Current Pain and Headache Reports

, Volume 16, Issue 3, pp 217–225 | Cite as

Spinal Cord Stimulation: Neurophysiological and Neurochemical Mechanisms of Action

Neuropathic Pain (R Raja, Section editor)


Chronic neuropathic pain can significantly reduce quality of life and place an economic burden on individuals and society. Spinal cord stimulation (SCS) is an alternative approach to the treatment of neuropathic pain when standard pharmacological agents have failed. However, an improved understanding of the mechanisms by which SCS inhibits pain is needed to enhance its clinical utility. This review summarizes important findings from recent studies of SCS in animal models of neuropathic pain, highlights current understanding of the spinal neurophysiological and neurochemical mechanisms by which SCS produces an analgesic effect, and discusses the potential clinical applicability of these findings and future directions for research.


Spinal cord stimulation Nerve injury Neuropathic pain Gate-control Dorsal horn Neurophysiology Rat Gamma-aminobutyric acid Serotonin Wide-dynamic-range neurons Pain modulation 


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Baron R. Mechanisms of disease: neuropathic pain–a clinical perspective. Nat Clin Pract Neurol. 2006;2:95–106.PubMedCrossRefGoogle Scholar
  2. 2.
    Meyerson BA, Linderoth B. Mode of action of spinal cord stimulation in neuropathic pain. J Pain Symptom Manage. 2006;31:S6–12.PubMedCrossRefGoogle Scholar
  3. 3.
    Kumar K, Taylor RS, Jacques L, Eldabe S, Meglio M, Molet J, Thomson S, O’Callaghan J, Eisenberg E, Milbouw G, Buchser E, Fortini G, Richardson J, North RB. Spinal cord stimulation versus conventional medical management for neuropathic pain: a multicentre randomised controlled trial in patients with failed back surgery syndrome. Pain. 2007;132:179–88.PubMedCrossRefGoogle Scholar
  4. 4.
    Cavanaugh DJ, Lee H, Lo L, Shields SD, Zylka MJ, Basbaum AI, Anderson DJ. Distinct subsets of unmyelinated primary sensory fibers mediate behavioral responses to noxious thermal and mechanical stimuli. Proc Natl Acad Sci U S A. 2009;106:9075–80.PubMedCrossRefGoogle Scholar
  5. 5.
    Yan LH, Hou JF, Liu MG, Li MM, Cui XY, Lu ZM, Zhang FK, An YY, Shi L, Chen J. Imbalance between excitatory and inhibitory amino acids at spinal level is associated with maintenance of persistent pain-related behaviors. Pharmacol Res. 2009;59:290–9.PubMedCrossRefGoogle Scholar
  6. 6.
    Torsney C, MacDermott AB. Disinhibition opens the gate to pathological pain signaling in superficial neurokinin 1 receptor-expressing neurons in rat spinal cord. J Neurosci. 2006;26:1833–43.PubMedCrossRefGoogle Scholar
  7. 7.
    Moore KA, Kohno T, Karchewski LA, Scholz J, Baba H, Woolf CJ. Partial peripheral nerve injury promotes a selective loss of GABAergic inhibition in the superficial dorsal horn of the spinal cord. J Neurosci. 2002;22:6724–31.PubMedGoogle Scholar
  8. 8.
    Linderoth B, Meyerson BA. Spinal cord stimulation: exploration of the physiological basis of a widely used therapy. Anesthesiology. 2010;113:1265–7.PubMedCrossRefGoogle Scholar
  9. 9.
    Melzack R, Wall PD. Pain mechanisms: a new theory. Science. 1965;150:971–9.PubMedCrossRefGoogle Scholar
  10. 10.
    Costigan M, Woolf CJ. No DREAM, No pain. Closing the spinal gate. Cell. 2002;108:297–300.PubMedCrossRefGoogle Scholar
  11. 11.
    • Daniele CA, MacDermott AB: Low-threshold primary afferent drive onto GABAergic interneurons in the superficial dorsal horn of the mouse. J.Neurosci. 2009, 29:686–695. This article provides complementary morphological and functional evidence that GABAergic inhibitory interneurons in superficial dorsal horn can be activated by convergent Aβ-fiber inputs, thus an important pain inhibitory mechanism supporting the gate-control theory. PubMedCrossRefGoogle Scholar
  12. 12.
