping via indirect propriospinal relay connections after spinal cord injury. Nat Med 14:69–74

    CAS  PubMed Central  PubMed  Google Scholar 

  • Cowley KC, Schmidt BJ (1994) A comparison of motor patterns induced by N-methyl-d-aspartate, acetylcholine and serotonin in the in vitro neonatal rat spinal cord. Neurosci Lett 171:147–150

    CAS  PubMed  Google Scholar 

  • Cowley KC, Zaporozhets E, Schmidt BJ (2008) Propriospinal neurons are sufficient for bulbospinal transmission of the locomotor command signal in the neonatal rat spinal cord. J Physiol 586:1623–1635

    CAS  PubMed Central  PubMed  Google Scholar 

  • Davies SJ, Fitch MT, Memberg SP, Hall AK, Raisman G, Silver J (1997) Regeneration of adult axons in white matter tracts of the central nervous system. Nature 390:680–683

    CAS  PubMed  Google Scholar 

  • De Deurwaerdere P, Navailles S, Berg KA, Clarke WP, Spampinato U (2004) Constitutive activity of the serotonin2C receptor inhibits in vivo dopamine release in the rat striatum and nucleus accumbens. J Neurosci 24:3235–3241

    PubMed  Google Scholar 

  • de Leon RD, Hodgson JA, Roy RR, Edgerton VR (1998) Locomotor capacity attributable to step training versus spontaneous recovery after spinalization in adult cats. J Neurophysiol 79:1329–1340

    PubMed  Google Scholar 

  • Di Pasquale E, Lindsay A, Feldman J, Monteau R, Hilaire G (1997) Serotonergic inhibition of phrenic motoneuron activity: an in vitro study in neonatal rat. Neurosci Lett 230:29–32

    PubMed  Google Scholar 

  • Dietz V, Harkema SJ (2004) Locomotor activity in spinal cord-injured persons. J Appl Physiol 5(96):1954–1960

    Google Scholar 

  • Dietz V, Sinkjaer T (2007) Spastic movement disorder: impaired reflex function and altered muscle mechanics. Lancet Neurol 6:725–733

    PubMed  Google Scholar 

  • Dimitrijevic MR, Gerasimenko Y, Pinter MM (1998) Evidence for a spinal central pattern generator in humans. Ann N Y Acad Sci 860:360–376

    CAS  PubMed  Google Scholar 

  • Eaton MJ, Santiago DI, Dancausse HA, Whittemore SR (1997) Lumbar transplants of immortalized serotonergic neurons alleviate chronic neuropathic pain. Pain 72(1–2):59–69

    CAS  PubMed  Google Scholar 

  • Eaton MJ, Pearse DD, McBroom JS, Berrocal YA (2008) The combination of human neuronal serotonergic cell implants and environmental enrichment after contusive SCI improves motor recovery over each individual strategy. Behav Brain Res 194(2):236–241

    CAS  PubMed  Google Scholar 

  • Eaton MJ, Berrocal Y, Wolfe SQ (2012) Potential for cell-transplant therapy with human precursors to treat. Potential for cell-transplant therapy with human neuronal precursores to treat neuropathic pain in models of PNS and CNS injury: comparison of hNT2.17 and hNT2.19 cell lines. Pain Res Treat 2012:356412

  • Eide PK, Hole K (1993) The role of 5-hydroxytryptamine (5-HT) receptor subtypes and plasticity in the 5-HT systems in the regulation of nociceptive sensitivity. Cephalalgia 13:75–85

    CAS  PubMed  Google Scholar 

  • Fedirchuk B, Nielsen J, Petersen N, Hultborn H (1998) Pharmacologically evoked fictive motor patterns in the acutely spinalized marmoset monkey (Callithrix jacchus). Exp Brain Res 122:351–361

    CAS  PubMed  Google Scholar 

  • Feraboli-Lohnherr D, Orsal D, Yakovleff A, Giménez Y, Ribotta M, Privat A (1997) Recovery of locomotor activity in the adult chronic spinal rat after sublesional transplantation of embryonic nervous cells: specific role of serotonergic neurons. Exp Brain Res 113(3):443–454

    CAS  PubMed  Google Scholar 

  • Feraboli-Lohnherr D, Barthe JY, Orsal D (1999) Serotonin-induced activation of the network for locomotion in adult spinal rats. J Neurosci Res 55:87–98

    CAS  PubMed  Google Scholar 

  • Filli L, Zörner B, Weinmann O, Schwab ME (2011) Motor deficits and recovery in rats with unilateral spinal cord hemisection mimic the Brown.Sequard syndrome. Brain 134(Pt 8):2261–2273

    PubMed  Google Scholar 

  • Forssberg H, Grillner S (1973) The locomotion of the acute spinal cat injected with clonidine i.v. Brain Res 50:184–186

    CAS  PubMed  Google Scholar 

  • Fouad K, Pedersen V, Schwab ME, Brosamle C (2001) Cervical sprouting of corticospinal fibers after thoracic spinal cord injury accompanies shifts in evoked motor responses. Curr Biol 11:1766–1770

