Advertisement

Pain Control pp 191-206 | Cite as

Modulation of Peripheral Inflammation by the Spinal Cord

  • Linda S. SorkinEmail author
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 227)

Abstract

The central nervous system, and the spinal cord in particular, is involved in multiple mechanisms that influence peripheral inflammation. Both pro- and anti-inflammatory feedback loops can involve just the peripheral nerves and spinal cord or can also include more complex, supraspinal structures such as the vagal nuclei and the hypothalamic-pituitary axis. Analysis is complicated by the fact that inflammation encompasses a constellation of end points from simple edema to changes in immune cell infiltration and pathology. Whether or not any of these individual elements is altered by any potential mechanism is determined by a complex algorithm including, but not limited to, chronicity of the inflammation, tissue type, instigating stimulus, and state/tone of the immune system. Accordingly, the pharmacology and anatomical substrate of spinal cord modulation of peripheral inflammation are discussed with regard to peripheral tissue type, inflammatory insult (initiating stimulus), and duration of the inflammation.

Keywords

Neurogenic inflammation Dorsal root reflex Adenosine Sympathetic nervous system Arthritis 

References

  1. Alvarez FJ, Kavookjian AM, Light AR (1992) Synaptic interactions between GABA-immunoreactive profiles and the terminals of functionally defined myelinated nociceptors in the monkey and cat spinal cord. J Neurosci 12(8):2901–2917PubMedGoogle Scholar
  2. Barber RP, Vaughn JE, Saito K, McLaughlin BJ, Roberts E (1978) GABAergic terminals are presynaptic to primary afferent terminals in the substantia gelatinosa of the rat spinal cord. Brain Res 141:35–55CrossRefPubMedGoogle Scholar
  3. Bernardi PS, Valtschanoff JG, Weinberg RJ, Schmidt HH, Rustioni A (1995) Synaptic interactions between primary afferent terminals and GABA and nitric oxide-synthesizing neurons in superficial laminae of the rat spinal cord. J Neurosci 15(2):1363–1371PubMedGoogle Scholar
  4. Bernik TR, Friedman SG, Ochani M, DiRaimo R, Ulloa L, Yang H, Sudan S, Czura CJ, Ivanova SM, Tracey KJ (2002) Pharmacological stimulation of the cholinergic antiinflammatory pathway. J Exp Med 195(6):781–788CrossRefPubMedCentralPubMedGoogle Scholar
  5. Boettger MK, Weber K, Gajda M, Brauer R, Schaible HG (2010a) Spinally applied ketamine or morphine attenuate peripheral inflammation and hyperalgesia in acute and chronic phases of experimental arthritis. Brain Behav Immun 24(3):474–485CrossRefPubMedGoogle Scholar
  6. Boettger MK, Weber K, Grossmann D, Gajda M, Bauer R, Bar KJ, Schulz S, Voss A, Geis C, Brauer R, Schaible HG (2010b) Spinal tumor necrosis factor alpha neutralization reduces peripheral inflammation and hyperalgesia and suppresses autonomic responses in experimental arthritis: a role for spinal tumor necrosis factor alpha during induction and maintenance of peripheral inflammation. Arthritis Rheum 62(5):1308–1318CrossRefPubMedGoogle Scholar
  7. Bong GW, Rosengren S, Firestein GS (1996) Spinal cord adenosine receptor stimulation in rats inhibits peripheral neutrophil accumulation. The role of N-methyl-D-aspartate receptors. J Clin Invest 98(12):2779–2785CrossRefPubMedCentralPubMedGoogle Scholar
  8. Borovikova LV, Ivanova S, Nardi D, Zhang M, Yang H, Ombrellino M, Tracey KJ (2000a) Role of vagus nerve signaling in CNI-1493-mediated suppression of acute inflammation. Auton Neurosci 85(1–3):141–147CrossRefPubMedGoogle Scholar
