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Spinal cord hyperexcitability and its role in pain and hyperalgesia

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Abstract

Sensitization of spinal cord nociceptive neurons is commonly interpreted as the cause for the hypersensitivity that characterizes chronic pain states in humans. However, in spite of much basic research in this area it has not been possible to demonstrate a direct link between the hyperexcitability of spinal cord neurons observed experimentally and the underlying mechanism of a chronic pain state. The word sensitization is also used in the literature with various and different meanings from the qualification of a cellular process of enhanced excitability at synaptic level to the characteristics of a chronic pain syndrome. In this article the various meanings of sensitization are described and the relevance of the hyperexcitability of spinal cord neurons to the generation of clinically relevant pain states is discussed. A proposal is made to restrict the use of the word sensitization to the cellular process of enhanced excitability observed experimentally after repetitive stimulation of nociceptive afferents. Caution is also recommended when associating neuronal sensitization in the spinal cord with the mechanisms of chronic pain conditions.

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References

  • Akopian AN, Sivilotti L, Wood JN (1996) A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons. Nature 379:257–262

    Article  PubMed  CAS  Google Scholar 

  • Burgess PR, Perl ER, Iggo A (1973) Cutaneous mechanoreceptors and nociceptors. In: Iggo A (ed) Handbook of Sensory Physiology. Somatosensory system, vol II. Springer, Berlin, pp 29–78

    Google Scholar 

  • Cao YQ, Mantyh PW, Carlson EJ, Gillespie AM, Epstein CJH, Basbaum AI (1998) Primary afferent tachykinins are required to experience moderate to intense pain. Nature 392:390–394

    Article  PubMed  CAS  Google Scholar 

  • Cervero F, Sharkey KA (1988) An electrophysiological and anatomical study of intestinal afferent fibres in the rat. J Physiol 401:381–397

    PubMed  CAS  Google Scholar 

  • Cervero F, Wolstencroft JH (1984) A positive feedback loop between spinal cord nociceptive pathways and antinociceptive areas of the cat’s brain stem. Pain 20:125–138

    Article  PubMed  CAS  Google Scholar 

  • Cervero F, Schouenborg J, Sjolund BH, Waddell PJ (1984) Cutaneous inputs to dorsal horn neurones in adult rats treated at birth with capsaicin. Brain Res 301:47–57

    Article  PubMed  CAS  Google Scholar 

  • Cervero F, Laird JMA, Brune K, Handwerker HO (2004) Referred visceral hyperalgesia: from sensations to molecular mechanisms. In: Handwerker HO, Brune K (eds) Hyperalgesia: molecular mechanisms and clinical implications. IASP Press, Seattle, pp 229–250

    Google Scholar 

  • De Felipe C, Herrero JF, O’Brien JA, Palmer JA, Doyle CA, Smith AJH, Laird JMA, Belmonte C, Cervero F, Hunt SP (1998) Altered nociception, analgesia and aggression in mice lacking the receptor for substance P. Nature 392:394–397

    Article  PubMed  Google Scholar 

  • Garcia-Nicas E, Laird JMA, Cervero F (2006) GABA A-receptor blockade reverses the injury-induced sensitization of nociceptor-specific (NS) neurons in the spinal dorsal horn of the rat. J Neurophysiol 96:661–670

    Article  PubMed  CAS  Google Scholar 

  • Herrero JF, Laird JMA, Lopez-Garcia JA (2000) Wind-up of spinal cord neurones and pain sensation: much ado about something? Prog Neurobiol 61:169–203

    Article  PubMed  CAS  Google Scholar 

  • Hill R (2000) NK1 (substance P) receptor antagonists––why are they not analgesic in humans? Trends Pharmacol Sci 21:244–246

    Article  PubMed  CAS  Google Scholar 

  • Iversen L (1998) Pharmacology––substance P equals pain substance? Nature 392:334–335

    Article  PubMed  CAS  Google Scholar 

  • Julius D, Basbaum AI (2001) Molecular mechanisms of nociception. Nature 413:203–210

    Article  PubMed  CAS  Google Scholar 

  • Khasar SG, Gold MS, Levine JD (1998) A tetrodotoxin-resistant sodium current mediates inflammatory pain in the rat. Neurosci Lett 256:17–20

    Article  PubMed  CAS  Google Scholar 

  • Laird J (2001) Gut feelings about tachykinin NK1 receptor antagonists. Trends Pharmacol Sci 22:169

    Article  PubMed  CAS  Google Scholar 

  • Laird JMA, De la Rubia PG, Cervero F (1995) Excitability changes of somatic and viscero-somatic nociceptive reflexes in the decerebrate-spinal rabbit: role of NMDA receptors. J Physiol 489:545–555