    CAS  PubMed  Google Scholar 

  • Fouad K, Rank MM, Vavrek R, Murray KC, Sanelli L, Bennett DJ (2010) Locomotion after spinal cord injury depends o constructive activity in serotonin receptors. J Neurophysiol 104(6):2975–2984

    CAS  PubMed Central  PubMed  Google Scholar 

  • Garcia-Alias G, Barkhuysen S, Buckle M, Fawcett JW (2009) Chondroitinase ABC treatment opens a window of opportunity for task-specific rehabilitation. Nat Neurosci 12:1145–1151

    CAS  PubMed  Google Scholar 

  • Geremia NM, Bao F, Rosenzweig TE, Hryciw T, Weaver L, Dekaban GA, Brown A (2012) CD11d antibody treatment improves recovery in spinal cord-injured mice. J Neurotrauma 29(3):539–550

    PubMed  Google Scholar 

  • Gerin C (2003) Possible role of 5-HT release in spinal cord regenerative processes. Molecular aspects of neuro-degenerative diseases conference, Sweden

  • Gerin C, Legrand A, Privat A (1994) Study of 5-HT release with a chronically implanted microdialysis probe in the ventral horn of the spinal cord of unrestrained rats during exercise on a treadmill. J Neurosci Methods 52:129–141

    CAS  PubMed  Google Scholar 

  • Gerin C, Becquet D, Privat A (1995) Direct evidence for the link between monoaminergic descending pathways and motor activity. I. A study with microdialysis probes implanted in the ventral funiculus of the spinal cord. Brain Res 704:191–201

    CAS  PubMed  Google Scholar 

  • Gerin CG, Hill A, Hill S, Smith K, Privat A (2010) Serotonin release variations during recovery of motor function after a spinal cord injury in rats. Synapse 64(11):855–861

    CAS  PubMed Central  PubMed  Google Scholar 

  • Gilmore J, Fedirchuk B (2004) The excitability of lumbar motoneurones in the neonatal rat is increased by a hyperpolarization of their voltage threshold for activation by descending serotonergic fibres. J Physiol 558:213–224

    CAS  PubMed Central  PubMed  Google Scholar 

  • Gimenez y Ribotta M, Privat A (1998) Biological interventions for spinal cord injury. Curr Opin Neurol 11:647–654

    PubMed  Google Scholar 

  • Giménez Y Ribotta M, Provencher J, Feraboli-Lohnherr D, Rossignol S, Privát A, Orsal D (2000) Activation of locomotion in adult chronic spinal rats is achieved by transplantation of embryonic raphe cells reinnervating a precise lumbar level. J Neurosci 20(13):5144–5152

    Google Scholar 

  • Giroux N, Rossignol S, Reader TA (1999) Autoradiographic study of alpha1- and alpha2-noradrenergic and serotonin1A receptors in the spinal cord of normal and chronically transected cats. J Comp Neurol 406:402–414

    CAS  PubMed  Google Scholar 

  • Golder FJ, Reier PJ, Bolser DC (2001) Altered respiratory motor drive after spinal cord injury: supraspinal and bilateral effects of a unilateral lesion. J Neurosci 21:8680–8689

    CAS  PubMed  Google Scholar 

  • Gorassini M, Yang JF, Siu M, Bennett DJ (2002) Intrinsic activation of human motoneurons: possible contribution to motor unit excitation. J Neurophysiol 87:1850–1858

    PubMed  Google Scholar 

  • Gorassini MA, Knash ME, Harvey PJ, Bennett DJ, Yang JF (2004) Role of motoneurons in the generation of muscle spasms after spinal cord injury. Brain 127:2247–2258

    PubMed  Google Scholar 

  • Grillner S (2002) The spinal locomotor CPG: a target after spinal cord injury. Prog Brain Res 137:97–108

    PubMed  Google Scholar 

  • Grillner S (2003) The motor infrastructure: from ion channels to neuronal networks. Nat Rev Neurosci 4:573–586

    CAS  PubMed  Google Scholar 

  • Grillner S, Wallen P (1985) Central pattern generators for locomotion, with special reference to vertebrates. Annu Rev Neurosci 8:233–261

    CAS  PubMed  Google Scholar 

  • Grillner S, Zangger P (1979) On the central generation of locomotion in the low spinal cat. Exp Brain Res 34:241–261

    CAS  PubMed  Google Scholar 

  • Gruner JA (1992) A monitored contusion model of spinal cord injury in the rat. J Neurotrauma 9(2):123–128

    CAS  PubMed  Google Scholar 

  • Gu M, Miyoshi K, Dubner R, Guo W, Zou S, Ren K, Noguchi K, Wei F (2011) Spinal 5-HT(3) receptor activation induces behavioural hypersensitivity via a neuronal-glial-neuronal signalling cascade. J Neurosci 31(36):12823–12836

