Archives of Neuroscience

Published by: Kowsar

Neuropathic Pain: A Review of Interneuronal Disinhibition

Juliana Mazini Alves 1 , * and Katia Lin 2 , 3
Authors Information
1 School of Medicine, Graduation Program, Federal University of Santa Catarina, (UFSC), Florianopolis, Santa Catarina, Brazil
2 Medical Sciences Post-graduate Program, Federal University of Santa Catarina, (UFSC), Florianopolis, Santa Catarina, Brazil
3 Neurology Division, Federal University of Santa Catarina, (UFSC), Florianopolis, Santa Catarina, Brazil
Article information
  • Archives of Neuroscience: January 2018, 5 (1); e12290
  • Published Online: January 10, 2018
  • Article Type: Review Article
  • Received: April 30, 2017
  • Revised: June 28, 2017
  • Accepted: December 23, 2017
  • DOI: 10.5812/archneurosci.12290

To Cite: Alves J M, Lin K. Neuropathic Pain: A Review of Interneuronal Disinhibition, Arch Neurosci. 2018 ; 5(1):e12290. doi: 10.5812/archneurosci.12290.

Copyright © 2018, Archives of Neuroscience. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License ( which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly cited.
1. Introduction
2. Evidence Acquisition
3. Primary Afferent Neurons and Nociception
4. Spinal Cord Organization
5. Mechanisms of Neuropathic Pain After Nerve Injury
6. Interneuronal Disinhibition
7. Conclusion
  • 1. Sandkuhler J. Models and mechanisms of hyperalgesia and allodynia. Physiol Rev. 2009;89(2):707-58. doi: 10.1152/physrev.00025.2008. [PubMed: 19342617].
  • 2. Basbaum AI, Bautista DM, Scherrer G, Julius D. Cellular and molecular mechanisms of pain. Cell. 2009;139(2):267-84. doi: 10.1016/j.cell.2009.09.028. [PubMed: 19837031].
  • 3. Todd AJ. Neuronal circuitry for pain processing in the dorsal horn. Nat Rev Neurosci. 2010;11(12):823-36. doi: 10.1038/nrn2947. [PubMed: 21068766].
  • 4. Sandkuhler J. The role of inhibition for the generation and amplification of pain. in, jose castro lopes, editor. current topics in pain,. 12th world congress on pain. the United States of America. IASP Press. Seattle,; 2009. p. 53-71.
  • 5. Todd A. Pain control, handbook of experimental pharmacology. In: Schaible HG, editor. Berlin: Springer; 2015. Plasticity of inhibition in the spinal cord; p. 171-90.
  • 6. 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(15):6724-31. [PubMed: 12151551].
  • 7. Decosterd I, Woolf CJ. Spared nerve injury: an animal model of persistent peripheral neuropathic pain. Pain. 2000;87(2):149-58. [PubMed: 10924808].
  • 8. Bennett GJ, Xie YK. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain. 1988;33(1):87-107. [PubMed: 2837713].
  • 9. Shir Y, Seltzer Z. A-fibers mediate mechanical hyperesthesia and allodynia and C-fibers mediate thermal hyperalgesia in a new model of causalgiform pain disorders in rats. Neurosci Lett. 1990;115(1):62-7. [PubMed: 2216058].
  • 10. Kim SH, Chung JM. An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain. 1992;50(3):355-63. [PubMed: 1333581].
  • 11. Hughes DI, Scott DT, Riddell JS, Todd AJ. Upregulation of substance P in low-threshold myelinated afferents is not required for tactile allodynia in the chronic constriction injury and spinal nerve ligation models. J Neurosci. 2007;27(8):2035-44. doi: 10.1523/JNEUROSCI.5401-06.2007. [PubMed: 17314299].