  9. Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI, Watkins LR, Wang H, Abumrad N, Eaton JW, Tracey KJ (2000b) Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 405(6785):458–462CrossRefPubMedGoogle Scholar
  10. Boyle DL, Moore J, Yang L, Sorkin LS, Firestein GS (2002) Stimulation of spinal adenosine (ADO) receptors inhibits inflammation and joint destruction in rat adjuvant arthritis. Arthritis Rheum 46(11):3076–3082CrossRefPubMedGoogle Scholar
  11. Boyle DL, Jones TL, Hammaker D, Svensson CI, Rosengren S, Albani S, Sorkin L, Firestein GS (2006) Regulation of peripheral inflammation by spinal p38 MAP kinase in rats. PLoS Med 3(9):e338CrossRefPubMedCentralPubMedGoogle Scholar
  12. Bressan E, Mitkovski M, Tonussi CR (2010) LPS-induced knee-joint reactive arthritis and spinal cord glial activation were reduced after intrathecal thalidomide injection in rats. Life Sci 87(15–16):481–489CrossRefPubMedGoogle Scholar
  13. Bressan E, Peres KC, Tonussi CR (2012) Evidence that LPS-reactive arthritis in rats depends on the glial activity and the fractalkine-TNF-alpha signaling in the spinal cord. Neuropharmacology 62(2):947–958CrossRefPubMedGoogle Scholar
  14. Brock SC, Tonussi CR (2008) Intrathecally injected morphine inhibits inflammatory paw edema: the involvement of nitric oxide and cyclic-guanosine monophosphate. Anesth Analg 106(3):965–971, table of contentsCrossRefPubMedGoogle Scholar
  15. Carlton SM, Hayes ES (1990) Light microscopic and ultrastructural analysis of GABA-immunoreactive profiles in the monkey spinal cord. J Comp Neurol 300(2):162–182CrossRefPubMedGoogle Scholar
  16. Castro-Lopes JM, Tavares I, Tolle TR, Coito A, Coimbra A (1992) Increase in GABAergic cells and GABA levels in the spinal cord in unilateral inflammation of the hindlimb in the rat. Eur J Neurosci 4(4):296–301CrossRefPubMedGoogle Scholar
  17. Castro-Lopes JM, Tavares I, Tölle TR, Coimbra A (1994) Carrageenan-induced inflammation of the hind foot provokes a rise of GABA-immunoreactive cells in the rat spinal cord that is prevented by peripheral neurectomy or neonatal capsaicin treatment. Pain 56(2):193–201CrossRefPubMedGoogle Scholar
  18. Cervero F, Laird JM (1996a) Mechanisms of allodynia: interactions between sensitive mechanoreceptors and nociceptors. Neuroreport 7(2):526–528CrossRefPubMedGoogle Scholar
  19. Cervero F, Laird JM (1996b) Mechanisms of touch-evoked pain (allodynia): a new model. Pain 68(1):13–23CrossRefPubMedGoogle Scholar
  20. Chen HS, He X, Wang Y, Wen WW, You HJ, Arendt-Nielsen L (2007) Roles of capsaicin-sensitive primary afferents in differential rat models of inflammatory pain: a systematic comparative study in conscious rats. Exp Neurol 204(1):244–251CrossRefPubMedGoogle Scholar
  21. Coderre TJ, Basbaum AI, Helms C, Levine JD (1991) High-dose epinephrine acts at alpha 2-adrenoceptors to suppress experimental arthritis. Brain Res 544(2):325–328CrossRefPubMedGoogle Scholar
  22. Colpaert FC, Donnerer J, Lembeck F (1983) Effects of capsaicin on inflammation and on the substance P content of nervous tissues in rats with adjuvant arthritis. Life Sci 32(16):1827–1834CrossRefPubMedGoogle Scholar
  23. Courtright LJ, Kuzell WC (1965) Sparing effect of neurological deficit and trauma on the course of adjuvant arthritis in the rat. Ann Rheum Dis 24(4):360–368CrossRefPubMedCentralPubMedGoogle Scholar
