Pain Control pp 171-190 | Cite as

Plasticity of Inhibition in the Spinal Cord

  • Andrew J. ToddEmail author
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 227)


Inhibitory interneurons, which use GABA and/or glycine as their principal transmitter, have numerous roles in regulating the transmission of sensory information through the spinal dorsal horn. These roles are likely to be performed by different populations of interneurons, each with specific locations in the synaptic circuitry of the region. Peripheral nerve injury frequently leads to neuropathic pain, and it is thought that loss of function of inhibitory interneurons in the dorsal horn contributes to this condition. Several mechanisms have been proposed for this disinhibition, including death of inhibitory interneurons, decreased transmitter release, diminished activity of these cells and reduced effectiveness of GABA and glycine as inhibitory transmitters. However, despite numerous studies on this important topic, it is still not clear which (if any) of these mechanisms contributes to neuropathic pain after nerve injury.


GABA Glycine Neuropathic pain Inhibitory interneuron 


  1. Akiyama T, Iodi Carstens M, Carstens E (2011) Transmitters and pathways mediating inhibition of spinal itch-signaling neurons by scratching and other counter stimuli. PLoS One 6:e22665CrossRefPubMedCentralPubMedGoogle Scholar
  2. Andrew D (2009) Sensitization of lamina I spinoparabrachial neurons parallels heat hyperalgesia in the chronic constriction injury model of neuropathic pain. J Physiol 587:2005–2017CrossRefPubMedCentralPubMedGoogle Scholar
  3. Antal M, Petko M, Polgar E, Heizmann CW, Storm-Mathisen J (1996) Direct evidence of an extensive GABAergic innervation of the spinal dorsal horn by fibres descending from the rostral ventromedial medulla. Neuroscience 73:509–518CrossRefPubMedGoogle Scholar
  4. Attal N, Jazat F, Kayser V, Guilbaud G (1990) Further evidence for ‘pain-related’ behaviours in a model of unilateral peripheral mononeuropathy. Pain 41:235–251CrossRefPubMedGoogle Scholar
  5. Azkue JJ, Zimmermann M, Hsieh TF, Herdegen T (1998) Peripheral nerve insult induces NMDA receptor-mediated, delayed degeneration in spinal neurons. Eur J Neurosci 10:2204–2206CrossRefPubMedGoogle Scholar
  6. Baseer N, Polgar E, Watanabe M, Furuta T, Kaneko T, Todd AJ (2012) Projection neurons in lamina III of the rat spinal cord are selectively innervated by local dynorphin-containing excitatory neurons. J Neurosci 32:11854–11863CrossRefPubMedCentralPubMedGoogle Scholar
  7. Bennett GJ, Xie YK (1988) A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 33:87–107CrossRefPubMedGoogle Scholar
  8. Bester H, Chapman V, Besson JM, Bernard JF (2000) Physiological properties of the lamina I spinoparabrachial neurons in the rat. J Neurophysiol 83:2239–2259PubMedGoogle Scholar
  9. Castro-Lopes JM, Coimbra A, Grant G, Arvidsson J (1990) Ultrastructural changes of the central scalloped (C1) primary afferent endings of synaptic glomeruli in the substantia gelatinosa Rolandi of the rat after peripheral neurotomy. J Neurocytol 19:329–337CrossRefPubMedGoogle Scholar
  10. Cordero-Erausquin M, Allard S, Dolique T, Bachand K, Ribeiro-da-Silva A, De Koninck Y (2009) Dorsal horn neurons presynaptic to lamina I spinoparabrachial neurons revealed by transynaptic labeling. J Comp Neurol 517:601–615CrossRefPubMedGoogle Scholar
  11. Coull JA, Boudreau D, Bachand K et al (2003) Trans-synaptic shift in anion gradient in spinal lamina I neurons as a mechanism of neuropathic pain. Nature 424:938–942CrossRefPubMedGoogle Scholar
  12. Coull JA, Beggs S, Boudreau D et al (2005) BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 438:1017–1021CrossRefPubMedGoogle Scholar
