Advertisement

Journal of Neuroimmune Pharmacology

, Volume 8, Issue 3, pp 547–563 | Cite as

Inflaming the Brain: CRPS a Model Disease to Understand Neuroimmune Interactions in Chronic Pain

  • C. Linnman
  • L. Becerra
  • D. Borsook
INVITED REVIEW

Abstract

We review current concepts in CRPS from a neuroimaging perspective and point out topics and potential mechanisms that are suitable to be investigated in the next step towards understanding the pathophysiology of CRPS. We have outlined functional aspects of the syndrome, from initiating lesion via inflammatory mechanisms to CNS change and associated sickness behavior, with current evidence for up-regulation of immunological factors in CRPS, neuroimaging of systemic inflammation, and neuroimaging findings in CRPS. The initiation, maintenances and CNS targets implicated in CRPS and in the neuro-inflammatory reflex are discussed in terms of CRPS symptoms and recent preclinical studies. Potential avenues for investigating CRPS with PET and fMRI are described, along with roles of inflammation, treatment and behavior in CRPS. It is our hope that this outline will provoke discussion and promote further empirical studies on the interactions between central and peripheral inflammatory pathways manifest in CRPS.

Keywords

CRPS Cytokine fMRI PET Glia Astrocyte Brain Inflammation 

Notes

Acknowledgments

Supported by grants to David Borsook from the Mayday Foundation, New York, National Institute of Neurological Disorders and Stroke (NINDS) R01NS065051 and NS064050; and to Clas Linnman from the International Association for the Study of Pain (IASP) early career award and IASP Research Grant, funded by the Scan|Design Foundation BY INGER & JENS BRUUN.

