Advertisement

Pain from the Arthritic Joint

  • Hans-Georg Schaible
  • Andrea Ebersberger
Chapter

Abstract

Nociceptive input from the joint is processed in spinal cord neurons which are either only activated by mechanical stimulation of the joint and other deep tissue, e.g. adjacent muscles, or in neurons which receive convergent inputs from joint, muscles and skin. Neurons with joint input show pronounced hyperexcitability during development of joint inflammation (enhanced responses to mechanical stimulation of the inflamed joint as well as to healthy adjacent deep structures, reduction of mechanical threshold in high threshold neurons and expansion of the receptive field). This state of hyperexcitability is maintained during persistent inflammation. The neurons are under strong control of descending inhibition which increases at least during the acute phase of inflammation. Both the induction of inflammation-induced spinal hyperexcitability and its maintenance are dependent on glutamate, substance P, neurokinin A, and CGRP. Spinal prostaglandin E2 supports the induction of spinal hyperexcitability. By contrast, spinal prostaglandin D2 rather attenuates spinal hyperexcitability during established inflammation.

Keywords

Receptive Field Spinal Cord Neuron Diffuse Noxious Inhibitory Control Joint Afferents Joint Input 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Abbreviations

AMPA

alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid

CGRP

calcitonin gene-related peptide

COX

cyclooxygenase

DNIC

diffuse noxious inhibitory control

FCA

Freund’s complete adjuvant

IkB

IkappaB protein

IKK

IκB Kinase

K/C

kaolin/carrageenan

NF-κB

nuclear factor-κB

NMDA

N-methyl-d-aspartate

nNOS, eNOS, iNOS

neuronal, endothelial, inducible nitric oxide synthase

NS

nociceptive specific (neuron)

PG

prostaglandin

WDR

wide dynamic range (neuron)