    CAS  PubMed Central  PubMed  Google Scholar 

  • Guertin PA (2004) Synergistic activation of the central pattern generator for locomotion by l-beta-3,4-dihydroxyphenylalanine and quipazine in adult paraplegic mice. Neurosci Lett 358:71–74

    CAS  PubMed  Google Scholar 

  • Guertin PA (2008) Anxiolytics may promote locomotor function recovery in spinal cord injury patients. Neuropsychiatr Dis Treat 4:759–763

    CAS  PubMed Central  PubMed  Google Scholar 

  • Gurevich I, Englander MT, Adlersberg M, Siegal NB, Schmauss C (2002) Modulation of serotonin 2C receptor editing by sustained changes in serotonergic neurotransmission. J Neurosci 22:10529–10532

    CAS  PubMed  Google Scholar 

  • Hadjiconstantinou M, Panula P, Lackovic Z, Neff NH (1984) Spinal cord serotonin: a biochemical and immunohistochemical study following transection. Brain Res 322:245–254

    CAS  PubMed  Google Scholar 

  • Hains BC, Johnson KM, McAdoo DJ, Eaton MJ, Hulsebosch CE (2001a) Engraftment of serotonergic precursors enhances locomotor function and attenuates chronic central pain behavior following spinal hemisection injury in the rat. Exp Neurol 171(2):361–378

    CAS  PubMed  Google Scholar 

  • Hains BC, Fullwood SD, Eaton MJ, Hulsebosch CE (2001b) Subdural engraftment of serotonergic neurons following spinal hemisection restores spinal serotonin, downregulates serotonin transporter, and increases BDNF tissue content in rat. Brain Res 913(1):35–46

    CAS  PubMed  Google Scholar 

  • Hains BC, Klein JP, Saab CY, Craner MJ, Black JA, Waxman SG (2003a) Upregulation of sodium channel Na1.3 and functional involvement in neuronal hyperexcitability associated with central neuropathic pain after spinal cord injury. J Neurosci 23(26):8881–8892

    CAS  PubMed  Google Scholar 

  • Hains BC, Johnson KM, Eaton MJ, Willis WD, Hulsebosch CE (2003b) Serotonergic neural precursor cell grafts attenuate bilateral hyperexcitability of dorsal horn neurons after spinal hemisection in rat. Neuroscience 116(4):1097–1110

    CAS  PubMed  Google Scholar 

  • Hains BC, Willis WD, Hulsebosch CE (2003c) Serotonin receptors 5-HT and 5-HT reduce hyperexcitability of dorsal horn neurons after chronic spinal cord hemisection injury in rat. Exp Brain Res 149(2):174–186

    CAS  PubMed  Google Scholar 

  • Hammar I, Jankowska E (2003) Modulatory effects of alpha1-, alpha2-, and beta-receptor agonists on feline spinal interneurons with monosynaptic input from group I muscle afferents. J Neurosci 23:332–338

    CAS  PubMed Central  PubMed  Google Scholar 

  • Harris-Warrick RM, Cohen AH (1985) Serotonin modulates the central pattern generator for locomotion in the isolated lamprey spinal cord. J Exp Biol 116:27–46

    CAS  PubMed  Google Scholar 

  • Harvey PJ, Li X, Li Y, Bennett DJ (2006a) 5-HT2 receptor activation facilitates a persistent sodium current and repetitive firing in spinal motoneurons of rats with and without chronic spinal cord injury. J Neurophysiol 96:1158–1170

    CAS  PubMed  Google Scholar 

  • Harvey PJ, Li X, Li Y, Bennett DJ (2006b) Endogenous monoamine receptor activation is essential for enabling persistent sodium currents and repetitive firing in rat spinal motoneurons. J Neurophysiol 96:1171–1186

    CAS  PubMed  Google Scholar 

  • Hayashi Y, Jacob-Vadakot S, Dugan EA, McBride S, Olexa R, Simansky K, Murray M, Shumsky JS (2010) 5-HT precursor loading, but not 5-HT receptor agonists, increases motor function after spinal cord contusion in adult rats. Exp Neurol 221:68–78

    CAS  PubMed Central  PubMed  Google Scholar 

  • Heckman CJ (1994) Alterations in synaptic input to motoneurons during partial spinal cord injury. Med Sci Sports Exerc 26:1480–1490

    CAS  PubMed  Google Scholar 

  • Heckman CJ, Gorassini MA, Bennett DJ (2005) Persistent inward currents in motoneuron dendrites: implications for motor output. Muscle Nerve 31:135–156

    CAS  Google Scholar 

  • Hentall ID, Gonzalez MM (2012) Promotion of recovery from thoracic spinal cord contusion in rats by stimulation of medullary raphe or its midbrain input. Neurorehabil Neural Repair 26(4):374–384

    PubMed  Google Scholar 

  • Herrick-Davis K, Grinde E, Niswender CM (1999) Serotonin 5-HT2C receptor RNA editing alters receptor basal activity: implications for serotonergic signal transduction. J Neurochem 73:1711–1717

