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Mechanisms of Disease: neuropathic pain—a clinical perspective


Neuropathic pain syndromes—pain after a lesion or disease of the peripheral or central nervous system—are clinically characterized by spontaneous and evoked types of pain, which are underpinned by various distinct pathophysiological mechanisms in the peripheral and central nervous systems. In some patients, the nerve lesion triggers molecular changes in nociceptive neurons, which become abnormally sensitive and develop pathological spontaneous activity. Inflammatory reactions of the damaged nerve trunk can induce ectopic nociceptor activity, causing spontaneous pain. The hyperactivity in nociceptors induces secondary changes in processing neurons in the spinal cord and brain, so that input from mechanoreceptive A-fibers is perceived as pain. Neuroplastic changes in the central pain modulatory systems can lead to further hyperexcitability. The treatment of neuropathic pain is still unsatisfactory, and a new hypothetical concept has been proposed, in which pain is analyzed on the basis of underlying mechanisms. The increased knowledge of pain-generating mechanisms and their translation into symptoms and signs might eventually allow a dissection of the mechanisms that operate in each patient. If a precise clinical phenotypic characterization of the neuropathic pain is combined with a selection of drugs that act on those mechanisms, it should ultimately be possible to design optimal treatments for individuals. This review discusses the conceptual framework of the novel mechanism-based classification, encouraging the reader to see neuropathic pain as a clinical entity rather than a compilation of single disease states.

Key Points

  • Neuropathic pain syndromes are chronic pain disorders caused by lesion or disease of the parts of the nervous system that normally signal pain

  • A disease- and anatomy-based system is often insufficient to classify neuropathic pain conditions, and analysis on the basis of underlying mechanisms provides an alternative approach

  • Molecular mechanisms that underlie the sensitization of primary afferent nociceptors include upregulation of voltage-gated sodium channels and various receptor proteins, and the release of growth factors from degenerating nerve fibers

  • As a consequence of peripheral nociceptor hyperactivity, dramatic secondary changes occur in the spinal cord dorsal horn, and there is also evidence of sensitization of neurons in the brain

  • A single symptom may be generated by several different mechanisms, so a specific symptom profile might be required to predict the underlying mechanism

  • By combining a systematic clinical examination and a precise phenotypic characterization with a selection of drugs that act on particular mechanisms, it should be possible to design optimal treatments for individual patients

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Figure 1: Proposed model for the relationship between neuropathic pain mechanisms and clinical symptoms and signs, and possible targets for therapeutic interventions.
Figure 2: Mechanisms of peripheral and central sensitization in neuropathic pain.


  1. 1

    Jensen TS and Baron R (2003) Translation of symptoms and signs into mechanisms in neuropathic pain. Pain 102: 1–8

    Article  Google Scholar 

  2. 2

    Woolf CJ et al. (1998) Towards a mechanism-based classification of pain? Pain 77: 227–229

    CAS  Article  Google Scholar 

  3. 3

    Dworkin RH et al. (2003) Advances in neuropathic pain: diagnosis, mechanisms, and treatment recommendations. Arch Neurol 60: 1524–1534

    Article  Google Scholar 

  4. 4

    Baron R (2000) Peripheral neuropathic pain: from mechanisms to symptoms. Clin J Pain 16: S12–20

    CAS  Article  Google Scholar 

  5. 5

    Janig W and Baron R (2003) Complex regional pain syndrome: mystery explained? Lancet Neurol 2: 687–697

    Article  Google Scholar 

  6. 6

    Bouhassira D et al. (2004) Development and validation of the Neuropathic Pain Symptom Inventory. Pain 108: 248–257

    Article  Google Scholar 

  7. 7

    Cruccu G et al. (2004) EFNS guidelines on neuropathic pain assessment. Eur J Neurol 11: 153–162

    CAS  Article  Google Scholar 

  8. 8

    Rasmussen PV et al. (2004) Symptoms and signs in patients with suspected neuropathic pain. Pain 110: 461–469

    Article  Google Scholar 

  9. 9

    Lai J et al. (2003) The role of voltage-gated sodium channels in neuropathic pain. Curr Opin Neurobiol 13: 291–297

    CAS  Article  Google Scholar 

  10. 10

    Wood JN et al. (2004) Voltage-gated sodium channels and pain pathways. J Neurobiol 61: 55–71