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. Abbadie C, Bhangoo S, De Koninck Y, Malcangio M, Melik-Parsadaniantz S, White FA (2009) Chemokines and pain mechanisms. Brain Res Rev 60(1):125–134. doi: 10.1016/j.brainresrev.2008.12.002 PubMedCrossRefGoogle Scholar
  2. Al-Amin H, Sarkis R, Atweh S, Jabbur S, Saade N (2011) Chronic dizocilpine or apomorphine and development of neuropathy in two animal models II: effects on brain cytokines and neurotrophins. Exp Neurol 228(1):30–40. doi: 10.1016/j.expneurol.2010.11.005 PubMedCrossRefGoogle Scholar
  3. Apkarian AV, Bushnell MC, Treede RD, Zubieta JK (2005) Human brain mechanisms of pain perception and regulation in health and disease. Eur J Pain 9(4):463–484PubMedCrossRefGoogle Scholar
  4. Austin PJ, Moalem-Taylor G (2010) The neuro-immune balance in neuropathic pain: involvement of inflammatory immune cells, immune-like glial cells and cytokines. J Neuroimmunol 229(1–2):26–50. doi: 10.1016/j.jneuroim.2010.08.013 PubMedCrossRefGoogle Scholar
  5. Azari P, Lindsay DR, Briones D, Clarke C, Buchheit T, Pyati S (2012) Efficacy and safety of ketamine in patients with complex regional pain syndrome: a systematic review. CNS Drugs 26(3):215–228. doi: 10.2165/11595200-000000000-00000 PubMedCrossRefGoogle Scholar
  6. Baier B, Karnath HO (2008) Tight link between our sense of limb ownership and self-awareness of actions. Stroke 39(2):486–488. doi: 10.1161/STROKEAHA.107.495606 PubMedCrossRefGoogle Scholar
  7. Baliki MN, Schnitzer TJ, Bauer WR, Apkarian AV (2011) Brain morphological signatures for chronic pain. PLoS One 6(10):e26010. doi: 10.1371/journal.pone.0026010 PubMedCrossRefGoogle Scholar
  8. Banati RB (2003) Neuropathological imaging: in vivo detection of glial activation as a measure of disease and adaptive change in the brain. Br Med Bull 65:121–131PubMedCrossRefGoogle Scholar
  9. Banati RB, Cagnin A, Brooks DJ, Gunn RN, Myers R, Jones T, Birch R, Anand P (2001) Long-term trans-synaptic glial responses in the human thalamus after peripheral nerve injury. Neuroreport 12(16):3439–3442PubMedCrossRefGoogle Scholar
  10. Baracos V, Rodemann HP, Dinarello CA, Goldberg AL (1983) Stimulation of muscle protein degradation and prostaglandin E2 release by leukocytic pyrogen (interleukin-1). A mechanism for the increased degradation of muscle proteins during fever. N Engl J Med 308(10):553–558. doi: 10.1056/NEJM198303103081002 PubMedCrossRefGoogle Scholar
  11. Benamar K, Geller EB, Adler MW (2008) Elevated level of the proinflammatory chemokine, RANTES/CCL5, in the periaqueductal grey causes hyperalgesia in rats. Eur J Pharmacol 592(1–3):93–95. doi: 10.1016/j.ejphar.2008.07.009 PubMedCrossRefGoogle Scholar
  12. Benatti C, Alboni S, Capone G, Corsini D, Caggia F, Brunello N, Tascedda F, Blom JM (2009) Early neonatal inflammation affects adult pain reactivity and anxiety related traits in mice: genetic background counts. Int J Dev Neurosci 27(7):661–668. doi: 10.1016/j.ijdevneu.2009.07.009 PubMedCrossRefGoogle Scholar
  13. Benatti C, Alboni S, Montanari C, Caggia F, Tascedda F, Brunello N, Blom JM (2011) Central effects of a local inflammation in three commonly used mouse strains with a different anxious phenotype. Behavioural Brain Research 224(1):23–34. doi: 10.1016/j.bbr.2011.05.011 PubMedCrossRefGoogle Scholar
  14. Benson S, Kattoor J, Wegner A, Hammes F, Reidick D, Grigoleit JS, Engler H, Oberbeck R, Schedlowski M, Elsenbruch S (2012) Acute experimental endotoxemia induces visceral hypersensitivity and altered pain evaluation in healthy humans. Pain 153(4):794–799. doi: 10.1016/j.pain.2011.12.001 PubMedCrossRefGoogle Scholar
  15. Bergstrom M, Kumlien E, Lilja A, Tyrefors N, Westerberg G, Langstrom B (1998) Temporal lobe epilepsy visualized with PET with 11C-L-deuterium-deprenyl–analysis of kinetic data. Acta Neurologica Scandinavica 98(4):224–231PubMedCrossRefGoogle Scholar
  16. Bernateck M, Rolke R, Birklein F, Treede RD, Fink M, Karst M (2007) Successful intravenous regional block with low-dose tumor necrosis factor-alpha antibody infliximab for treatment of complex regional pain syndrome 1. Anesth Analg 105(4):1148–1151. doi: 10.1213/01.ane.0000278867.24601.a0 PubMedCrossRefGoogle Scholar
  17. Bernateck M, Karst M, Gratz KF, Meyer GJ, Fischer MJ, Knapp WH, Koppert W, Brunkhorst T (2010) The first scintigraphic detection of tumor necrosis factor-alpha in patients with complex regional pain syndrome type 1. Anesth Analg 110(1):211–215. doi: 10.1213/ANE.0b013e3181c4bab7 PubMedCrossRefGoogle Scholar