    CAS  PubMed  Google Scholar 

  • Holstege JC, Bongers CM (1991) A glycinergic projection from the ventromedial lower brainstem to spinal motoneurons. An ultrastructural double labeling study in rat. Brain Res 566:308–315

    CAS  PubMed  Google Scholar 

  • Holstege JC, Kuypers HGJM (1987) Brainstem projections to spinal motoneurons: an update. Neuroscience 23:809–821

    CAS  PubMed  Google Scholar 

  • Hornung JP (2003) The human raphe nuclei and the serotonergic system. J Chem Neuroanat 26:331–343

    CAS  PubMed  Google Scholar 

  • Hultborn H, Brownstone RB, Toth TI, Gossard JP (2004) Key mechanisms for setting the input-output gain across the motoneuron pool. Prog Brain Res 143:77–95

    PubMed  Google Scholar 

  • Hunanyan AS, García-Alías G, Alessi V, Levine JM, Fawcett JW, Mendell LM, Arvanian VL (2010) Role of chondroitin sulfate proteoglycans in axonal conduction in mammalian spinal cord. J Neuroscience 30:7761–7769

    CAS  Google Scholar 

  • Husch A, Van Patten GN, Hong DN, Scaperotti MM, Cramer N, Harris-Warrick RM (2012) Spinal cord injury induces serotonin supersensitivity without increasing excitability of mouse V2a interneurons. J Neurosci 32(38):13145–13154

    CAS  PubMed Central  PubMed  Google Scholar 

  • Jacobs BL (1991) Serotonin and behavior: emphasis on motor control. J Clin Psychiatry 52(Suppl):17–23

    PubMed  Google Scholar 

  • Jacobs BL, Fornal CA (1993) 5-HT and motor control: a hypothesis. Trends Neurosci 16:346–352

    CAS  PubMed  Google Scholar 

  • Jacobs BL, Martin-Cora FJ, Fornal CA (2002) Activity of medullary serotonergic neurons in freely moving animals. Brain Res Brain Res Rev 40:45–52

    CAS  PubMed  Google Scholar 

  • Jane JA, Evans JP, Fisher LE (1964) An investigation concerning the restitution of motor function following injury to the spinal cord. J Neurosurg 21:167–171

    CAS  PubMed  Google Scholar 

  • Jankowska E (1992) Interneuronal relay in spinal pathways from proprioceptors. Prog Neurobiol 38:335–378

    CAS  PubMed  Google Scholar 

  • Jankowska E, Riddell JS, Skoog B, Noga BR (1993) Gating of transmission to motoneurones by stimuli applied in the locus coeruleus and raphe nuclei of the cat. J Physiol 461:705–722

    CAS  PubMed Central  PubMed  Google Scholar 

  • Jankowska E, Lackberg ZS, Dyrehag LE (1994) Effects of monoamines on transmission from group II muscle afferents in sacral segments in the cat. Eur J Neurosci 6:1058–1061

    CAS  PubMed  Google Scholar 

  • Jankowska E, Hammar I, Chojnicka B, Heden CH (2000) Effects of monoamines on interneurons in four spinal reflex pathways from group I and/or group II muscle afferents. Eur J Neurosci 12:701–714

    CAS  PubMed  Google Scholar 

  • Jordan LM, Liu J, Hedlund PB, Akay T, Pearson KG (2008) Descending command systems for the initiation of locomotion in mammals. Brain Res Rev 57:183–191

    CAS  PubMed  Google Scholar 

  • Kayser V, Aubel B, Hamon M, Bourgoin S (2002) The antimigraine 5-HT1B/1D receptor agonists, sumatriptan, zolmitriptan and dihydroergotamine, attenuate pain related behaviour in a rat model of trigeminal neuropathic pain. Br J Pharmacol 137:1287–1297

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kayser V, Elfassi IE, Aubel B, Melfort M, Julius D, Gingrich JA, Hamon M, Bourgoin S (2007) Mechanical, thermal and formalin-induced nociception is differentially altered in 5-HT1A−/−, 5-HT1B−/−, 5-HT2A−/−, 5-HT3A−/− and 5-HTT−/− knock-out male mice. Pain 130:235–248

    CAS  PubMed  Google Scholar 

  • Kayser V, Bourgoin S, Viguier F, Michot B, Hamon M (2010) In: Beaulieu P, Lussier D, Porreca F, Dickenson AH (eds) Toward deciphering the respective roles of multiple 5-HT receptors in the complex serotonin-mediated pain control. Pharmacology of pain. IASP Press, Seattle

    Google Scholar 

  • Kiehn O, Kjaerulff O (1996) Spatiotemporal characteristics of 5-HT and dopamine-induced rhythmic hindlimb activity in the in vitro neonatal rat. J Neurophysiol 75:1472–1482