  13. Davidson S, Zhang X, Khasabov SG, Simone DA, Giesler GJ Jr (2009) Relief of itch by scratching: state-dependent inhibition of primate spinothalamic tract neurons. Nat Neurosci 12:544–546CrossRefPubMedCentralPubMedGoogle Scholar
  14. Decosterd I, Woolf CJ (2000) Spared nerve injury: an animal model of persistent peripheral neuropathic pain. Pain 87:149–158CrossRefPubMedGoogle Scholar
  15. Eaton MJ, Plunkett JA, Karmally S, Martinez MA, Montanez K (1998) Changes in GAD- and GABA-immunoreactivity in the spinal dorsal horn after peripheral nerve injury and promotion of recovery by lumbar transplant of immortalized serotonergic precursors. J Chem Neuroanat 16:57–72CrossRefPubMedGoogle Scholar
  16. Engle MP, Merrill MA, Marquez De Prado B, Hammond DL (2012) Spinal nerve ligation decreases gamma-aminobutyric acid B receptors on specific populations of immunohistochemically identified neurons in L5 dorsal root ganglion of the rat. J Comp Neurol 520:1663–1677CrossRefPubMedCentralPubMedGoogle Scholar
  17. Graham BA, Brichta AM, Callister RJ (2007) Moving from an averaged to specific view of spinal cord pain processing circuits. J Neurophysiol 98:1057–1063CrossRefPubMedGoogle Scholar
  18. Grudt TJ, Perl ER (2002) Correlations between neuronal morphology and electrophysiological features in the rodent superficial dorsal horn. J Physiol 540:189–207CrossRefPubMedCentralPubMedGoogle Scholar
  19. Hantman AW, van den Pol AN, Perl ER (2004) Morphological and physiological features of a set of spinal substantia gelatinosa neurons defined by green fluorescent protein expression. J Neurosci 24:836–842CrossRefPubMedGoogle Scholar
  20. Heinke B, Ruscheweyh R, Forsthuber L, Wunderbaldinger G, Sandkuhler J (2004) Physiological, neurochemical and morphological properties of a subgroup of GABAergic spinal lamina II neurones identified by expression of green fluorescent protein in mice. J Physiol 560:249–266CrossRefPubMedCentralPubMedGoogle Scholar
  21. Hughes DI, Sikander S, Kinnon CM, Boyle KA, Watanabe M, Callister RJ, Graham BA (2012) Morphological, neurochemical and electrophysiological features of parvalbumin-expressing cells: a likely source of axo-axonic inputs in the mouse spinal dorsal horn. J Physiol 590:3927–3951CrossRefPubMedCentralPubMedGoogle Scholar
  22. Hwang JH, Yaksh TL (1997) The effect of spinal GABA receptor agonists on tactile allodynia in a surgically-induced neuropathic pain model in the rat. Pain 70:15–22CrossRefPubMedGoogle Scholar
  23. Ibuki T, Hama AT, Wang XT, Pappas GD, Sagen J (1997) Loss of GABA-immunoreactivity in the spinal dorsal horn of rats with peripheral nerve injury and promotion of recovery by adrenal medullary grafts. Neuroscience 76:845–858CrossRefPubMedGoogle Scholar
  24. Iwagaki N, Garzillo F, Polgar E, Riddell JS, Todd AJ (2013) Neurochemical characterisation of lamina II inhibitory interneurons that express GFP in the PrP-GFP mouse. Mol Pain 9:56CrossRefPubMedCentralPubMedGoogle Scholar
  25. Kardon AP, Polgár E, Hachisuka J et al (2014) Dynorphin acts as a neuromodulator to inhibit itch in the dorsal horn of the spinal cord. Neuron 82:573–586CrossRefPubMedCentralPubMedGoogle Scholar
  26. Kawamura T, Akira T, Watanabe M, Kagitani Y (1997) Prostaglandin E1 prevents apoptotic cell death in superficial dorsal horn of rat spinal cord. Neuropharmacology 36:1023–1030CrossRefPubMedGoogle Scholar
  27. Keller AF, Beggs S, Salter MW, De Koninck Y (2007) Transformation of the output of spinal lamina I neurons after nerve injury and microglia stimulation underlying neuropathic pain. Mol Pain 3:27CrossRefPubMedCentralPubMedGoogle Scholar
  28. Kim SH, Chung JM (1992) An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain 50:355–363CrossRefPubMedGoogle Scholar