    Takazawa T, MacDermott AB. Synaptic pathways and inhibitory gates in the spinal cord dorsal horn. Ann N Y Acad Sci. 2010;1198:153–8.PubMedCrossRefGoogle Scholar
  13. 13.
    Saade N, Atweh AF, Tabet MS, Jabbur SJ. Inhibition of nociceptive withdrawal flexion reflexes through a dorsal column-brainstem-spinal loop. Brain Res. 1985;335:306–8.PubMedCrossRefGoogle Scholar
  14. 14.
    Marchand S, Bushnell MC, Molina-Negro P, Martinez SN, Duncan GH. The effects of dorsal column stimulation on measures of clinical and experimental pain in man. Pain. 1991;45:249–57.PubMedCrossRefGoogle Scholar
  15. 15.
    •• Guan Y, Wacnik PW, Yang F, Carteret AF, Chung CY, Meyer RA, Raja SN: Spinal cord stimulation-induced analgesia: electrical stimulation of dorsal column and dorsal roots attenuates dorsal horn neuronal excitability in neuropathic rats. Anesthesiology 2010, 113:1392–1405. This electrophysiological study demonstrates that SCS attenuates dorsal horn neuronal excitability in nerve-injured rats. It provides an important cellular mechanism underlying SCS analgesia and an in vivo model allows the neurophysiologic basis for the actions of SCS to be studied. PubMedCrossRefGoogle Scholar
  16. 16.
    Cogiamanian F, Vergari M, Schiaffi E, Marceglia S, Ardolino G, Barbieri S, Priori A. Transcutaneous spinal cord direct current stimulation inhibits the lower limb nociceptive flexion reflex in human beings. Pain. 2011;152:370–5.PubMedCrossRefGoogle Scholar
  17. 17.
    Gybels J, Kupers R. Central and peripheral electrical stimulation of the nervous system in the treatment of chronic pain. Acta Neurochir Suppl (Wien). 1987;38:64–75.CrossRefGoogle Scholar
  18. 18.
    Meyerson BA, Ren B, Herregodts P, Linderoth B. Spinal cord stimulation in animal models of mononeuropathy: effects on the withdrawal response and the flexor reflex. Pain. 1995;61:229–43.PubMedCrossRefGoogle Scholar
  19. 19.
    • Song Z, Ultenius C, Meyerson BA, Linderoth B: Pain relief by spinal cord stimulation involves serotonergic mechanisms: an experimental study in a rat model of mononeuropathy. Pain 2009, 147:241–248. This study provides important evidence that spinal 5-HT system contributes to SCS analgesia, and that activation of descending serotonergic pathways by SCS may attenuate spinal pain transmission by activation of local GABAergic circuitry. PubMedCrossRefGoogle Scholar
  20. 20.
    Gerasimenko YP, Lavrov IA, Courtine G, Ichiyama RM, Dy CJ, Zhong H, Roy RR, Edgerton VR. Spinal cord reflexes induced by epidural spinal cord stimulation in normal awake rats. J Neurosci Methods. 2006;157:253–63.PubMedCrossRefGoogle Scholar
  21. 21.
    Yang F, Carteret AF, Wacnik PW, Chung CY, Xing L, Dong X, Meyer RA, Raja SN, Guan Y: Bipolar spinal cord stimulation attenuates mechanical hypersensitivity at an intensity that activates a small portion of A-fiber afferents in spinal nerve-injured rats. Neuroscience 2011.Google Scholar
  22. 22.
    Feirabend HK, Choufoer H, Ploeger S, Holsheimer J, van Gool JD. Morphometry of human superficial dorsal and dorsolateral column fibres: significance to spinal cord stimulation. Brain. 2002;125:1137–49.PubMedCrossRefGoogle Scholar
  23. 23.
    Holsheimer J. Computer modelling of spinal cord stimulation and its contribution to therapeutic efficacy. Spinal Cord. 1998;36:531–40.PubMedCrossRefGoogle Scholar
  24. 24.
    Woolf CJ. Central sensitization: uncovering the relation between pain and plasticity. Anesthesiology. 2007;106:864–7.PubMedCrossRefGoogle Scholar
  25. 25.