    CAS  Article  Google Scholar 

  11. 11

    Amir R et al. (2002) Oscillatory mechanism in primary sensory neurones. Brain 125: 421–435

    Article  Google Scholar 

  12. 12

    Jacobs JM et al. (1976) Vascular leakage in the dorsal root ganglia of the rat, studied with horseradish peroxidase. J Neurol Sci 29: 95–107

    CAS  Article  Google Scholar 

  13. 13

    Nystrom B and Hagbarth KE (1981) Microelectrode recordings from transected nerves in amputees with phantom limb pain. Neurosci Lett 27: 211–216

    CAS  Article  Google Scholar 

  14. 14

    Dib-Hajj SD et al. (2005) Gain-of-function mutation in Nav1.7 in familial erythromelalgia induces bursting of sensory neurons. Brain 128: 1847–1854

    CAS  Article  Google Scholar 

  15. 15

    Meier T et al. (2003) Efficacy of lidocaine patch 5% in the treatment of focal peripheral neuropathic pain syndromes: a randomized, double-blind, placebo-controlled study. Pain 106: 151–158

    CAS  Article  Google Scholar 

  16. 16

    Catarina MJ et al. (2000) Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science 288: 306–313

    Article  Google Scholar 

  17. 17

    Hudson LJ et al. (2001) VR1 protein expression increases in undamaged DRG neurons after partial nerve injury. Eur J Neurosci 13: 2105–2114

    CAS  Article  Google Scholar 

  18. 18

    Hong S and Wiley JW (2005) Early painful diabetic neuropathy is associated with differential changes in the expression and function of vanilloid receptor 1. J Biol Chem 280: 618–627

    CAS  Article  Google Scholar 

  19. 19

    Ma W et al. (2005) Medium and large injured dorsal root ganglion cells increase TRPV-1, accompanied by increased α2C-adrenoceptor co-expression and functional inhibition by clonidine. Pain 113: 386–394

    CAS  Article  Google Scholar 

  20. 20

    Davis JB et al. (2000) Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia. Nature 405: 183–187

    CAS  Article  Google Scholar 

  21. 21

    Baron R (2000) Capsaicin and nociception: from basic mechanisms to novel drugs. Lancet 356: 785–787

    CAS  Article  Google Scholar 

  22. 22

    Alessandri-Haber N et al. (2004) Transient receptor potential vanilloid 4 is essential in chemotherapy-induced neuropathic pain in the rat. J Neurosci 24: 4444–4452

    CAS  Article  Google Scholar 

  23. 23

    Petersen KL et al. (2000) Capsaicin evoked pain and allodynia in post-herpetic neuralgia. Pain 88: 125–133

    CAS  Article  Google Scholar 

  24. 24

    Baron R et al. (2001) Histamine-induced itch converts into pain in neuropathic hyperalgesia. Neuroreport 12: 3475–3478

    CAS  Article  Google Scholar 

  25. 25

    Orstavik K et al. (2003) Pathological C-fibres in patients with a chronic painful condition. Brain 126: 567–578

    Article  Google Scholar 

  26. 26

    Patapoutian A et al. (2003) ThermoTRP channels and beyond: mechanisms of temperature sensation. Nat Rev Neurosci 4: 529–539

    CAS  Article  Google Scholar 

  27. 27

    McKemy DD et al. (2002) Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature 416: 52–58

    CAS  Article  Google Scholar 

  28. 28

    Wasner G et al. (2004) Topical menthol—a human model for cold pain by activation and sensitization of C nociceptors. Brain 127: 1159–1171

    Article  Google Scholar 

  29. 29

    Price MP et al. (2001) The DRASIC cation channel contributes to the detection of cutaneous touch and acid stimuli in mice. Neuron 32: 1071–1083

    CAS  Article  Google Scholar 

  30. 30

    Baron R et al. (1999) Causalgia and reflex sympathetic dystrophy: does the sympathetic nervous system contribute to the generation of pain? Muscle Nerve 22: 678–695

    CAS  Article  Google Scholar 

  31. 31

    Price DD et al. (1998) Analysis of peak magnitude and duration of analgesia produced by local anesthetics injected into sympathetic ganglia of complex regional pain syndrome patients. Clin J Pain 14: 216–226