  24. Cronstein BN, Levin RI, Philips M, Hirschhorn R, Abramson SB, Weissmann G (1992) Neutrophil adherence to endothelium is enhanced via adenosine A1 receptors and inhibited via adenosine A2 receptors. J Immunol 148(7):2201–2206PubMedGoogle Scholar
  25. Cruwys SC, Garrett NE, Kidd BL (1995) Sensory denervation with capsaicin attenuates inflammation and nociception in arthritic rats. Neurosci Lett 193(3):205–207CrossRefPubMedGoogle Scholar
  26. Daher JB, Tonussi CR (2003) A spinal mechanism for the peripheral anti-inflammatory action of indomethacin. Brain Res 962(1–2):207–212CrossRefPubMedGoogle Scholar
  27. Donnerer J, Amann R, Lembeck F (1991) Neurogenic and non-neurogenic inflammation in the rat paw following chemical sympathectomy. Neuroscience 45(3):761–765CrossRefPubMedGoogle Scholar
  28. Ebbinghaus M, Gajda M, Boettger MK, Schaible HG, Brauer R (2012) The anti-inflammatory effects of sympathectomy in murine antigen-induced arthritis are associated with a reduction of Th1 and Th17 responses. Ann Rheum Dis 71(2):253–261CrossRefPubMedGoogle Scholar
  29. Ferrell WR, Russell NJ (1986) Extravasation in the knee induced by antidromic stimulation of articular C fibre afferents of the anaesthetized cat. J Physiol 379:407–416CrossRefPubMedCentralPubMedGoogle Scholar
  30. Green PG, Basbaum AI, Helms C, Levine JD (1991) Purinergic regulation of bradykinin-induced plasma extravasation and adjuvant-induced arthritis in the rat. Proc Natl Acad Sci U S A 88(10):4162–4165CrossRefPubMedCentralPubMedGoogle Scholar
  31. Green PG, Miao FJ, Strausbaugh H, Heller P, Janig W, Levine JD (1998) Endocrine and vagal controls of sympathetically dependent neurogenic inflammation. Ann N Y Acad Sci 840:282–288CrossRefPubMedGoogle Scholar
  32. Harle P, Mobius D, Carr DJ, Scholmerich J, Straub RH (2005) An opposing time-dependent immune-modulating effect of the sympathetic nervous system conferred by altering the cytokine profile in the local lymph nodes and spleen of mice with type II collagen-induced arthritis. Arthritis Rheum 52(4):1305–1313CrossRefPubMedGoogle Scholar
  33. Harle P, Pongratz G, Albrecht J, Tarner IH, Straub RH (2008) An early sympathetic nervous system influence exacerbates collagen-induced arthritis via CD4+CD25+ cells. Arthritis Rheum 58(8):2347–2355CrossRefPubMedGoogle Scholar
  34. Holzer P (1991) Capsaicin: cellular targets, mechanisms of action, and selectivity for thin sensory neurons. Pharmacol Rev 43:144–201Google Scholar
  35. Hood VC, Cruwys SC, Urban L, Kidd BL (2001) The neurogenic contribution to synovial leucocyte infiltration and other outcome measures in a guinea pig model of arthritis. Neurosci Lett 299(3):201–204CrossRefPubMedGoogle Scholar
  36. Kane D, Lockhart JC, Balint PV, Mann C, Ferrell WR, McInnes IB (2005) Protective effect of sensory denervation in inflammatory arthritis (evidence of regulatory neuroimmune pathways in the arthritic joint). Ann Rheum Dis 64(2):325–327CrossRefPubMedCentralPubMedGoogle Scholar
  37. Kelley JM, Hughes LB, Bridges SL Jr (2008) Does gamma-aminobutyric acid (GABA) influence the development of chronic inflammation in rheumatoid arthritis? J Neuroinflammation 5:1CrossRefPubMedCentralPubMedGoogle Scholar
  38. Levine JD, Moskowitz MA, Basbaum AI (1985) The contribution of neurogenic inflammation in experimental arthritis. J Immunol 135(2 Suppl):843s–847sPubMedGoogle Scholar
  39. Levine JD, Dardick SJ, Roizen MF, Helms C, Basbaum AI (1986) Contribution of sensory afferents and sympathetic efferents to joint injury in experimental arthritis. J Neurosci 6:3423–3429PubMedGoogle Scholar