    Latremoliere A, Woolf CJ. Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J Pain. 2009;10:895–926.PubMedCrossRefGoogle Scholar
  26. 26.
    Guan Y, Borzan J, Meyer RA, Raja SN. Windup in dorsal horn neurons is modulated by endogenous spinal mu-opioid mechanisms. J Neurosci. 2006;26:4298–307.PubMedCrossRefGoogle Scholar
  27. 27.
    Yakhnitsa V, Linderoth B, Meyerson BA. Spinal cord stimulation attenuates dorsal horn neuronal hyperexcitability in a rat model of mononeuropathy. Pain. 1999;79:223–33.PubMedCrossRefGoogle Scholar
  28. 28.
    Stiller CO, Cui JG, O’Connor WT, Brodin E, Meyerson BA, Linderoth B. Release of gamma-aminobutyric acid in the dorsal horn and suppression of tactile allodynia by spinal cord stimulation in mononeuropathic rats. Neurosurgery. 1996;39:367–74.PubMedCrossRefGoogle Scholar
  29. 29.
    •• Maeda Y, Wacnik PW, Sluka KA: Low frequencies, but not high frequencies of bi-polar spinal cord stimulation reduce cutaneous and muscle hyperalgesia induced by nerve injury. Pain 2008, 138:143–152. This animal behavioral study uses a miniature quadripolar electrode to mimic the actions of SCS in clinical situations. It demonstrates that stimulation frequency is important to the effectiveness of SCS and that repeated SCS results in a cumulative pain relief in nerve-injured rats. PubMedCrossRefGoogle Scholar
  30. 30.
    Smits H, Ultenius C, Deumens R, Koopmans GC, Honig WM, van Kleef M, Linderoth B, Joosten EA. Effect of spinal cord stimulation in an animal model of neuropathic pain relates to degree of tactile “allodynia”. Neuroscience. 2006;143:541–6.PubMedCrossRefGoogle Scholar
  31. 31.
    Campbell JN, Meyer RA. Mechanisms of neuropathic pain. Neuron. 2006;52:77–92.PubMedCrossRefGoogle Scholar
  32. 32.
    Djouhri L, Koutsikou S, Fang X, McMullan S, Lawson SN. Spontaneous pain, both neuropathic and inflammatory, is related to frequency of spontaneous firing in intact C-fiber nociceptors. J Neurosci. 2006;26:1281–92.PubMedCrossRefGoogle Scholar
  33. 33.
    Buonocore M, Bonezzi C, Barolat G. Neurophysiological evidence of antidromic activation of large myelinated fibres in lower limbs during spinal cord stimulation. Spine. 2008;33:E90–3. Phila Pa 1976.PubMedCrossRefGoogle Scholar
  34. 34.
    Takazawa T, MacDermott AB. Glycinergic and GABAergic tonic inhibition fine tune inhibitory control in regionally distinct subpopulations of dorsal horn neurons. J Physiol. 2010;588:2571–87.PubMedCrossRefGoogle Scholar
  35. 35.
    Narikawa K, Furue H, Kumamoto E, Yoshimura M. In vivo patch-clamp analysis of IPSCs evoked in rat substantia gelatinosa neurons by cutaneous mechanical stimulation. J Neurophysiol. 2000;84:2171–4.PubMedGoogle Scholar
  36. 36.
    Shimoji K, Shimizu H, Maruyama Y, Matsuki M, Kuribayashi H, Fujioka H. Dorsal column stimulation in man: facilitation of primary afferent depolarization. Anesth Analg. 1982;61:410–3.PubMedCrossRefGoogle Scholar
  37. 37.
    Barron KW, Croom JE, Ray CA, Chandler MJ, Foreman RD. Spinal integration of antidromic mediated cutaneous vasodilation during dorsal spinal cord stimulation in the rat. Neurosci Lett. 1999;260:173–6.PubMedCrossRefGoogle Scholar
  38. 38.
    Schoffnegger D, Heinke B, Sommer C, Sandkuhler J. Physiological properties of spinal lamina II GABAergic neurons in mice following peripheral nerve injury. J Physiol. 2006;577:869–78.PubMedCrossRefGoogle Scholar
  39. 39.