  • 12. Perry MJ, Lawson SN. Differences in expression of oligosaccharides, neuropeptides, carbonic anhydrase and neurofilament in rat primary afferent neurons retrogradely labelled via skin, muscle or visceral nerves. Neuroscience. 1998;85(1):293-310. [PubMed: 9607720].
  • 13. Bear MF, Connors BW, Paradiso MA. Neuroscience, exploring the brain. 3 ed. Philadelphia: Pa, Lippincott Williams and Wilkins; 2007.
  • 14. Braz J, Solorzano C, Wang X, Basbaum AI. Transmitting pain and itch messages: a contemporary view of the spinal cord circuits that generate gate control. Neuron. 2014;82(3):522-36. doi: 10.1016/j.neuron.2014.01.018. [PubMed: 24811377].
  • 15. Rexed B. The cytoarchitectonic organization of the spinal cord in the cat. J Comp Neurol. 1952;96(3):414-95. [PubMed: 14946260].
  • 16. Stewart W, Maxwell DJ. Distribution of and organisation of dorsal horn neuronal cell bodies that possess the muscarinic m2 acetylcholine receptor. Neuroscience. 2003;119(1):121-35. [PubMed: 12763074].
  • 17. Perel P, Roberts I, Sena E, Wheble P, Briscoe C, Sandercock P, et al. Comparison of treatment effects between animal experiments and clinical trials: systematic review. BMJ. 2007;334(7586):197. doi: 10.1136/bmj.39048.407928.BE. [PubMed: 17175568].
  • 18. Melzack R, Wall PD. Pain mechanisms: a new theory. Science. 1965;150(3699):971-9. [PubMed: 5320816].
  • 19. Taylor BK. Spinal inhibitory neurotransmission in neuropathic pain. Curr Pain Headache Rep. 2009;13(3):208-14. [PubMed: 19457281].
  • 20. Hwang JH, Yaksh TL. The effect of spinal GABA receptor agonists on tactile allodynia in a surgically-induced neuropathic pain model in the rat. Pain. 1997;70(1):15-22. [PubMed: 9106805].
  • 21. Scholz J, Broom DC, Youn DH, Mills CD, Kohno T, Suter MR, et al. 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. 2005;25(32):7317-23. doi: 10.1523/JNEUROSCI.1526-05.2005. [PubMed: 16093381].
  • 22. Coggeshall RE, Lekan HA, White FA, Woolf CJ. A-fiber sensory input induces neuronal cell death in the dorsal horn of the adult rat spinal cord. J Comp Neurol. 2001;435(3):276-82. [PubMed: 11406811].
  • 23. Polgar E, Hughes DI, Arham AZ, Todd AJ. 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. 2005;25(28):6658-66. doi: 10.1523/JNEUROSCI.1490-05.2005. [PubMed: 16014727].
  • 24. Polgar E, Hughes DI, Riddell JS, Maxwell DJ, Puskar Z, Todd AJ. 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. 2003;104(1-2):229-39. [PubMed: 12855333].
  • 25. Polgar E, Gray S, Riddell JS, Todd AJ. 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. 2004;111(1-2):144-50. doi: 10.1016/j.pain.2004.06.011. [PubMed: 15327818].
  • 26. Polgar E, Todd AJ. 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. 2008;156(1):193-202. doi: 10.1016/j.neuroscience.2008.07.009. [PubMed: 18675320].
  • 27. Kohno T, Moore KA, Baba H, Woolf CJ. Peripheral nerve injury alters excitatory synaptic transmission in lamina II of the rat dorsal horn. J Physiol. 2003;548(Pt 1):131-8. doi: 10.1113/jphysiol.2002.036186. [PubMed: 12576493].
  • 28. Leitner J, Westerholz S, Heinke B, Forsthuber L, Wunderbaldinger G, Jager T, et al. Impaired excitatory drive to spinal GABAergic neurons of neuropathic mice. PLoS One. 2013;8(8):73370. doi: 10.1371/journal.pone.0073370. [PubMed: 24009748].