  29. Leitner J, Westerholz S, Heinke B et al (2013) Impaired excitatory drive to spinal GABAergic neurons of neuropathic mice. PLoS One 8:e73370CrossRefPubMedCentralPubMedGoogle Scholar
  30. Light AR, Trevino DL, Perl ER (1979) Morphological features of functionally defined neurons in the marginal zone and substantia gelatinosa of the spinal dorsal horn. J Comp Neurol 186:151–171CrossRefPubMedGoogle Scholar
  31. Lu Y, Perl ER (2005) Modular organization of excitatory circuits between neurons of the spinal superficial dorsal horn (laminae I and II). J Neurosci 25:3900–3907CrossRefPubMedGoogle Scholar
  32. Lu Y, Dong H, Gao Y et al (2013) A feed-forward spinal cord glycinergic neural circuit gates mechanical allodynia. J Clin Invest 123:4050–4062CrossRefPubMedGoogle Scholar
  33. Mackie M, Hughes DI, Maxwell DJ, Tillakaratne NJ, Todd AJ (2003) Distribution and colocalisation of glutamate decarboxylase isoforms in the rat spinal cord. Neuroscience 119:461–472CrossRefPubMedGoogle Scholar
  34. Malan TP, Mata HP, Porreca F (2002) Spinal GABA(A) and GABA(B) receptor pharmacology in a rat model of neuropathic pain. Anesthesiology 96:1161–1167CrossRefPubMedGoogle Scholar
  35. Maxwell DJ, Belle MD, Cheunsuang O, Stewart A, Morris R (2007) Morphology of inhibitory and excitatory interneurons in superficial laminae of the rat dorsal horn. J Physiol 584:521–533CrossRefPubMedCentralPubMedGoogle Scholar
  36. Miraucourt LS, Dallel R, Voisin DL (2007) Glycine inhibitory dysfunction turns touch into pain through PKCgamma interneurons. PLoS One 2:e1116CrossRefPubMedCentralPubMedGoogle Scholar
  37. Molander C, Wang HF, Rivero-Melian C, Grant G (1996) Early decline and late restoration of spinal cord binding and transganglionic transport of isolectin B4 from Griffonia simplicifolia I after peripheral nerve transection or crush. Restor Neurol Neurosci 10:123–133PubMedGoogle Scholar
  38. Moore KA, Kohno T, Karchewski LA, Scholz J, Baba H, Woolf CJ (2002) Partial peripheral nerve injury promotes a selective loss of GABAergic inhibition in the superficial dorsal horn of the spinal cord. J Neurosci 22:6724–6731PubMedGoogle Scholar
  39. Oliva AA Jr, Jiang M, Lam T, Smith KL, Swann JW (2000) Novel hippocampal interneuronal subtypes identified using transgenic mice that express green fluorescent protein in GABAergic interneurons. J Neurosci 20:3354–3368PubMedGoogle Scholar
  40. Peirs C, Patil S, Bouali-Benazzouz R, Artola A, Landry M, Dallel R (2014) Protein kinase C gamma interneurons in the rat medullary dorsal horn: distribution and synaptic inputs to these neurons, and subcellular localization of the enzyme. J Comp Neurol 522:393–413CrossRefPubMedGoogle Scholar
  41. Polgár E, Todd AJ (2008) Tactile allodynia can occur in the spared nerve injury model in the rat without selective loss of GABA or GABA(A) receptors from synapses in laminae I-II of the ipsilateral spinal dorsal horn. Neuroscience 156:193–202CrossRefPubMedCentralPubMedGoogle Scholar
  42. Polgár E, Shehab SAS, Watt C, Todd AJ (1999) GABAergic neurons that contain neuropeptide Y selectively target cells with the Neurokinin 1 receptor in laminae III and IV of the rat spinal cord. J Neurosci 19:2637–2646PubMedGoogle Scholar
  43. Polgár E, Hughes DI, Riddell JS, Maxwell DJ, Puskar Z, Todd AJ (2003) Selective loss of spinal GABAergic or glycinergic neurons is not necessary for development of thermal hyperalgesia in the chronic constriction injury model of neuropathic pain. Pain 104:229–239CrossRefPubMedGoogle Scholar
  44. Polgár E, Gray S, Riddell JS, Todd AJ (2004) Lack of evidence for significant neuronal loss in laminae I-III of the spinal dorsal horn of the rat in the chronic constriction injury model. Pain 111:144–150CrossRefPubMedGoogle Scholar