    Baba H, Yoshimura M, Nishi S, Shimoji K. Synaptic responses of substantia gelatinosa neurones to dorsal column stimulation in rat spinal cord in vitro. J Physiol. 1994;478(Pt 1):87–99.PubMedGoogle Scholar
  40. 40.
    Cui JG, O’Connor WT, Ungerstedt U, Linderoth B, Meyerson BA. Spinal cord stimulation attenuates augmented dorsal horn release of excitatory amino acids in mononeuropathy via a GABAergic mechanism. Pain. 1997;73:87–95.PubMedCrossRefGoogle Scholar
  41. 41.
    Cui JG, Meyerson BA, Sollevi A, Linderoth B. Effect of spinal cord stimulation on tactile hypersensitivity in mononeuropathic rats is potentiated by simultaneous GABA(B) and adenosine receptor activation. Neurosci Lett. 1998;247:183–6.PubMedCrossRefGoogle Scholar
  42. 42.
    Lind G, Schechtmann G, Winter J, Meyerson BA, Linderoth B. Baclofen-enhanced spinal cord stimulation and intrathecal baclofen alone for neuropathic pain: Long-term outcome of a pilot study. Eur J Pain. 2008;12:132–6.PubMedCrossRefGoogle Scholar
  43. 43.
    Lind G, Meyerson BA, Winter J, Linderoth B. Intrathecal baclofen as adjuvant therapy to enhance the effect of spinal cord stimulation in neuropathic pain: a pilot study. Eur J Pain. 2004;8:377–83.PubMedCrossRefGoogle Scholar
  44. 44.
    Schechtmann G, Lind G, Winter J, Meyerson BA, Linderoth B. Intrathecal clonidine and baclofen enhance the pain-relieving effect of spinal cord stimulation: a comparative placebo-controlled, randomized trial. Neurosurgery. 2010;67:173–81.PubMedCrossRefGoogle Scholar
  45. 45.
    Janssen SP, Truin M, van Kleff M, Joosten EA. Differential GABAergic disinhibition during the development of painful peripheral neuropathy. Neuroscience. 2011;184:183–94.PubMedCrossRefGoogle Scholar
  46. 46.
    Schechtmann G, Song Z, Ultenius C, Meyerson BA, Linderoth B. Cholinergic mechanisms involved in the pain relieving effect of spinal cord stimulation in a model of neuropathy. Pain. 2008;139:136–45.PubMedCrossRefGoogle Scholar
  47. 47.
    Cui JG, Linderoth B, Meyerson BA. Effects of spinal cord stimulation on touch-evoked allodynia involve GABAergic mechanisms. An experimental study in the mononeuropathic rat. Pain. 1996;66:287–95.PubMedCrossRefGoogle Scholar
  48. 48.
    Linderoth B, Gazelius B, Franck J, Brodin E. Dorsal column stimulation induces release of serotonin and substance P in the cat dorsal horn. Neurosurgery. 1992;31:289–96.PubMedCrossRefGoogle Scholar
  49. 49.
    Liu FY, Qu XX, Ding X, Cai J, Jiang H, Wan Y, Han JS, Xing GG. Decrease in the descending inhibitory 5-HT system in rats with spinal nerve ligation. Brain Res. 2010;1330:45–60.PubMedCrossRefGoogle Scholar
  50. 50.
    Liu FY, Xing GG, Qu XX, Xu IS, Han JS, Wan Y. Roles of 5-hydroxytryptamine (5-HT) receptor subtypes in the inhibitory effects of 5-HT on C-fiber responses of spinal wide dynamic range neurons in rats. J Pharmacol Exp Ther. 2007;321:1046–53.PubMedCrossRefGoogle Scholar
  51. 51.
    Suzuki R, Rahman W, Rygh LJ, Webber M, Hunt SP, Dickenson AH. Spinal-supraspinal serotonergic circuits regulating neuropathic pain and its treatment with gabapentin. Pain. 2005;117:292–303.PubMedCrossRefGoogle Scholar
  52. 52.
    •• Song Z, Meyerson BA, Linderoth B: Spinal 5-HT receptors that contribute to the pain-relieving effects of spinal cord stimulation in a rat model of neuropathy. Pain 2011, 152:1666–1673. This extensive in vivo pharmacological study offers critical information about the respective roles of different spinal 5-HT receptor subtypes in SCS analgesia under neuropathic pain condition. It suggests that activation of 5-HT2A,3,4 receptors is important to SCS analgesia, partly via GABAergic interneurons. PubMedCrossRefGoogle Scholar
  53. 53.