    PubMed  CAS  Google Scholar 

  • Laird JMA, Olivar T, Roza C, De Felipe C, Hunt SP, Cervero F (2000) Deficits in visceral pain and hyperalgesia of mice with a disruption of the tachykinin NK1 receptor gene. Neuroscience 98:345–352

    Article  PubMed  CAS  Google Scholar 

  • Laird JMA, Souslova V, Wood JN, Cervero F (2002) Deficits in visceral pain and referred hyperalgesia in Nav1.8 (SNS/PN3)-null mice. J Neurosci 22:8352–8356

    PubMed  CAS  Google Scholar 

  • MacKenzie J (1909) Symptoms and their interpretation. Shaw and sons, London

    Google Scholar 

  • Melzack R, Wall PD (1965) Pain mechanisms: a new theory. Science 150:971–979

    Article  PubMed  CAS  Google Scholar 

  • Meyer RA, Campbell JN (1981) Myelinated nociceptive afferents account for the hyperalgesia that follows a burn to the hand. Science 213:1527–1529

    Article  PubMed  CAS  Google Scholar 

  • Meyer RA, Campbell JN, Raja SN (1985) Peripheral neural mechanisms of cutaneous hyperalgesia. Adv Pain Res Ther 9:53–71

    Google Scholar 

  • Perry MJ, Lawson SN (1998) Differences in expression of oligosaccharides, neuropeptides, carbonic anhydrase and neurofilament in rat primary afferent neurons retrogradely labelled via skin, muscle or visceral nerves. Neuroscience 85:293–310

    Article  PubMed  CAS  Google Scholar 

  • Porreca F, Lai J, Bian D et al (1999) A comparison of the potential role of the tetrodotoxin-insensitive sodium channels PN3/SNS and NaN/SNS2 in rat models of chronic pain. Proc Natl Acad Sci USA 96:7640–7644

    Article  PubMed  CAS  Google Scholar 

  • Roza C, Laird JMA, Souslova V, Wood JN, Cervero F (2003) The tetrodotoxin-resistant Na + channel Nav1.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice. J Physiol 550:921–926

    Article  PubMed  CAS  Google Scholar 

  • Sandkuhler J (2007) Understanding LTP in pain pathways. Mol Pain 3:9

    Article  PubMed  Google Scholar 

  • Schaible HG, Schmidt RF (1988) Time course of mechanosensitivity changes in articular afferents during a developing experimental arthritis. J Neurophysiol 60:2180–2195

    PubMed  CAS  Google Scholar 

  • Schmidt RF (1971) Pre-synaptic inhibition in the vertebrate nervous system. Rev Physiol Biochem Pharmacol 63:21–101

    Google Scholar 

  • Tattersall JEH, Cervero F, Lumb BM (1986) Viscerosomatic neurones in the lower thoracic spinal cord of the cat: excitations and inhibitions evoked by splanchnic and somatic nerve volleys and by stimulation of brain stem nuclei. J Neurophysiol 56:1411–1423

    PubMed  CAS  Google Scholar 

  • Treede RD, Meyer RA, Raja SN, Campbell JN (1992) Peripheral and central mechanisms of cutaneous hyperalgesia. Prog Neurobiol 38:397–421

    Article  PubMed  CAS  Google Scholar 

  • Woolf CJ (1983) Evidence for a central component of post-injury pain hypersensitivity. Nature 306:686–688

    Article  PubMed  CAS  Google Scholar 

  • Woolf CJ (1996) Windup and central sensitization are not equivalent. Pain 66:105–108

    Article  PubMed  CAS  Google Scholar 

  • Woolf CJ, Mannion RJ (1999) Neuropathic pain: aetiology, symptoms, mechanisms, and management. Lancet 353:1959–1964

    Article  PubMed  CAS  Google Scholar 

  • Woolf CJ, Salter MW (2000) Neuronal plasticity: increasing the gain in pain. Science 288:1765–1769

    Article  PubMed  CAS  Google Scholar 

  • Zimmer A, Zimmer AM, Baffi J, Usdin T, Reynolds K, Konig M, Palkovits M, Mezey E (1998) Hypoalgesia in mice with a targeted deletion of the tachykinin 1 gene. Proc Natl Acad Sci USA 95:2630–2635

    Article  PubMed  CAS  Google Scholar 

Download references

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Authors and Affiliations

  1. Anesthesia Research Unit, Faculty of Medicine, Faculty of Dentistry, Alan Edwards Center for Research on Pain, McGill University, McIntyre Medical Bldg. Room 1207, 3655 Promenade Sir William Osler, Montreal, QC, H3G 1Y6, Canada

    Fernando Cervero

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  1. Fernando Cervero
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Correspondence to Fernando Cervero.

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Cervero, F. Spinal cord hyperexcitability and its role in pain and hyperalgesia. Exp Brain Res 196, 129–137 (2009). https://doi.org/10.1007/s00221-009-1789-2

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