  40. Levine JD, Coderre TJ, Helms C, Basbaum AI (1988) Beta 2-adrenergic mechanisms in experimental arthritis. Proc Natl Acad Sci U S A 85(12):4553–4556CrossRefPubMedCentralPubMedGoogle Scholar
  41. Lin Q, Wu J, Willis WD (1999) Dorsal root reflexes and cutaneous neurogenic inflammation after intradermal injection of capsaicin in rats. J Neurophysiol 82(5):2602–2611PubMedGoogle Scholar
  42. Lin Q, Zou X, Willis WD (2000) Adelta and C primary afferents convey dorsal root reflexes after intradermal injection of capsaicin in rats. J Neurophysiol 84(5):2695–2698PubMedGoogle Scholar
  43. Lorton D, Lubahn C, Klein N, Schaller J, Bellinger DL (1999) Dual role for noradrenergic innervation of lymphoid tissue and arthritic joints in adjuvant-induced arthritis. Brain Behav Immun 13(4):315–334CrossRefPubMedGoogle Scholar
  44. Lubahn CL, Schaller JA, Bellinger DL, Sweeney S, Lorton D (2004) The importance of timing of adrenergic drug delivery in relation to the induction and onset of adjuvant-induced arthritis. Brain Behav Immun 18(6):563–571CrossRefPubMedGoogle Scholar
  45. Mapp PI, Kidd BL, Gibson SJ, Terry JM, Revell PA, Ibrahim NB, Blake DR, Polak JM (1990) Substance P-, calcitonin gene-related peptide- and C-flanking peptide of neuropeptide Y-immunoreactive fibres are present in normal synovium but depleted in patients with rheumatoid arthritis. Neuroscience 37(1):143–153CrossRefPubMedGoogle Scholar
  46. Melzack R, Wall PD (1965) Pain mechanisms: a new theory. Science 150:7CrossRefGoogle Scholar
  47. Miller LE, Justen HP, Scholmerich J, Straub RH (2000) The loss of sympathetic nerve fibers in the synovial tissue of patients with rheumatoid arthritis is accompanied by increased norepinephrine release from synovial macrophages. FASEB J 14(13):2097–2107CrossRefPubMedGoogle Scholar
  48. Miller LE, Weidler C, Falk W, Angele P, Schaumburger J, Scholmerich J, Straub RH (2004) Increased prevalence of semaphorin 3C, a repellent of sympathetic nerve fibers, in the synovial tissue of patients with rheumatoid arthritis. Arthritis Rheum 50(4):1156–1163CrossRefPubMedGoogle Scholar
  49. Moreira AL, Sampaio EP, Zmuidzinas A, Frindt P, Smith KA, Kaplan G (1993) Thalidomide exerts its inhibitory action on tumor necrosis factor alpha by enhancing mRNA degradation. J Exp Med 177(6):1675–1680CrossRefPubMedGoogle Scholar
  50. Nolte D, Lorenzen A, Lehr HA, Zimmer FJ, Klotz KN, Messmer K (1992) Reduction of postischemic leukocyte-endothelium interaction by adenosine via A2 receptor. Naunyn Schmiedebergs Arch Pharmacol 346(2):234–237CrossRefPubMedGoogle Scholar
  51. Pinter E, Than M, Chu DQ, Fogg C, Brain SD (2002) Interaction between interleukin 1beta and endogenous neurokinin 1 receptor agonists in mediating plasma extravasation and neutrophil accumulation in the cutaneous microvasculature of the rat. Neurosci Lett 318(1):13–16CrossRefPubMedGoogle Scholar
  52. Pongratz G, Straub RH (2010) The B cell, arthritis, and the sympathetic nervous system. Brain Behav Immun 24(2):186–192CrossRefPubMedGoogle Scholar
  53. Rees H, Sluka KA, Westlund KN, Willis WD (1994) Do dorsal root reflexes augment peripheral inflammation? Neuroreport 5(7):821–824CrossRefPubMedGoogle Scholar
  54. Rees H, Sluka KA, Westlund KN, Willis WD (1995) The role of glutamate and GABA receptors in the generation of dorsal root reflexes by acute arthritis in the anaesthetized rat. J Physiol 484(Pt 2):437–445CrossRefPubMedCentralPubMedGoogle Scholar