    Wei F, Dubner R, Zou S, Ren K, Bai G, Wei D, Guo W. Molecular depletion of descending serotonin unmasks its novel facilitatory role in the development of persistent pain. J Neurosci. 2010;30:8624–36.PubMedCrossRefGoogle Scholar
  54. 54.
    Asante CO, Dickenson AH. Descending serotonergic facilitation mediated by spinal 5-HT3 receptors engages spinal rapamycin-sensitive pathways in the rat. Neurosci Lett. 2010;484:108–12.PubMedCrossRefGoogle Scholar
  55. 55.
    Fukushima T, Ohtsubo T, Tsuda M, Yanagawa Y, Hori Y. Facilitatory actions of serotonin type 3 receptors on GABAergic inhibitory synaptic transmission in the spinal superficial dorsal horn. J Neurophysiol. 2009;102:1459–71.PubMedCrossRefGoogle Scholar
  56. 56.
    Wang YY, Wu SX, Liu XY, Wang W, Li YQ. Effects of c-fos antisense oligodeoxynucleotide on 5-HT-induced upregulation of preprodynorphin, preproenkephalin, and glutamic acid decarboxylase mRNA expression in cultured rat spinal dorsal horn neurons. Biochem Biophys Res Commun. 2003;309:631–6.PubMedCrossRefGoogle Scholar
  57. 57.
    Levin BE, Hubschmann OR. Dorsal column stimulation: Effect on human cerebrospinal fluid and plasma catecholamines. Neurology. 1980;30:65–71.PubMedGoogle Scholar
  58. 58.
    Song Z, Meyerson BA, Linderoth B. Muscarinic receptor activation potentiates the effect of spinal cord stimulation on pain-related behavior in rats with mononeuropathy. Neurosci Lett. 2008;436:7–12.PubMedCrossRefGoogle Scholar
  59. 59.
    Radhakrishnan R, Sluka KA. Spinal muscarinic receptors are activated during low or high frequency TENS-induced antihyperalgesia in rats. Neuropharmacology. 2003;45:1111–9.PubMedCrossRefGoogle Scholar
  60. 60.
    Schechtmann G, Wallin J, Meyerson BA, Linderoth B. Intrathecal clonidine potentiates suppression of tactile hypersensitivity by spinal cord stimulation in a model of neuropathy. Anesth Analg. 2004;99:135–9.PubMedCrossRefGoogle Scholar
  61. 61.
    Zhang HM, Chen SR, Cai YQ, Richardson TE, Driver LC, Lopez-Berestein G, Pan HL. Signaling mechanisms mediating muscarinic enhancement of GABAergic synaptic transmission in the spinal cord. Neuroscience. 2009;158:1577–88.PubMedCrossRefGoogle Scholar
  62. 62.
    Chen SR, Pan HL. Spinal GABAB receptors mediate antinociceptive actions of cholinergic agents in normal and diabetic rats. Brain Res. 2003;965:67–74.PubMedCrossRefGoogle Scholar
  63. 63.
    Gassner M, Ruscheweyh R, Sandkuhler J. Direct excitation of spinal GABAergic interneurons by noradrenaline. Pain. 2009;145:204–10.PubMedCrossRefGoogle Scholar
  64. 64.
    Miraucourt LS, Moisset X, Dallel R, Voisin DL. Glycine inhibitory dysfunction induces a selectively dynamic, morphine-resistant, and neurokinin 1 receptor- independent mechanical allodynia. J Neurosci. 2009;29:2519–27.PubMedCrossRefGoogle Scholar
  65. 65.
    Lind G, Schechtmann G, Winter J, Linderoth B. Drug-enhanced spinal stimulation for pain: a new strategy. Acta Neurochir Suppl. 2007;97:57–63.PubMedCrossRefGoogle Scholar
  66. 66.
    Song Z, Meyerson BA, Linderoth B: The interaction between antidepressant drugs and the pain-relieving effect of spinal cord stimulation in a rat model of neuropathy. Anesth Analg 2011.Google Scholar
  67. 67.