  45. Polgár E, Hughes DI, Arham AZ, Todd AJ (2005) Loss of neurons from laminas I-III of the spinal dorsal horn is not required for development of tactile allodynia in the spared nerve injury model of neuropathic pain. J Neurosci 25:6658–6666CrossRefPubMedGoogle Scholar
  46. Polgár E, Campbell AD, MacIntyre LM, Watanabe M, Todd AJ (2007) Phosphorylation of ERK in neurokinin 1 receptor-expressing neurons in laminae III and IV of the rat spinal dorsal horn following noxious stimulation. Mol Pain 3:4CrossRefPubMedCentralPubMedGoogle Scholar
  47. Polgár E, Al-Khater KM, Shehab S, Watanabe M, Todd AJ (2008) Large projection neurons in lamina I of the rat spinal cord that lack the neurokinin 1 receptor are densely innervated by VGLUT2-containing axons and possess GluR4-containing AMPA receptors. J Neurosci 28:13150–13160CrossRefPubMedCentralPubMedGoogle Scholar
  48. Polgár E, Al Ghamdi KS, Todd AJ (2010) Two populations of neurokinin 1 receptor-expressing projection neurons in lamina I of the rat spinal cord that differ in AMPA receptor subunit composition and density of excitatory synaptic input. Neuroscience 167:1192–1204CrossRefPubMedCentralPubMedGoogle Scholar
  49. Polgar E, Sardella TC, Watanabe M, Todd AJ (2011) Quantitative study of NPY-expressing GABAergic neurons and axons in rat spinal dorsal horn. J Comp Neurol 519:1007–1023CrossRefPubMedCentralPubMedGoogle Scholar
  50. Polgar E, Durrieux C, Hughes DI, Todd AJ (2013a) A quantitative study of inhibitory interneurons in laminae I-III of the mouse spinal dorsal horn. PLoS One 8:e78309CrossRefPubMedCentralPubMedGoogle Scholar
  51. Polgar E, Sardella TC, Tiong SY, Locke S, Watanabe M, Todd AJ (2013b) Functional differences between neurochemically defined populations of inhibitory interneurons in the rat spinal dorsal horn. Pain 154:2606–2615CrossRefPubMedCentralPubMedGoogle Scholar
  52. Puskár Z, Polgár E, Todd AJ (2001) A population of large lamina I projection neurons with selective inhibitory input in rat spinal cord. Neuroscience 102:167–176CrossRefPubMedGoogle Scholar
  53. Rexed B (1952) The cytoarchitectonic organization of the spinal cord in the cat. J Comp Neurol 96:414–495CrossRefPubMedGoogle Scholar
  54. Ribeiro-da-Silva A, Coimbra A (1982) Two types of synaptic glomeruli and their distribution in laminae I-III of the rat spinal cord. J Comp Neurol 209:176–186CrossRefPubMedGoogle Scholar
  55. Ross SE, Mardinly AR, McCord AE et al (2010) Loss of inhibitory interneurons in the dorsal spinal cord and elevated itch in Bhlhb5 mutant mice. Neuron 65:886–898CrossRefPubMedCentralPubMedGoogle Scholar
  56. Sandkuhler J (2009) Models and mechanisms of hyperalgesia and allodynia. Physiol Rev 89:707–758CrossRefPubMedGoogle Scholar
  57. Schneider SP, Walker TM (2007) Morphology and electrophysiological properties of hamster spinal dorsal horn neurons that express VGLUT2 and enkephalin. J Comp Neurol 501:790–809CrossRefPubMedGoogle Scholar
  58. Schoffnegger D, Heinke B, Sommer C, Sandkuhler J (2006) Physiological properties of spinal lamina II GABAergic neurons in mice following peripheral nerve injury. J Physiol 577:869–878CrossRefPubMedCentralPubMedGoogle Scholar
  59. Scholz J, Broom DC, Youn DH et al (2005) Blocking caspase activity prevents transsynaptic neuronal apoptosis and the loss of inhibition in lamina II of the dorsal horn after peripheral nerve injury. J Neurosci 25:7317–7323CrossRefPubMedGoogle Scholar
  60. Shehab SA, Al-Marashda K, Al-Zahmi A, Abdul-Kareem A, Al-Sultan MA (2008) Unmyelinated primary afferents from adjacent spinal nerves intermingle in the spinal dorsal horn: a possible mechanism contributing to neuropathic pain. Brain Res 1208:111–119CrossRefPubMedGoogle Scholar
  61. Sivilotti L, Woolf CJ (1994) The contribution of GABAA and glycine receptors to central sensitization: disinhibition and touch-evoked allodynia in the spinal cord. J Neurophysiol 72:169–179PubMedGoogle Scholar