  18. Berthier M, Starkstein S, Leiguarda R (1988) Asymbolia for pain: a sensory-limbic disconnection syndrome. Ann Neurol 24(1):41–49. doi: 10.1002/ana.410240109 PubMedCrossRefGoogle Scholar
  19. Binukumar BK, Bal A, Gill KD (2011) Chronic dichlorvos exposure: microglial activation, proinflammatory cytokines and damage to nigrostriatal dopaminergic system. Neuromolecular Med 13(4):251–265. doi: 10.1007/s12017-011-8156-8 PubMedCrossRefGoogle Scholar
  20. Birklein F, Schmelz M (2008) Neuropeptides, neurogenic inflammation and complex regional pain syndrome (CRPS). Neurosci Lett 437(3):199–202. doi: 10.1016/j.neulet.2008.03.081 PubMedCrossRefGoogle Scholar
  21. Biswal BB, Mennes M, Zuo XN, Gohel S, Kelly C, Smith SM, Beckmann CF, Adelstein JS, Buckner RL, Colcombe S, Dogonowski AM, Ernst M, Fair D, Hampson M, Hoptman MJ, Hyde JS, Kiviniemi VJ, Kotter R, Li SJ, Lin CP, Lowe MJ, Mackay C, Madden DJ, Madsen KH, Margulies DS, Mayberg HS, McMahon K, Monk CS, Mostofsky SH, Nagel BJ, Pekar JJ, Peltier SJ, Petersen SE, Riedl V, Rombouts SA, Rypma B, Schlaggar BL, Schmidt S, Seidler RD, Siegle GJ, Sorg C, Teng GJ, Veijola J, Villringer A, Walter M, Wang L, Weng XC, Whitfield-Gabrieli S, Williamson P, Windischberger C, Zang YF, Zhang HY, Castellanos FX, Milham MP (2010) Toward discovery science of human brain function. Proc Natl Acad Sci U S A 107(10):4734–4739. doi: 10.1073/pnas.0911855107 PubMedCrossRefGoogle Scholar
  22. Bruehl S, Chung OY (2006) Psychological and behavioral aspects of complex regional pain syndrome management. Clin J Pain 22(5):430–437. doi: 10.1097/01.ajp.0000194282.82002.79 PubMedCrossRefGoogle Scholar
  23. Bruehl S, Harden RN, Galer BS, Saltz S, Backonja M, Stanton-Hicks M (2002) Complex regional pain syndrome: are there distinct subtypes and sequential stages of the syndrome? Pain 95(1–2):119–124PubMedCrossRefGoogle Scholar
  24. Brydon L, Harrison NA, Walker C, Steptoe A, Critchley HD (2008) Peripheral inflammation is associated with altered substantia nigra activity and psychomotor slowing in humans. Biol Psychiatry 63(11):1022–1029. doi: 10.1016/j.biopsych.2007.12.007 PubMedCrossRefGoogle Scholar
  25. Cao H, Zhang YQ (2008) Spinal glial activation contributes to pathological pain states. Neurosci Biobehav Rev 32(5):972–983. doi: 10.1016/j.neubiorev.2008.03.009 PubMedCrossRefGoogle Scholar
  26. Capuron L, Pagnoni G, Demetrashvili M, Woolwine BJ, Nemeroff CB, Berns GS, Miller AH (2005) Anterior cingulate activation and error processing during interferon-alpha treatment. Biol Psychiatry 58(3):190–196. doi: 10.1016/j.biopsych.2005.03.033 PubMedCrossRefGoogle Scholar
  27. Capuron L, Pagnoni G, Demetrashvili MF, Lawson DH, Fornwalt FB, Woolwine B, Berns GS, Nemeroff CB, Miller AH (2007) Basal ganglia hypermetabolism and symptoms of fatigue during interferon-alpha therapy. Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology 32(11):2384–2392. doi: 10.1038/sj.npp.1301362 CrossRefGoogle Scholar
  28. Carter SF, Scholl M, Almkvist O, Wall A, Engler H, Langstrom B, Nordberg A (2012) Evidence for astrocytosis in prodromal Alzheimer disease provided by 11C-deuterium-L-deprenyl: a multitracer PET paradigm combining 11C-Pittsburgh compound B and 18F-FDG. Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine 53(1):37–46. doi: 10.2967/jnumed.110.087031 Google Scholar
  29. Ching AS, Kuhnast B, Damont A, Roeda D, Tavitian B, Dolle F (2012) Current paradigm of the 18-kDa translocator protein (TSPO) as a molecular target for PET imaging in neuroinflammation and neurodegenerative diseases. Insights Imaging 3(1):111–119. doi: 10.1007/s13244-011-0128-x PubMedCrossRefGoogle Scholar
  30. Clark AK, Gentry C, Bradbury EJ, McMahon SB, Malcangio M (2007) Role of spinal microglia in rat models of peripheral nerve injury and inflammation. European Journal of Pain 11(2):223–230. doi: 10.1016/j.ejpain.2006.02.003 PubMedCrossRefGoogle Scholar
  31. Cooper MS, Clark VP (2012) Neuroinflammation, neuroautoimmunity, and the co-morbidities of complex regional pain syndrome. J Neuroimmune Pharmacol. doi: 10.1007/s11481-012-9392-x
  32. Covey WC, Ignatowski TA, Renauld AE, Knight PR, Nader ND, Spengler RN (2002) Expression of neuron-associated tumor necrosis factor alpha in the brain is increased during persistent pain. Reg Anesth Pain Med 27(4):357–366PubMedGoogle Scholar