    Fuentes R, Petersson P, Siesser WB, Caron MG, Nicolelis MA. Spinal cord stimulation restores locomotion in animal models of Parkinson’s disease. Science. 2009;323:1578–82.PubMedCrossRefGoogle Scholar
  68. 68.
    Gao J, Wu M, Li L, Qin C, Farber JP, Linderoth B, Foreman RD. Effects of spinal cord stimulation with “standard clinical” and higher frequencies on peripheral blood flow in rats. Brain Res. 2010;1313:53–61.PubMedCrossRefGoogle Scholar
  69. 69.
    Maeda Y, Ikeuchi M, Wacnik P, Sluka KA. Increased c-fos immunoreactivity in the spinal cord and brain following spinal cord stimulation is frequency-dependent. Brain Res. 2009;1259:40–50.PubMedCrossRefGoogle Scholar
  70. 70.
    Waltz JM. Spinal cord stimulation: a quarter century of development and investigation. A review of its development and effectiveness in 1,336 cases. Stereotact Funct Neurosurg. 1997;69:288–99.PubMedCrossRefGoogle Scholar
  71. 71.
    Kumar K, Taylor RS, Jacques L, Eldabe S, Meglio M, Molet J, Thomson S, O’Callaghan J, Eisenberg E, Milbouw G, Buchser E, Fortini G, Richardson J, North RB. The effects of spinal cord stimulation in neuropathic pain are sustained: a 24-month follow-up of the prospective randomized controlled multicenter trial of the effectiveness of spinal cord stimulation. Neurosurgery. 2008;63:762–70.PubMedCrossRefGoogle Scholar
  72. 72.
    Li J, Simone DA, Larson AA. Windup leads to characteristics of central sensitization. Pain. 1999;79:75–82.PubMedCrossRefGoogle Scholar
  73. 73.
    Wallin J, Fiska A, Tjolsen A, Linderoth B, Hole K. Spinal cord stimulation inhibits long-term potentiation of spinal wide dynamic range neurons. Brain Res. 2003;973:39–43.PubMedCrossRefGoogle Scholar
  74. 74.
    Ji RR, Kohno T, Moore KA, Woolf CJ. Central sensitization and LTP: do pain and memory share similar mechanisms? Trends Neurosci. 2003;26:696–705.PubMedCrossRefGoogle Scholar
  75. 75.
    Ikeda H, Stark J, Fischer H, Wagner M, Drdla R, Jager T, Sandkuhler J. Synaptic amplifier of inflammatory pain in the spinal dorsal horn. Science. 2006;312:1659–62.PubMedCrossRefGoogle Scholar
  76. 76.
    Truin M, van Kleef M, Linderoth B, Smits H, Janssen SP, Joosten EA. Increased efficacy of early spinal cord stimulation in an animal model of neuropathic pain. Eur J Pain. 2011;15:111–7.PubMedCrossRefGoogle Scholar
  77. 77.
    Truin M, Janssen SP, van Kleef M, Joosten EA. Successful pain relief in non-responders to spinal cord stimulation: The combined use of ketamine and spinal cord stimulation. Eur J Pain. 2011;15:1049.PubMedCrossRefGoogle Scholar
  78. 78.
    Wu M, Linderoth B, Foreman RD. Putative mechanisms behind effects of spinal cord stimulation on vascular diseases: a review of experimental studies. Auton Neurosci. 2008;138:9–23.PubMedCrossRefGoogle Scholar
  79. 79.
    Wu M, Komori N, Qin C, Farber JP, Linderoth B, Foreman RD. Extracellular signal-regulated kinase (ERK) and protein kinase B (AKT) pathways involved in spinal cord stimulation (SCS)-induced vasodilation. Brain Res. 2008;1207:73–83.PubMedCrossRefGoogle Scholar
  80. 80.
    Smits H, Kleef MV, Honig W, Gerver J, Gobrecht P, Joosten EA. Spinal cord stimulation induces c-Fos expression in the dorsal horn in rats with neuropathic pain after partial sciatic nerve injury. Neurosci Lett. 2009;450:70–3.PubMedCrossRefGoogle Scholar
  81. 81.