    CAS  PubMed  Google Scholar 

  • Kim D, Adipudi V, Shibayama M, Giszter S, Tessler A, Murray M, Simansky KJ (1999) Direct agonists for serotonin receptors enhance locomotor function in rats that received neural transplants after neonatal spinal transection. J Neurosci 19(14):6213–6224

    CAS  PubMed  Google Scholar 

  • Kong XY, Wienecke J, Chen M, Hultborn H, Zhang M (2011) The time course of serotonin 2A receptor expression after spinal transection of rats: an immunohistochemical study. Neuroscience 177:114–126

    CAS  PubMed  Google Scholar 

  • Kuhn RA, Macht MB (1948) Some manifestations of reflex activity in spinal man with particular reference to the occurrence of extensor spasm. Bull Johns Hopkins Hosp 84:43–75

    Google Scholar 

  • Landry ES, Guertin PA (2004) Differential effects of 5-HT1 and 5-HT2 receptor agonists on hindlimb movements in paraplegic mice. Prog Neuropsychopharmacol Biol Psychiatry 28:1053–1060

    CAS  PubMed  Google Scholar 

  • Laporte AM, Doyen C, Nevo IT, Chauveau J, Hauw JJ, Hamon M (1996) Autoradiographic mapping of serotonin 5-HT1A, 5-HT1D, 5-HT2A and 5-HT3 receptors in the aged human spinal cord. J Chem Neuroanat 11:67–75

    CAS  PubMed  Google Scholar 

  • Lee JK, Johnson CS, Wrathall JR (2007) Up-regulation of 5-HT2 receptors is involved in the increased H-reflex amplitude after contusive spinal cord injury. Exp Neurol 203:502–511

    CAS  PubMed Central  PubMed  Google Scholar 

  • Lee JK, Chow R, Xie F, Chow SY, Tolentino KE, Zheng B (2010) Combined genetic attenuation of myelin and seamphorin-mediated growth inhibition is insufficient to promote serotoninergic axon regeneration. J Neurosci 30(32):10899–108904

    CAS  PubMed Central  PubMed  Google Scholar 

  • Li Y, Gorassini MA, Bennett DJ (2004a) Role of persistent sodium and calcium currents in motoneuron firing and spasticity in chronic spinal rats. J Neurophysiol 91:767–783

    CAS  PubMed  Google Scholar 

  • Li Y, Harvey PJ, Li X, Bennett DJ (2004b) Spastic long-lasting reflexes in the chronic spinal rat, studied in vitro. J Neurophysiol 91:2236–2246

    CAS  PubMed  Google Scholar 

  • Lin CY, Lee YS, Lin VW, Silver J (2012) Fibronectin inhibits chronic pain development after spinal cord injury. J Neurotrauma 29(3):589–599

    PubMed Central  PubMed  Google Scholar 

  • Lindsey AE, LoVerso RL, Tovar CA, Hill CE, Beattie MS, Bresnahan JC (2000) An analysis of changes in sensory thresholds to mild tactile and cold stimuli after experimental spinal cord injury in the rat. Neurorehabil Neural Repair 14(4):287–300

    CAS  PubMed  Google Scholar 

  • Lundberg A (1982) Inhibitory control from the brainstem of transmission from primary afferents to motoneurons, primary afferent terminals and ascending pathways. In: Sjolund B, Bjorklund A (eds) Brainstem control of spinal mechanisms. Elsevier, New York, pp 179–224

    Google Scholar 

  • Madriaga MA, McPhee LC, Chersa T, Christie KJ, Whelan PJ (2004) Modulation of locomotor activity by multiple 5-HT and dopaminergic receptor subtypes in the neonatal mouse spinal cord. J Neurophysiol 92:1566–1576

    CAS  PubMed  Google Scholar 

  • Mantilla CB, Bailey JP, Zhan WZ, Sieck GC (2012) Phrenic motoneuron expression of serotoninergic and glutamatergic receptors following upper cervical spinal cord injury. Exp Neurol 234(1):191–199

    CAS  PubMed Central  PubMed  Google Scholar 

  • Manuel NA, Wallis DI, Crick H (1995) Ketanserin-sensitive depressant actions of 5-HT receptor agonists in the neonatal rat spinal cord. Br J Pharmacol 116:2647–2654

    CAS  PubMed Central  PubMed  Google Scholar 

  • Marlier L, Poulat P, Rajaofetra N, Privat A (1991a) Modifications of serotonin-, substance P- and calcitonin gene-related peptide-like immunoreactivities in the dorsal horn of the spinal cord of arthritic rats: a quantitative immunocytochemical study. Exp Brain Res 85:482–490

    CAS  PubMed  Google Scholar 

  • Marlier L, Teilhac JR, Cerruti C, Privat A (1991b) Autoradiographic mapping of 5-HT1, 5-HT1A, 5-HT1B and 5-HT2 receptors in the rat spinal cord. Brain Res 550:15–23