  • 29. Ibuki T, Hama AT, Wang XT, Pappas GD, Sagen J. Loss of GABA-immunoreactivity in the spinal dorsal horn of rats with peripheral nerve injury and promotion of recovery by adrenal medullary grafts. Neuroscience. 1997;76(3):845-58. [PubMed: 9135056].
  • 30. Eaton MJ, Plunkett JA, Karmally S, Martinez MA, Montanez K. 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. 1998;16(1):57-72. [PubMed: 9924973].
  • 31. Coull JA, Beggs S, Boudreau D, Boivin D, Tsuda M, Inoue K, et al. BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature. 2005;438(7070):1017-21. doi: 10.1038/nature04223. [PubMed: 16355225].
  • 32. Coull JA, Boudreau D, Bachand K, Prescott SA, Nault F, Sik A, et al. Trans-synaptic shift in anion gradient in spinal lamina I neurons as a mechanism of neuropathic pain. Nature. 2003;424(6951):938-42. doi: 10.1038/nature01868. [PubMed: 12931188].
  • 33. 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(Pt 3):869-78. doi: 10.1113/jphysiol.2006.118034. [PubMed: 17053034].
  • 34. Kim DK, Kwak J, Kim SJ, Kim J. Long-lasting enhancement in the intrinsic excitability of deep dorsal horn neurons. Pain. 2008;139(1):181-9. doi: 10.1016/j.pain.2008.03.025. [PubMed: 18472218].
  • 35. Hains BC, Saab CY, Klein JP, Craner MJ, Waxman SG. Altered sodium channel expression in second-order spinal sensory neurons contributes to pain after peripheral nerve injury. J Neurosci. 2004;24(20):4832-9. doi: 10.1523/JNEUROSCI.0300-04.2004. [PubMed: 15152043].
  • 36. Provinciali L, Lattanzi S, Chiarlone R, Fogliardi A, Intelligente F, Irace C, et al. [Topical pharmacologic approach with 5% lidocaine medicated plaster in the treatment of localized neuropathic pain]. Minerva Med. 2014;105(6):515-27. [PubMed: 25392960].
  • 37. Lattanzi S, Provinciali L. Topical lidocaine for localized neuropathic pain. Arch Neurosci. 2016;3(1):28698. doi: 10.5812/archneurosci.28698.
  • 38. Finnerup NB, Attal N, Haroutounian S, McNicol E, Baron R, Dworkin RH, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 2015;14(2):162-73. doi: 10.1016/S1474-4422(14)70251-0. [PubMed: 25575710].
  • 39. de Leon-Casasola OA, Mayoral V. The topical 5% lidocaine medicated plaster in localized neuropathic pain: a reappraisal of the clinical evidence. J Pain Res. 2016;9:67-79. doi: 10.2147/JPR.S99231. [PubMed: 26929664].
  • 40. Miraucourt LS, Dallel R, Voisin DL. Glycine inhibitory dysfunction turns touch into pain through PKCgamma interneurons. PLoS One. 2007;2(11):1116. doi: 10.1371/journal.pone.0001116. [PubMed: 17987109].
  • 41. Lu Y, Dong H, Gao Y, Gong Y, Ren Y, Gu N, et al. A feed-forward spinal cord glycinergic neural circuit gates mechanical allodynia. J Clin Invest. 2013;123(9):4050-62. doi: 10.1172/JCI70026. [PubMed: 23979158].
  • 42. Foster E, Wildner H, Tudeau L, Haueter S, Ralvenius WT, Jegen M, et al. Targeted ablation, silencing, and activation establish glycinergic dorsal horn neurons as key components of a spinal gate for pain and itch. Neuron. 2015;85(6):1289-304. doi: 10.1016/j.neuron.2015.02.028. [PubMed: 25789756].

Featured Image:

Creative Commons License Except where otherwise noted, this work is licensed under Creative Commons Attribution Non Commercial 4.0 International License .
Readers' Comments