    CAS  Article  Google Scholar 

  32. 32

    Raja SN et al. (1998) Role of α-adrenoceptors in neuroma pain in amputees. Anesthesiology 89: A1083

    Article  Google Scholar 

  33. 33

    Choi B and Rowbotham MC (1997) Effect of adrenergic receptor activation on post-herpetic neuralgia pain and sensory disturbances. Pain 69: 55–63

    CAS  Article  Google Scholar 

  34. 34

    Ali Z et al. (2000) Intradermal injection of norepinephrine evokes pain in patients with sympathetically maintained pain. Pain 88: 161–168

    CAS  Article  Google Scholar 

  35. 35

    Baron R et al. (2002) Relation between sympathetic vasoconstrictor activity and pain and hyperalgesia in complex regional pain syndromes: a case-control study. Lancet 359: 1655–1660

    CAS  Article  Google Scholar 

  36. 36

    Schattschneider J et al. (2005) No adrenergic sensitization of afferent neurons in painful sensory neuropathy. J Neurol [10.1007/s00415-005-0976-8]

  37. 37

    Wasner G et al. (2005) Postherpetic neuralgia: topical lidocaine is effective in nociceptor-deprived skin. J Neurol 252: 677–686

    CAS  Article  Google Scholar 

  38. 38

    Wu G et al. (2001) Early onset of spontaneous activity in uninjured C-fiber nociceptors after injury to neighboring nerve fibers. J Neurosci 21: RC140

    CAS  Article  Google Scholar 

  39. 39

    Sommer C (2003) Painful neuropathies. Curr Opin Neurol 16: 623–628

    Article  Google Scholar 

  40. 40

    Marchand F et al. (2005) Role of the immune system in chronic pain. Nat Rev Neurosci 6: 521–532

    CAS  Article  Google Scholar 

  41. 41

    Lindenlaub T and Sommer C (2003) Cytokines in sural nerve biopsies from inflammatory and non-inflammatory neuropathies. Acta Neuropathol (Berl) 105: 593–602

    CAS  Google Scholar 

  42. 42

    Hains BC et al. (2004) Altered sodium channel expression in second-order spinal sensory neurons contributes to pain after peripheral nerve injury. J Neurosci 24: 4832–4839

    CAS  Article  Google Scholar 

  43. 43

    Ji RR and Woolf CJ (2001) Neuronal plasticity and signal transduction in nociceptive neurons: implications for the initiation and maintenance of pathological pain. Neurobiol Dis 8: 1–10

    CAS  Article  Google Scholar 

  44. 44

    Tal M and Bennett GJ (1994) Extra-territorial pain in rats with a peripheral mononeuropathy: mechano-hyperalgesia and mechano-allodynia in the territory of an uninjured nerve. Pain 57: 375–382

    CAS  Article  Google Scholar 

  45. 45

    Luo ZD et al. (2001) Upregulation of dorsal root ganglion α2δ calcium channel subunit and its correlation with allodynia in spinal nerve-injured rats. J Neurosci 21: 1868–1875

    CAS  Article  Google Scholar 

  46. 46

    Gracely RH et al. (1992) Painful neuropathy: altered central processing maintained dynamically by peripheral input. Pain 51: 175–194

    CAS  Article  Google Scholar 

  47. 47

    Moore KA et al. (2002) Partial peripheral nerve injury promotes a selective loss of GABAergic inhibition in the superficial dorsal horn of the spinal cord. J Neurosci 22: 6724–6731

    CAS  Article  Google Scholar 

  48. 48

    Coull JA et al. (2003) Trans-synaptic shift in anion gradient in spinal lamina I neurons as a mechanism of neuropathic pain. Nature 424: 938–942

    CAS  Article  Google Scholar 

  49. 49

    Vanegas H and Schaible HG (2004) Descending control of persistent pain: inhibitory or facilitatory? Brain Res Brain Res Rev 46: 295–309

    Article  Google Scholar 

  50. 50

    Ossipov MH et al. (2000) Spinal and supraspinal mechanisms of neuropathic pain. Ann NY Acad Sci 909: 12–24

    CAS  Article  Google Scholar 

  51. 51

    Zambreanu L et al. (2005) A role for the brainstem in central sensitisation in humans: evidence from functional magnetic resonance imaging. Pain 114: 397–407