References

  1. Abbadie C, Besson J-M (1992) C-fos expression in rat lumbar spinal cord during the development of adjuvant-induced arthritis. Neuroscience 48:985–993.PubMedCrossRefGoogle Scholar
  2. Andreeva L, Rang HP (1993) Effect of bradykinin and prostaglandins on the release of calcitonin gene-related peptide-like immunoreactivity from the rat spinal cord in vitro. Br J Pharmacol 108:185–190.PubMedGoogle Scholar
  3. Arendt-Nielsen L, Laursen RJ, Drewes AM (2000) Referred pain as an indicator for neural plasticity. In: J Sandkühler, B Bromm, GF Gebhart (Eds) Progress in Brain Research, vol. 129. Elsevier, Amsterdam, pp. 343–356.Google Scholar
  4. Bajaj P, Bajaj P, Graven-Nielsen T, Arendt-Nielsen L (2001) Osteoarthritis and its association with muscle hyperalgesia: an experimental controlled study. Pain 93:107–114.PubMedCrossRefGoogle Scholar
  5. Bär K-J, Natura G, Telleria-Diaz A, Teschner P, Vogel R, Vasquez E, Schaible H-G, Ebersberger A (2004) Changes in the effect of spinal prostaglandin E2 during inflammation – Prostaglandin E (EP1–EP4) receptors in spinal nociceptive processing of input from the normal or inflamed knee joint. J Neurosci 24:642–651.PubMedCrossRefGoogle Scholar
  6. Barnes PJ, Karin M (1997) Nuclear factor-κB – a pivotal transcription factor in chronic inflammatory diseases. New Engl J Med 336:1066–1071.PubMedCrossRefGoogle Scholar
  7. Boettger MK, Hensellek S, Richter F, Gajda M, Stöckigt R, Segond von Banchet G, Bräuer R, Schaible H-G (2008) Antinociceptive effects of TNF-α neutralization in a rat model of antigen-induced arthritis. Evidence for a neuronal target. Arthritis Rheum 58:2368–2378.PubMedCrossRefGoogle Scholar
  8. Calvino B, Villanueva L, LeBars D (1987) Dorsal horn (convergent) neurones in the intact anaesthetized arthritic rat. II. Heterotopic inhibitory influences. Pain 31:359–379.PubMedCrossRefGoogle Scholar
  9. Cervero F, Schaible H-G, Schmidt RF (1991) Tonic descending inhibition of spinal cord neurones driven by joint afferents in normal cats and in cats with an inflamed knee joint. Exp Brain Res 83:675–678.PubMedCrossRefGoogle Scholar
  10. Chen L-W, Egan L, Li Z-W, Greten FR, Kagnoff MF, Karin M (2003) The two faces of IKK and NF-κB inhibition: prevention of systemic inflammation but increased local injury following intestinal ischemia-reperfusion. Nat Med 9:575–581.PubMedCrossRefGoogle Scholar
  11. Coggeshall RE, Hong KAP, Langford LA, Schaible H-G, Schmidt RF (1983) Discharge characteristics of fine medial articular afferents at rest and during passive movements of inflamed knee joints. Brain Res 272:185–188.PubMedCrossRefGoogle Scholar
  12. Danziger N, Weil-Fugazza J, LeBars D, Bouhassira D (1999) Alteration of descending modulation of nociception during the course of monoarthritis in the rat. J Neurosci 19:2394–2400.PubMedGoogle Scholar
  13. Danziger N, Weil-Fugazza J, LeBars D, Bouhassira D (2001) Stage-dependent changes in the modulation of nociceptive neuronal activity during the course of inflammation. Eur J Neurosci 13:230–240.PubMedCrossRefGoogle Scholar
  14. Dougherty PM, Sluka KA, Sorkin LS, Westlund KN, Willis WD (1992) Neural changes in the acute arthritis in monkeys. I. Parallel enhancement of responses of spinothalamic tract neurons to mechanical stimulation and excitatory amino acids. Brain Res Rev 17:1–13.PubMedCrossRefGoogle Scholar
  15. Ebersberger A, Buchmann M, Ritzeler O, Michaelis M, Schaible H-G (2006) The role of spinal nuclear factor-κB in spinal hyperexcitability. NeuroReport 17:1615–1618.PubMedCrossRefGoogle Scholar
  16. Ebersberger A, Charbel Issa P, Vanegas H, Schaible H-G (2000) Differential effects of CGRP and CGRP8-37 upon responses to NMDA and AMPA in spinal nociceptive neurons with knee input in the rat. Neuroscience 99:171–178.PubMedCrossRefGoogle Scholar
  17. Ebersberger A, Grubb BD, Willingale HL, Gardiner NJ, Nebe J, Schaible H-G (1999) The intraspinal release of prostaglandin E2 in a model of acute arthritis is accompanied by an upregulation of cyclooxygenase-2 in the rat spinal cord. Neuroscience 93:775–781.PubMedCrossRefGoogle Scholar
  18. Ferrell WR, Wood L, Baxendale RH (1998) The effect of acute joint inflammation on flexion reflex excitability in the decerebrate, low spinal cat. Quart J Exp Physiol 373:353–365.Google Scholar