    CAS  PubMed  Google Scholar 

  • Massey JM, Hubscher CH, Wagoner MR, Decker JA, Amps J, Silver J, Onifer SM (2006) Chondroitinase ABC digestion of the perineuronal net promotes functional collateral sprouting in the cuneate nucleus after cervical spinal cord injury. J Neuroscience 26:4406–4414

    CAS  Google Scholar 

  • Mayer DJ (1984) Analgesia produced by electrical stimulation of the brain. Prog Neuropsychopharmacol Biol Psychiatry 8:557–564

    CAS  PubMed  Google Scholar 

  • Maynard FM, Karunas RS, Waring WP 3rd (1990) Epidemiology of spasticity following traumatic spinal cord injury. Arch Phys Med Rehabil 71:566–569

    CAS  PubMed  Google Scholar 

  • McEwen ML, Van Hartesveldt C, Stehouwer DJ (1997) L-DOPA and quipazine elicit air-stepping in neonatal rats with spinal cord transections. Behav Neurosci 111:825–833

    CAS  PubMed  Google Scholar 

  • Millan MJ (2002) Descending control of pain. Prog Neurobiol 66:355–474

    CAS  PubMed  Google Scholar 

  • Miller JF, Paul KD, Lee RH, Rymer WZ, Heckman CJ (1996) Restoration of extensor excitability in the acute spinal cat by the 5-HT2 agonist DOI. J Neurophysiol 75:620–628

    CAS  PubMed  Google Scholar 

  • Minassian K, Persy I, Rattay F, Pinter MM, Kern H, Dimitrijevic MR (2007) Human lumbar cord circuitries can be activated by extrinsic tonic input to generate locomotor-like activity. Hum Mov Sci 26:275–295

    CAS  PubMed  Google Scholar 

  • Murray KC, Nakae A, Stephens MJ, Rank M, D’Amico J, Harvey PJ, Li X, Harris RL, Ballou EW, Anelli R, Heckman CJ, Mashimo T, Vavrek R, Sanelli L, Gorassini MA, Bennett DJ, Fouad K (2010) Recovery of motoneuron and locomotor function after spinal injury depends on constitutive activity in 5-HCT2C receptors. Nat Med 16(6):694–700

    CAS  PubMed Central  PubMed  Google Scholar 

  • Murray KC, Stephens MJ, Rank M, D’Amico J, Gorassini MA, Bennett DJ (2011a) Polysynaptic excitatory postsynaptic potentials that trigger spasms after spinal cord injury in rats are inhibited by 5-HT1B and 5-HT1F receptors. J Neurophysiol 106(2):925–943

    CAS  PubMed Central  PubMed  Google Scholar 

  • Murray KC, Stephens MJ, Ballou EW, Heckman CJ, Bennett DJ (2011b) Motoneuron excitability and muscle spasms are regulated by 5-HT2B and 5-HT2C receptor activity. J Neurophysiol 105(2):731–748

    PubMed Central  PubMed  Google Scholar 

  • Navarrett S, Collier L, Cardozo C, Dracheva S (2012) Alterations of serotonin 2C and 2A receptors in response to T10 spinal transaction in rats. Neurosci Lett 506(1):74–78

    CAS  PubMed  Google Scholar 

  • Nielsen JB, Crone C, Hultborn H (2007) The spinal pathophysiology of spasticity—from a basic science point of view. Acta Physiol (Oxf) 189:171–180

    CAS  Google Scholar 

  • Niswender CM, Copeland SC, Herrick-Davis K, Emeson RB, Sanders-Bush E (1999) RNA editing of the human serotonin 5-hydroxytryptamine 2C receptor silences constitutive activity. J Biol Chem 274:9472–9478

    CAS  PubMed  Google Scholar 

  • Norton JA, Bennett DJ, Knash ME, Murray KC, Gorassini MA (2008) Changes in sensory-evoked synaptic activation of motoneurons after spinal cord injury in man. Brain 131:1478–1491

    PubMed Central  PubMed  Google Scholar 

  • Noth J (1991) Trends in the pathophysiology and pharmacotherapy of spasticity. J Neurol 238:131–139

    CAS  PubMed  Google Scholar 

  • Novakovic SD, Tzoumaka E, McGivern JG, Haraguchi M, Sangameswaran L, Gogas KR, Eglen RM, Hunter JC (1998) Distribution of the tetrodotoxin-resistant sodium channel PN3 in rat sensory neurons in normal and neuropathic conditions. J Neurosci 18(6):2174–2187

    CAS  PubMed  Google Scholar 

  • Obata H, Saito S, Ishizaki K, Goto F (2000) Antinociception in rat by sarpogrelate, a selective 5-HT2A receptor antagonist, is peripheral. Eur J Pharmacol 404:95–102

    CAS  PubMed  Google Scholar 

  • Obata H, Saito S, Sakurazawa S, Sasaki M, Usui T, Goto F (2004) Antiallodynic effects of intrathecally administered 5-HT2C receptor agonists in rats with nerve injury. Pain 108:163–169