  62. Tiong SY, Polgar E, van Kralingen JC, Watanabe M, Todd AJ (2011) Galanin-immunoreactivity identifies a distinct population of inhibitory interneurons in laminae I-III of the rat spinal cord. Mol Pain 7:36CrossRefPubMedCentralPubMedGoogle Scholar
  63. Todd AJ (1996) GABA and glycine in synaptic glomeruli of the rat spinal dorsal horn. Eur J Neurosci 8:2492–2498CrossRefPubMedGoogle Scholar
  64. Todd AJ (2010) Neuronal circuitry for pain processing in the dorsal horn. Nat Rev Neurosci 11:823–836CrossRefPubMedCentralPubMedGoogle Scholar
  65. Todd AJ (2012) How to recognise collateral damage in partial nerve injury models of neuropathic pain. Pain 153:11–12CrossRefPubMedGoogle Scholar
  66. Todd AJ, Koerber HR (2012) Neuroanatomical substrates of spinal nociception. In: McMahon S, Koltzenburg M, Tracey I, DC T (eds) Wall and Melzack’s textbook of pain, 6th edn. Elsevier, Edinburgh, pp 73–90Google Scholar
  67. Torsney C, MacDermott AB (2006) Disinhibition opens the gate to pathological pain signaling in superficial neurokinin 1 receptor-expressing neurons in rat spinal cord. J Neurosci 26:1833–1843CrossRefPubMedGoogle Scholar
  68. Whiteside GT, Munglani R (2001) Cell death in the superficial dorsal horn in a model of neuropathic pain. J Neurosci Res 64:168–173CrossRefPubMedGoogle Scholar
  69. Woodbury CJ, Koerber HR (2003) Widespread projections from myelinated nociceptors throughout the substantia gelatinosa provide novel insights into neonatal hypersensitivity. J Neurosci 23:601–610PubMedGoogle Scholar
  70. Yaksh TL (1989) Behavioral and autonomic correlates of the tactile evoked allodynia produced by spinal glycine inhibition: effects of modulatory receptor systems and excitatory amino acid antagonists. Pain 37:111–123CrossRefPubMedGoogle Scholar
  71. Yasaka T, Kato G, Furue H et al (2007) Cell-type-specific excitatory and inhibitory circuits involving primary afferents in the substantia gelatinosa of the rat spinal dorsal horn in vitro. J Physiol 581:603–618CrossRefPubMedCentralPubMedGoogle Scholar
  72. Yasaka T, Tiong SYX, Hughes DI, Riddell JS, Todd AJ (2010) Populations of inhibitory and excitatory interneurons in lamina II of the adult rat spinal dorsal horn revealed by a combined electrophysiological and anatomical approach. Pain 151:475–488CrossRefPubMedCentralPubMedGoogle Scholar
  73. Yasaka T, Tiong SYX, Polgár E, Watanabe M, Kumamoto E, Riddell JS, Todd AJ (2014) A putative relay circuit providing low-threshold mechanoreceptive input to lamina I projection neurons via vertical cells in lamina II of the rat dorsal horn. Mol Pain 10:3CrossRefPubMedCentralPubMedGoogle Scholar
  74. Yowtak J, Lee KY, Kim HY, Wang J, Kim HK, Chung K, Chung JM (2011) Reactive oxygen species contribute to neuropathic pain by reducing spinal GABA release. Pain 152:844–852CrossRefPubMedCentralPubMedGoogle Scholar
  75. Yowtak J, Wang J, Kim HY, Lu Y, Chung K, Chung JM (2013) Effect of antioxidant treatment on spinal GABA neurons in a neuropathic pain model in the mouse. Pain 154:2469–2476CrossRefPubMedGoogle Scholar
  76. Zeilhofer HU, Wildner H, Yevenes GE (2012) Fast synaptic inhibition in spinal sensory processing and pain control. Physiol Rev 92:193–235CrossRefPubMedCentralPubMedGoogle Scholar
  77. Zylka MJ, Rice FL, Anderson DJ (2005) Topographically distinct epidermal nociceptive circuits revealed by axonal tracers targeted to Mrgprd. Neuron 45:17–25CrossRefPubMedGoogle Scholar

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© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  1. 1.Institute of Neuroscience and PsychologyCollege of Medical Veterinary and Life Sciences, University of GlasgowGlasgowUK

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