  19. Fields HL, Clanton CH, Anderson SD (1977) Somatosensory properties of spinoreticular neurons in the cat. Brain Res 120:49–66.PubMedCrossRefGoogle Scholar
  20. Grigg P, Schaible H-G, Schmidt RF (1986) Mechanical sensitivity of group III and IV afferents from posterior articular nerve in normal and inflamed cat knee. J Neurophysiol 55:635–643.PubMedGoogle Scholar
  21. Grill M, Heinemann A, Hoefler G, Peskar BA, Schuligoi R (2008) Effect of endotoxin treatment on the expression and localization of spinal cyclooxygenase, prostaglandin synthases, and PGD2 receptors. J Neurochem 104:1345–1357.PubMedCrossRefGoogle Scholar
  22. Grubb BD, Birrell J, McQueen DS, Iggo A (1991) The role of PGE2 in the sensitization of mechanoreceptors in normal and inflamed ankle joints of the rat. Exp Brain Res 84:383–392.PubMedCrossRefGoogle Scholar
  23. Grubb BD, Stiller RU, Schaible H-G (1993) Dynamic changes in the receptive field properties of spinal cord neurons with ankle input in rats with unilateral adjuvant-induced inflammation in the ankle region. Exp Brain Res 92:441–452.PubMedCrossRefGoogle Scholar
  24. Guilbaud G, Iggo A, Tegner R (1985) Sensory receptors in ankle joint capsules of normal and arthritic rats. Exp Brain Res 58:29–40.PubMedCrossRefGoogle Scholar
  25. He X, Proske U, Schaible H-G, Schmidt RF (1988) Acute inflammation of the knee joint in the cat alters responses of flexor motoneurones to leg movements. J Neurophysiol 59:326–340.PubMedGoogle Scholar
  26. Hope PJ, Jarrott B, Schaible H-G, Clarke RW, Duggan AW (1990) Release and spread of immunoreactive neurokinin A in the cat spinal cord in a model of acute arthritis. Brain Res 533:292–299.PubMedCrossRefGoogle Scholar
  27. Infante C, Diaz M, Hernández A, Constandil L, Pelissier T (2007) Expression of nitric oxide synthase isoforms in the dorsal horn of monoarthritic rats: effects of competitive and uncompetitive N-methyl-d-aspartate antagonists. Arth Res Ther 9:R53.CrossRefGoogle Scholar
  28. Inglis JJ, Notley CA, Essex D, Wilson AW, Feldmann M, Anand P, Williams R (2007) Collagen-induced arthritis as a model of hyperalgesia. Functional and cellular analysis of the analgesic actions of tumor necrosis factor blockade. Arthritis Rheum 56:4015–4023.CrossRefGoogle Scholar
  29. Jenkins DW, Feniuk W, Humphrey PP (2001) Characterization of the prostanoid receptor types involved in mediating calcitonin gene-related peptide release from cultured rat trigeminal neurones. Br J Pharmacol 134:1296–1302.PubMedCrossRefGoogle Scholar
  30. Kellgren JH (1939) Some painful joint condition and their relation to osteoarthritis. Clin Sci 4:193–205.Google Scholar
  31. Kellgren JH, Samuel EP (1950) The sensitivity and innervation of the articular capsule. J Bone Joint Surg 32-B:84–91.Google Scholar
  32. LeBars D, Villanueva L (1998) Electrophysiological evidence for the activation of descending inhibitory controls by nociceptive afferent pathways. In: HL Fields, J-M Besson (Eds) Progress in Brain Research, vol. 77. Elsevier, Amsterdam, pp. 275–299.Google Scholar
  33. Lee KM, Kang BS, Lee HL, Son SJ, Hwang SH, Kim DS, Park J-S, Cho H-J (2004) Spinal NF-κB activation induces COX-2 upregulation and contributes to inflammatory pain hypersensitivity. Eur J Neurosci 19:3375–3381.PubMedCrossRefGoogle Scholar
  34. Lewis T (1938) Suggestions relating to the study of somatic pain. Br Med J 1:321–325.PubMedCrossRefGoogle Scholar
  35. Lewis T (1942) Pain. MacMillan, London.Google Scholar
  36. Liang X, Wu L, Hand T, Andreasson K (2005) Prostaglandin D2 mediates neuronal protection via the DP1 receptor. J Neurochem 92:477–486.PubMedCrossRefGoogle Scholar
  37. Martindale JC, Wilson AW Reeve AJ, Chessell IP, Headley PM (2007) Chronic secondary hypersensitivity of dorsal horn neurones following inflammation of the knee joint. Pain 133:79–86.PubMedCrossRefGoogle Scholar
  38. Menétrey D, Besson J-M (1982) Electrophysiological characteristics of dorsal horn cells in rats with cutaneous inflammation resulting from chronic arthritis. Pain 13:343–364.PubMedCrossRefGoogle Scholar