    CAS  PubMed  Google Scholar 

  • Oyama T, Ueda M, Kuraishi Y, Akaike A, Satoh M (1996) Dual effect of serotonin on formalin-induced nociception in the rat spinal cord. Neurosci Res 25:129–135

    CAS  PubMed  Google Scholar 

  • Perrier JF, Delgado-Lezama R (2005) Synaptic release of serotonin induced by stimulation of the raphe nucleus promotes plateau potentials in spinal motoneurons of the adult turtle. J Neurosci 25:7993–7999

    CAS  PubMed  Google Scholar 

  • Perrier JF, Hounsgaard J (2003) 5-HT2 receptors promote plateau potentials in turtle spinal motoneurons by facilitating an L-type calcium current. J Neurophysiol 89:954–959

    CAS  PubMed  Google Scholar 

  • Perrin FE, Gerber YN, Teigell M, Lonjon N, Boniface G, Bauchet L, Rodriguez JJ, Hugnot JP, Privat AM (2011) Anatomical study of serotoninergic innervation and 5-HT(1A) receptos in the human spinal cord. Cell Death Dis 2:e218

    CAS  PubMed Central  PubMed  Google Scholar 

  • Pichon X, Wattiez AS, Becamel C, Ehrlich I, Bockaert J, Eschalier A, Marin P, Courteix C (2010) Disrupting 5-HT(2A) receptor/PDZ protein interactions reduces hyperalgesia and enhances SSRI efficacy in neuropathic pain. Mol Ther 18:1462–1470

    CAS  PubMed Central  PubMed  Google Scholar 

  • Rajaofetra N, Passagia JG, Marlier L, Poulat P, Pellas F, Sandillon F, Verschuere B, Gouy D, Geffard M, Privat A (1992) Serotoninergic, noradrenergic, and peptidergic innervation of Onuf’s nucleus of normal and transected spinal cords of baboons (Papio papio). J Comp Neurol 318:1–17

    CAS  PubMed  Google Scholar 

  • Ramer LM, Au E, Richter MW, Liu J, Tetzlaff W, Roskams AJ (2004) Peripheral olfactory ensheathing cells reduce scar and cavity formation and promote regeneration after spinal cord injury. J Comp Neurol 473(1):1–15

    PubMed  Google Scholar 

  • Rekling JC, Funk GD, Bayliss DA, Dong XW, Feldman JL (2000) Synaptic control of motoneuronal excitability. Physiol Rev 80:767–852

    CAS  PubMed  Google Scholar 

  • Ribotta MG, Provencher J, Feraboli-Lohnherr D, Rossignol S, Privat A, Orsal D (2000) Activation of locomotion in adult chronic spinal rats is achieved by transplantation of embryonic raphe cells reinnervating a precise lumbar level. J Neurosci 20:5144–5152

    CAS  PubMed  Google Scholar 

  • Saruhashi Y, Young W, Perkins R (1996) The recovery of 5-HT immunoreactivity in lumbosacral spinal cord and locomotor function after thoracic hemisection. Exp Neurol 139:203–213

    CAS  PubMed  Google Scholar 

  • Schmidt BJ, Jordan LM (2000) The role of serotonin in reflex modulation and locomotor rhythm production in the mammalian spinal cord. Brain Res Bull 53:689–710

    CAS  PubMed  Google Scholar 

  • Schwartz EJ, Gerachshenko T, Alford S (2005) 5-HT prolongs ventral root bursting via presynaptic inhibition of synaptic activity during fictive locomotion in lamprey. J Neurophysiol 93:980–988

    CAS  PubMed  Google Scholar 

  • Selkirk JV, Scott C, Ho M, Burton MJ, Watson J, Gaster LM, Collin L, Jones BJ, Middlemiss DN, Price GW (1998) SB-224289—a novel selective (human) 5-HT1B receptor antagonist with negative intrinsic activity. Br J Pharmacol 125:202–208

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sharma A, Sharma HS (2012) Monoclonal antibodies as novel neurotherapeutic agents in CNS injury and repair. Int Rev Neurobiol 102:23–45

    CAS  PubMed  Google Scholar 

  • Sharma A, Punhani T, Fone K (1997) Distribution of 5-hydroxytryptamine2C receptor protein in adult rat brain and spinal cord determined using a receptor-directed antibody: effect of 5,7-dihydroxy-tryptamine. Synapse 27:45–56

    CAS  PubMed  Google Scholar 

  • Singer JH, Bellingham MC, Berger AJ (1996) Presynaptic inhibition of glutamatergic synaptic transmission to rat motoneurons by serotonin. J Neurophysiol 76:799–807

    CAS  PubMed  Google Scholar 

  • Skagerberg G, Björklund A (1985) Topographic principles in the spinal projections of serotonergic and non-serotonergic brainstem neurons in the rat. Neuroscience 15:445–480