  55. Rose FR, Hirschhorn R, Weissmann G, Cronstein BN (1988) Adenosine promotes neutrophil chemotaxis. J Exp Med 167(3):1186–1194CrossRefPubMedGoogle Scholar
  56. Schmidt RF (1971) Presynaptic inhibition in the vertebrate nervous system. Rev Physiol Biochem Pharmacol 63:21–101Google Scholar
  57. Sluka KA, Westlund KN (1993) Centrally administered non-NMDA but not NMDA receptor antagonists block peripheral knee joint inflammation. Pain 55(2):217–225CrossRefPubMedGoogle Scholar
  58. Sluka KA, Willis WD, Westlund KN (1993) Joint inflammation and hyperalgesia are reduced by spinal bicuculline. Neuroreport 5(2):109–112CrossRefPubMedGoogle Scholar
  59. Sluka KA, Jordan HH, Westlund KN (1994a) Reduction in joint swelling and hyperalgesia following post-treatment with a non-NMDA glutamate receptor antagonist. Pain 59(1):95–100CrossRefPubMedGoogle Scholar
  60. Sluka KA, Lawand NB, Westlund KN (1994b) Joint inflammation is reduced by dorsal rhizotomy and not by sympathectomy or spinal cord transection. Ann Rheum Dis 53(5):309–314CrossRefPubMedCentralPubMedGoogle Scholar
  61. Sluka KA, Rees H, Westlund KN, Willis WD (1995) Fiber types contributing to dorsal root reflexes induced by joint inflammation in cats and monkeys. J Neurophysiol 74(3):981–989PubMedGoogle Scholar
  62. Sorkin LS, Moore J, Boyle DL, Yang L, Firestein GS (2003) Regulation of peripheral inflammation by spinal adenosine: role of somatic afferent fibers. Exp Neurol 184(1):162–168CrossRefPubMedGoogle Scholar
  63. Straub RH, Harle P (2005) Sympathetic neurotransmitters in joint inflammation. Rheum Dis Clin North Am 31(1):43–59, viiiCrossRefPubMedGoogle Scholar
  64. Straub RH, Mayer M, Kreutz M, Leeb S, Scholmerich J, Falk W (2000) Neurotransmitters of the sympathetic nerve terminal are powerful chemoattractants for monocytes. J Leukoc Biol 67(4):553–558PubMedGoogle Scholar
  65. Svensson CI, Marsala M, Westerlund A, Calcutt NA, Campana WM, Freshwater JD, Catalano R, Feng Y, Protter AA, Scott B, Yaksh TL (2003) Activation of p38 mitogen-activated protein kinase in spinal microglia is a critical link in inflammation-induced spinal pain processing. J Neurochem 86(6):1534–1544CrossRefPubMedGoogle Scholar
  66. Waldburger JM, Firestein GS (2010) Regulation of peripheral inflammation by the central nervous system. Curr Rheumatol Rep 12(5):370–378CrossRefPubMedCentralPubMedGoogle Scholar
  67. Waldburger JM, Boyle DL, Edgar M, Sorkin LS, Levine YA, Pavlov VA, Tracey K, Firestein GS (2008a) Spinal p38 MAP kinase regulates peripheral cholinergic outflow. Arthritis Rheum 58(9):2919–2921CrossRefPubMedGoogle Scholar
  68. Waldburger JM, Boyle DL, Pavlov VA, Tracey KJ, Firestein GS (2008b) Acetylcholine regulation of synoviocyte cytokine expression by the alpha7 nicotinic receptor. Arthritis Rheum 58(11):3439–3449CrossRefPubMedGoogle Scholar
  69. Wang H, Yu M, Ochani M, Amella CA, Tanovic M, Susarla S, Li JH, Yang H, Ulloa L, Al-Abed Y, Czura CJ, Tracey KJ (2003) Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature 421(6921):384–388CrossRefPubMedGoogle Scholar
  70. Wang J, Ren Y, Zou X, Fang L, Willis WD, Lin Q (2004) Sympathetic influence on capsaicin-evoked enhancement of dorsal root reflexes in rats. J Neurophysiol 92(4):2017–2026CrossRefPubMedGoogle Scholar
  71. Willis WD Jr (1999) Dorsal root potentials and dorsal root reflexes: a double-edged sword. Exp Brain Res 124(4):395–421CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  1. 1.Department of AnesthesiologyUniversity of California, San DiegoLa JollaUSA

Personalised recommendations