    Ji RR, Baba H, Brenner GJ, Woolf CJ. Nociceptive-specific activation of ERK in spinal neurons contributes to pain hypersensitivity. Nat Neurosci. 1999;2:1114–9.PubMedCrossRefGoogle Scholar
  82. 82.
    Suzuki R, Morcuende S, Webber M, Hunt SP, Dickenson AH. Superficial NK1-expressing neurons control spinal excitability through activation of descending pathways. Nat Neurosci. 2002;5:1319–26.PubMedCrossRefGoogle Scholar
  83. 83.
    Rees H, Roberts MH. Activation of cells in the anterior pretectal nucleus by dorsal column stimulation in the rat. J Physiol. 1989;417:361–73.PubMedGoogle Scholar
  84. 84.
    El-Khoury C, Hawwa N, Baliki M, Atweh SF, Jabbur SJ, Saade NE. Attenuation of neuropathic pain by segmental and supraspinal activation of the dorsal column system in awake rats. Neuroscience. 2002;112:541–53.PubMedCrossRefGoogle Scholar
  85. 85.
    Saade NE, Tabet MS, Soueidan SA, Bitar M, Atweh SF, Jabbur SJ. Supraspinal modulation of nociception in awake rats by stimulation of the dorsal column nuclei. Brain Res. 1986;369:307–10.PubMedCrossRefGoogle Scholar
  86. 86.
    Salibi NA, Saade NE, Banna NR, Jabbur SJ. Dorsal column input into the reticular formation. Nature. 1980;288:481–3.PubMedCrossRefGoogle Scholar
  87. 87.
    Ren B, Linderoth B, Meyerson BA. Effects of spinal cord stimulation on the flexor reflex and involvement of supraspinal mechanisms: an experimental study in mononeuropathic rats. J Neurosurg. 1996;84:244–9.PubMedCrossRefGoogle Scholar
  88. 88.
    Ossipov MH, Lai J, Malan Jr TP, Porreca F. Spinal and supraspinal mechanisms of neuropathic pain. Ann N Y Acad Sci. 2000;909:12–24.PubMedCrossRefGoogle Scholar
  89. 89.
    Vera-Portocarrero LP, Zhang ET, Ossipov MH, Xie JY, King T, Lai J, Porreca F. Descending facilitation from the rostral ventromedial medulla maintains nerve injury-induced central sensitization. Neuroscience. 2006;140:1311–20.PubMedCrossRefGoogle Scholar
  90. 90.
    Gardell LR, Vanderah TW, Gardell SE, Wang R, Ossipov MH, Lai J, Porreca F. Enhanced evoked excitatory transmitter release in experimental neuropathy requires descending facilitation. J Neurosci. 2003;23:8370–9.PubMedGoogle Scholar
  91. 91.
    Suzuki R, Dickenson A. Spinal and supraspinal contributions to central sensitization in peripheral neuropathy. Neurosignals. 2005;14:175–81.PubMedCrossRefGoogle Scholar
  92. 92.
    King T, Vera-Portocarrero L, Gutierrez T, Vanderah TW, Dussor G, Lai J, Fields HL, Porreca F. Unmasking the tonic-aversive state in neuropathic pain. Nat Neurosci. 2009;12:1364–6.PubMedCrossRefGoogle Scholar
  93. 93.
    Qu C, King T, Okun A, Lai J, Fields HL, Porreca F. Lesion of the rostral anterior cingulate cortex eliminates the aversiveness of spontaneous neuropathic pain following partial or complete axotomy. Pain. 2011;152:1641–8.PubMedCrossRefGoogle Scholar
  94. 94.
    Pedersen LH, Blackburn-Munro G. Pharmacological characterisation of place escape/avoidance behaviour in the rat chronic constriction injury model of neuropathic pain. Psychopharmacology (Berl). 2006;185:208–17.CrossRefGoogle Scholar
  95. 95.
    Stiller CO, Linderoth B, O’Connor WT, Franck J, Falkenberg T, Ungerstedt U, Brodin E. Repeated spinal cord stimulation decreases the extracellular level of gamma-aminobutyric acid in the periaqueductal gray matter of freely moving rats. Brain Res. 1995;699:231–41.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Division of Pain Medicine, Department of Anesthesiology and Critical Care MedicineJohns Hopkins UniversityBaltimoreUSA

Personalised recommendations