    CAS  Article  Google Scholar 

  52. 52

    Wieseler-Frank J et al. (2005) Central proinflammatory cytokines and pain enhancement. Neurosignals 14: 166–174

    CAS  Article  Google Scholar 

  53. 53

    Guilbaud G et al. (1992) Primary somatosensory cortex in rats with pain-related behaviours due to a peripheral mononeuropathy after moderate ligation of one sciatic nerve: neuronal responsivity to somatic stimulation. Exp Brain Res 92: 227–245

    CAS  Article  Google Scholar 

  54. 54

    Flor H et al. (1995) Phantom-limb pain as a perceptual correlate of cortical reorganization following arm amputation. Nature 375: 482–484

    CAS  Article  Google Scholar 

  55. 55

    Pleger B et al. (2004) Mean sustained pain levels are linked to hemispherical side-to-side differences of primary somatosensory cortex in the complex regional pain syndrome I. Exp Brain Res 155: 115–119

    Article  Google Scholar 

  56. 56

    Maihofner C et al. (2005) Brain processing during mechanical hyperalgesia in complex regional pain syndrome: a functional MRI study. Pain 114: 93–103

    Article  Google Scholar 

  57. 57

    Willoch F et al. (2000) Phantom limb pain in the human brain: unraveling neural circuitries of phantom limb sensations using positron emission tomography. Ann Neurol 48: 842–849

    CAS  Article  Google Scholar 

  58. 58

    Willoch F et al. (2004) Central poststroke pain and reduced opioid receptor binding within pain processing circuitries: a [11C]diprenorphine PET study. Pain 108: 213–220

    CAS  Article  Google Scholar 

  59. 59

    Baron R et al. (1999) Brain processing of capsaicin-induced secondary hyperalgesia: a functional MRI study. Neurology 53: 548–557

    CAS  Article  Google Scholar 

  60. 60

    Baron R et al. (2000) Activation of the somatosensory cortex during Aβ-fiber mediated hyperalgesia: a MSI study. Brain Res 871: 75–82

    CAS  Article  Google Scholar 

  61. 61

    Maihofner C et al. (2004) Cortical reorganization during recovery from complex regional pain syndrome. Neurology 63: 693–701

    Article  Google Scholar 

  62. 62

    Pleger B et al. (2005) Sensorimotor retuning in complex regional pain syndrome parallels pain reduction. Ann Neurol 57: 425–429

    Article  Google Scholar 

  63. 63

    Fields HL et al. (1998) Postherpetic neuralgia: irritable nociceptors and deafferentation. Neurobiol Dis 5: 209–227

    CAS  Article  Google Scholar 

  64. 64

    Lombard MC and Larabi Y (1983) Electrophysiological study of cervical dorsal horn cells in partially deafferented rats. In Advances in Pain Research and Therapy, 147–154 (Ed Bonica JJ) New York: Raven Press

    Google Scholar 

  65. 65

    Loeser JD et al. (1967) Chronic deafferentation of human spinal cord neurons. J Neurosurg 29: 48–50

    Google Scholar 

  66. 66

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

    CAS  Article  Google Scholar 

  67. 67

    Rolke R et al. Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): standardized protocol and reference values. Pain, in press

  68. 68

    Mogil JS et al. (1999) Heritability of nociception I: responses of 11 inbred mouse strains on 12 measures of nociception. Pain 80: 67–82

    CAS  Article  Google Scholar 

  69. 69

    Zubieta JK et al. (2003) COMT val158met genotype affects μ-opioid neurotransmitter responses to a pain stressor. Science 299: 1240–1243

    CAS  Article  Google Scholar 

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R Baron is supported by the Deutsche Forschungsgemeinschaft (DFG Ba 1921), the German Ministry of Research and Education, German Research Network on Neuropathic Pain (BMBF, 01EM01/04) and an unrestricted educational grant from Pfizer, Germany.

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Competing interests

Ralf Baron has acted as a consultant for Grünenthal, Mundipharma, Schwarz-Pharma, Bayer Health Care, Life Science Vision and Novartis in Germany, and Allergan and Renovis in the US. He has also acted as a consultant and has received research funding from Pfizer Pharma GmbH, Germany.

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Baron, R. Mechanisms of Disease: neuropathic pain—a clinical perspective. Nat Rev Neurol 2, 95–106 (2006).

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