  39. Menétrey D, Gannon A, Levine JD, Basbaum AI (1989) Expression of c-fos protein in interneurons and projection neurons of the rat spinal cord in response to noxious somatic, articular, and visceral stimulation. J Comp Neurol 285:177–195.PubMedCrossRefGoogle Scholar
  40. Mense S (1997) Pathophysiologic basis of muscle pain syndromes. Myofasc Pain – Update in diagnosis and treatment. Phys Med Rehabil Clin N Am 8:23–53.Google Scholar
  41. Meyers DER, Snow PJ (1982) The responses to somatic stimuli of deep spinothalamic tract cells in the lumbar spinal cord of the cat. J Physiol 329:355–371.PubMedGoogle Scholar
  42. Minami T, Okuda-Ashitaka E, Nishizawa M, Mori H, Ito S (1997) Inhibition of nociceptin-induced allodynia in conscious mice by prostaglandin D2. Br J Pharmacol 122:605–610.PubMedCrossRefGoogle Scholar
  43. Nakae K, Hayashi F, Hayashi M, Yamamoto N, Iino T, Yoshikawa S, Gupta J (2005) Functional role of prostacyclin receptor in rat dorsal root ganglion neurons. Neurosci Lett 388:132–137.PubMedGoogle Scholar
  44. Neugebauer V, Lücke T, Grubb BD, Schaible H-G (1994a) The involvement of N-methyl-d-aspartate (NMDA) and non-NMDA receptors in the responsiveness of rat spinal neurons with input from the chronically inflamed ankle. Neurosci Lett 170:237–240.PubMedCrossRefGoogle Scholar
  45. Neugebauer V, Lücke T, Schaible H-G (1993) N-methyl-d-aspartate (NMDA) and non-NMDA receptor antagonists block the hyperexcitability of dorsal horn neurones during development of acute arthritis in rat’s knee joint. J Neurophysiol 70:1365–1377.PubMedGoogle Scholar
  46. Neugebauer V, Lücke T, Schaible H-G (1994b) Requirement of metabotropic glutamate receptors for the generation of inflammation-evoked hyperexcitability in rat spinal cord neurons. Eur J Neurosci 6:1179–1186.PubMedCrossRefGoogle Scholar
  47. Neugebauer V, Rümenapp P, Schaible H-G (1996a) The role of spinal neurokinin-2 receptors in the processing of nociceptive information from the joint and in the generation and maintenance of inflammation-evoked hyperexcitability of dorsal horn neurons in the rat. Eur J Neurosci 8:249–260.PubMedCrossRefGoogle Scholar
  48. Neugebauer V, Rümenapp P, Schaible H-G (1996b) Calcitonin gene-related peptide is involved in the generation and maintenance of hyperexcitability of dorsal horn neurons observed during development of acute inflammation in rat's knee joint. Neuroscience 71:1095–1109.PubMedCrossRefGoogle Scholar
  49. Neugebauer V, Schaible H-G (1990) Evidence for a central component in the sensitization of spinal neurons with joint input during development of acute arthritis in cat's knee. J Neurophysiol 64:299–311.PubMedGoogle Scholar
  50. Neugebauer V, Weiretter F, Schaible H-G (1995) The involvement of substance P and neurokinin-1 receptors in the hyperexcitability of dorsal horn neurons during development of acute arthritis in rat's knee joint. J Neurophysiol 73:1574–1583.PubMedGoogle Scholar
  51. Rudomin P, Hernández E (2008) Changes in synaptic effectiveness of myelinated joint afferents during capsaicin-induced inflammation of the footpad in the anaesthetized cat. Exp Brain Res 187:71–84.PubMedCrossRefGoogle Scholar
  52. Schaible H-G (2006a) Basic mechanisms of deep somatic pain. In: McMahon SB, Koltzenburg M (Eds) Wall and Melzack's Textbook of Pain, 5th edn. Elsevier, Churchill, Livingston, pp. 621–633.Google Scholar
  53. Schaible H-G (2006b) Peripheral and central mechanisms of pain generation. In: Stein C (Ed) Handbook of Experimental Pharmacalogy, vol. 177. Springer-Verlag, Berlin, Heidelberg, pp. 4–28.Google Scholar
  54. Schaible H-G, Freudenberger U, Neugebauer V, Stiller U (1994) Intraspinal release of immunoreactive calcitonin gene-related peptide during development of inflammation in the joint in vivo – a study with antibody microprobes in cat and rat. Neuroscience 62:1293–1305.PubMedCrossRefGoogle Scholar
  55. Schaible H-G, Grubb BD (1993) Afferent and spinal mechanisms of joint pain. Pain 55:5–54.PubMedCrossRefGoogle Scholar
  56. Schaible H-G, Jarrott B, Hope PJ, Duggan AW (1990) Release of immunoreactive substance P in the cat spinal cord during development of acute arthritis in cat's knee: A study with antibody bearing microprobes. Brain Res 529:214–223.PubMedCrossRefGoogle Scholar