    CAS  PubMed  Google Scholar 

  • Suzuki R, Rygh LJ, Dickenson AH (2004) Bad news from the brain: descending 5-HT pathways that control spinal pain processing. Trends Pharmacol Sci 25:613–617

    CAS  PubMed  Google Scholar 

  • Taylor J, Munson J, Vierck C Jr (1999) Effects of dorsolateral spinal lesions on stretch reflex threshold and stiffness in awake cats. Eur J Neurosci 11:363–368

    CAS  PubMed  Google Scholar 

  • Thomas SL, Gorassini MA (2005) Increases in corticospinal tract function by treadmill training after incomplete spinal cord injury. J Neurophysiol 94:2844–2855

    PubMed  Google Scholar 

  • Thompson CK, Hornby TG (2013) Divergent modulation of clinical measures of volitional and reflexive motor behaviors following serotoninergic medication in human incomplete spinal cord injury. J Neurotrauma 30(6):498–502

    PubMed Central  PubMed  Google Scholar 

  • Udina E, D’Amico J, Bergquist AJ, Gorassini MA (2010) Amphetamine increases persistent inward currents in human motoneurons estimated from paired motor-unit activity. J Neurophysiol 103:1295–1303

    CAS  PubMed Central  PubMed  Google Scholar 

  • Van Meeteren NL, Eggers R, Lankhorst AJ, Gispen WH, Hamers FP (2003) Locomotor recovery after spinal cord contusion injury in rats is improved by spontaneous exercise. J Neurotrauma 20(10):1029–1037

    PubMed  Google Scholar 

  • Vavrek R, Girgis J, Tetzlaff W, Hiebert GW, Fouad K (2006) BDNF promotes connections of corticospinal neurons onto spared descending interneurons in spinal cord injured rats. Brain 129:1534–1545

    CAS  PubMed  Google Scholar 

  • Viala D, Buser P (1971) Methods of obtaining locomotor rhythms in the spinal rabbit by pharmacological treatments (DOPA, 5-HTP, D-amphetamine). Brain Res 35:151–165

    CAS  PubMed  Google Scholar 

  • Wang X, Duffy P, McGee AW, Hasan O, Gould G, Tu N, Harel NY, Huang Y, Carson RE, Weinzimmer D, Ropchan J, Benowitz LI, Cafferty WB, Strittmatter SM (2011) Recovery from chronic spinal cord contusion after Nogo receptor intervention. Ann Neurol 70(5):805–821

    CAS  PubMed Central  PubMed  Google Scholar 

  • Weidner N, Ner A, Salimi N, Tuszynski MH (2001) Spontaneous corticospinal axonal plasticity and functional recovery after adult central nervous system injury. Proc Natl Acad Sci USA 98:3513–3518

    CAS  PubMed Central  PubMed  Google Scholar 

  • Westphal RS, Sanders-Bush E (1994) Reciprocal binding properties of 5-hydroxytryptamine type 2C receptor agonists and inverse agonists. Mol Pharmacol 46:937–942

    CAS  PubMed  Google Scholar 

  • Wirz M, Zemon DH, Rupp R, Scheel A, Colombo G, Dietz V, Hornby TG (2005) Effectiveness of automated locomotor training in patients with chronic incomplete spinal cord injury: a multicenter trial. Arch Phys Med Rehabil 86:672–680

    PubMed  Google Scholar 

  • Yaksh TL, Wilson PR (1979) Spinal serotonin terminal system mediates antinociception. J Pharmacol Exp Ther 208(3):446–453

    CAS  PubMed  Google Scholar 

  • Yoshimura M, Furue H (2006) Mechanisms for the anti-nociceptive actions of the descending noradrenergic and serotonergic systems in the spinal cord. J Pharmacol Sci 101:107–117

    CAS  PubMed  Google Scholar 

  • Young W (1996) Spinal cord regeneration. Science 273(5274):451

    CAS  PubMed  Google Scholar 

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  1. Department of Neurology, Christian Doppler Klinik, Paracelsus Medical University and Center for Cognitive Neuroscience, Salzburg, Austria

    Raffaele Nardone, Yvonne Höller, Aljoscha Thomschewski, Peter Höller, Stefan Golaszewski & Eugen Trinka

  2. Department of Neurology, Franz Tappeiner Hospital, Via Rossini, 5, 39012, Merano (BZ), Italy

    Raffaele Nardone, Piergiorgio Lochner & Francesco Brigo

  3. Spinal Cord Injury and Tissue Regeneration Center, Paracelsus Medical University, Salzburg, Austria

    Raffaele Nardone, Yvonne Höller, Aljoscha Thomschewski, Peter Höller & Eugen Trinka

  4. Department of Neurological, Neuropsychological, Morphological and Movement Sciences, Section of Clinical Neurology, University of Verona, Verona, Italy

    Francesco Brigo

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Nardone, R., Höller, Y., Thomschewski, A. et al. Serotonergic transmission after spinal cord injury. J Neural Transm 122, 279–295 (2015). https://doi.org/10.1007/s00702-014-1241-z

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