  57. Schaible H-G, Neugebauer V, Cervero F, Schmidt RF (1991) Changes in tonic descending inhibition of spinal neurons with articular input during the development of acute arthritis in the cat. J Neurophysiol 66:1021–1032.PubMedGoogle Scholar
  58. Schaible H-G, Schmidt RF (1985) Effects of an experimental arthritis on the sensory properties of fine articular afferent units. J Neurophysiol 54:1109–1122.PubMedGoogle Scholar
  59. Schaible H-G, Schmidt RF (1988) Time course of mechanosensitivity changes in articular afferents during a developing experimental arthritis. J Neurophysiol 60:2180–2195.PubMedGoogle Scholar
  60. Schaible H-G, Schmidt RF, Willis WD (1987) Enhancement of the responses of ascending tract cells in the cat spinal cord by acute inflammation of the knee joint. Exp Brain Res 66:489–499.PubMedCrossRefGoogle Scholar
  61. Segond von Banchet G, Petrow PK, Bräuer R, Schaible H-G (2000) Monoarticular antigen-induced arthritis leads to pronounced bilateral upregulation of the expression of neurokinin 1 and bradykinin 2 receptors in dorsal root ganglion neurones of rats. Arthritis Res 2:424–427.CrossRefGoogle Scholar
  62. Sharif Naeini R, Cahill CM, Ribeiro-da-Silva A, Ménard HA, Henry JL (2005) Remodelling of spinal nociceptive mechanisms in an animal model of monoarthritis. Eur J Neurosci 22:2005–2015.PubMedCrossRefGoogle Scholar
  63. Sluka KA (2002) Stimulation of deep somatic tissue with capsaicin produces long-lasting mechanical allodynia and heat hypoalgesia that depends on early activation of the cAMP pathway. J Neurosci 22:5687–5693.PubMedGoogle Scholar
  64. Sluka KA, Westlund K (1992) An experimental arthritis in rats: dorsal horn aspartate and glutamate increases. Neurosci Lett 145:141–144.PubMedCrossRefGoogle Scholar
  65. Sorkin LS, Westlund KN, Sluka KA, Dougherty PH, Willis WD (1992) Neural changes in acute arthritis in monkeys. IV: time course of amino acid release into the lumbar dorsal horn. Brain Res Rev 17:39–50.PubMedCrossRefGoogle Scholar
  66. Sun S, Cao H, Han M, Li TT, Pan HL, Zhao ZQ, Zhang YQ (2007) New evidence for the involvement of spinal fraktalkine receptor in pain facilitation and spinal glial activation in rat model of monoarthritis. Pain 129:64–75.PubMedCrossRefGoogle Scholar
  67. Tegeder I, Niederberger E, Schmidt R, Kunz S, Gühring H, Ritzeler O, Michaelis M, Geisslinger G (2004) Specific inhibition of IκB kinase reduces hyperalgesia in inflammatory and neuropathic pain models in rats. J Neurosci 24:1637–1645.PubMedCrossRefGoogle Scholar
  68. Telleria-Diaz A, Ebersberger A, Vasquez E, Schache F, Kahlenbach J, Schaible H-G (2008) Different effects of spinally applied prostaglandin D2 (PGD2) on responses of dorsal horn neurons with knee input in normal rats and in rats with acute knee inflammation. Neuroscience 156:184–192.PubMedCrossRefGoogle Scholar
  69. Vanegas H, Schaible H-G (2001) Prostaglandins and cyclooxygenases in the spinal cord. Prog Neurobiol 64:327–363.PubMedCrossRefGoogle Scholar
  70. Vasquez E, Bär K-J, Ebersberger A, Klein B, Vanegas H, Schaible H-G (2001) Spinal prostaglandins are involved in the development but not the maintenance of inflammation-induced spinal hyperexcitability. J Neurosci 21:9001–9008.PubMedGoogle Scholar
  71. Willingale HL, Gardiner NJ, McLymont N, Giblett S, Grubb BD (1997) Prostanoids synthesized by cyclo-oxygenase isoforms in rat spinal cord and their contribution to the development of neuronal hyperexcitability. Br J Pharmacol 122:1593–1604.PubMedCrossRefGoogle Scholar
  72. Woolf CJ, Wall PD (1986) Relative effectiveness of C primary afferent fibres of different origins in evoking a prolonged facilitation of the flexor reflex in the rat. J Neurosci 6:1433–1442.PubMedGoogle Scholar
  73. Yang LC, Marsala M, Yaksh TL (1996) Characterization of time course of spinal amino acids, citrulline and PGE2 release after carrageenan/kaolin-induced knee inflammation: a chronic microdialysis study. Pain 67:345–354.PubMedCrossRefGoogle Scholar
  74. Yu X-M, Mense S (1990) Response properties and descending control of rat dorsal horn neurons with deep receptive fields. Neuroscience 39:823–831.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Department of PhysiologyFriedrich-Schiller-University of JenaJenaGermany

Personalised recommendations