  33. Craig AD (2003) Pain mechanisms: labeled lines versus convergence in central processing. Annu Rev Neurosci 26:1–30PubMedCrossRefGoogle Scholar
  34. Craig AD (2009) How do you feel–now? The anterior insula and human awareness. Nat Rev Neurosci 10(1):59–70PubMedCrossRefGoogle Scholar
  35. Czlonkowska A, Ciesielska A, Gromadzka G, Kurkowska-Jastrzebska I (2006) Gender differences in neurological disease: role of estrogens and cytokines. Endocrine 29(2):243–256. doi: 10.1385/ENDO:29:2:243 PubMedCrossRefGoogle Scholar
  36. Czura CJ, Tracey KJ (2005) Autonomic neural regulation of immunity. Journal of Internal Medicine 257(2):156–166. doi: 10.1111/j.1365-2796.2004.01442.x PubMedCrossRefGoogle Scholar
  37. Danfors T, Ahs F, Appel L, Linnman C, Fredrikson M, Furmark T, Kumlien E (2011) Increased neurokinin-1 receptor availability in temporal lobe epilepsy: a positron emission tomography study using [(11)C]GR205171. Epilepsy Res 97(1–2):183–189. doi: 10.1016/j.eplepsyres.2011.08.006 PubMedCrossRefGoogle Scholar
  38. Dantzer R, Kelley KW (2007) Twenty years of research on cytokine-induced sickness behavior. Brain, Behavior, and Immunity 21(2):153–160. doi: 10.1016/j.bbi.2006.09.006 PubMedCrossRefGoogle Scholar
  39. Darnall BD, Aickin M, Zwickey H (2010) Pilot study of inflammatory responses following a negative imaginal focus in persons with chronic pain: analysis by sex/gender. Gender Medicine 7(3):247–260. doi: 10.1016/j.genm.2010.06.003 PubMedCrossRefGoogle Scholar
  40. de Jong JR, Vlaeyen JW, Onghena P, Cuypers C, den Hollander M, Ruijgrok J (2005) Reduction of pain-related fear in complex regional pain syndrome type I: the application of graded exposure in vivo. Pain 116(3):264–275. doi: 10.1016/j.pain.2005.04.019 PubMedCrossRefGoogle Scholar
  41. de Jong JR, Vlaeyen JW, de Gelder JM, Patijn J (2011) Pain-related fear, perceived harmfulness of activities, and functional limitations in complex regional pain syndrome type I. The Journal of Pain: Official Journal of the American Pain Society 12(12):1209–1218. doi: 10.1016/j.jpain.2011.06.010 CrossRefGoogle Scholar
  42. de Mos M, de Bruijn AG, Huygen FJ, Dieleman JP, Stricker BH, Sturkenboom MC (2007) The incidence of complex regional pain syndrome: a population-based study. Pain 129(1–2):12–20. doi: 10.1016/j.pain.2006.09.008 PubMedCrossRefGoogle Scholar
  43. de Mos M, Huygen FJ, Stricker BH, Dieleman JP, Sturkenboom MC (2009) Estrogens and the risk of complex regional pain syndrome (CRPS). Pharmacoepidemiol Drug Saf 18(1):44–52. doi: 10.1002/pds.1683 PubMedCrossRefGoogle Scholar
  44. Del Valle L, Schwartzman RJ, Alexander G (2009) Spinal cord histopathological alterations in a patient with longstanding complex regional pain syndrome. Brain, Behavior, and Immunity 23(1):85–91. doi: 10.1016/j.bbi.2008.08.004 PubMedCrossRefGoogle Scholar
  45. Derbyshire SW, Nichols TE, Firestone L, Townsend DW, Jones AK (2002) Gender differences in patterns of cerebral activation during equal experience of painful laser stimulation. J Pain 3(5):401–411PubMedCrossRefGoogle Scholar
  46. Diamond B, Tracey KJ (2011) Mapping the immunological homunculus. Proc Natl Acad Sci U S A 108(9):3461–3462. doi: 10.1073/pnas.1100329108 PubMedCrossRefGoogle Scholar
  47. Dirckx M, Stronks DL, Groeneweg G, Huygen FJ (2012) Effect of immunomodulating medications in complex regional pain syndrome: a systematic review. Clin J Pain 28(4):355–363. doi: 10.1097/AJP.0b013e31822efe30 PubMedCrossRefGoogle Scholar
  48. Eccles R (2005) Understanding the symptoms of the common cold and influenza. Lancet Infect Dis 5(11):718–725. doi: 10.1016/S1473-3099(05)70270-X PubMedCrossRefGoogle Scholar
  49. Eccles R, Loose I, Jawad M, Nyman L (2003) Effects of acetylsalicylic acid on sore throat pain and other pain symptoms associated with acute upper respiratory tract infection. Pain Med 4(2):118–124PubMedCrossRefGoogle Scholar
  50. Edwards RR, Kronfli T, Haythornthwaite JA, Smith MT, McGuire L, Page GG (2008) Association of catastrophizing with interleukin-6 responses to acute pain. Pain 140(1):135–144. doi: 10.1016/j.pain.2008.07.024 PubMedCrossRefGoogle Scholar
  51. Eickhoff SB, Laird AR, Grefkes C, Wang LE, Zilles K, Fox PT (2009) Coordinate-based activation likelihood estimation meta-analysis of neuroimaging data: a random-effects approach based on empirical estimates of spatial uncertainty. Human Brain Mapping 30(9):2907–2926. doi: 10.1002/hbm.20718 PubMedCrossRefGoogle Scholar
  52. Eisenberger NI, Inagaki TK, Rameson LT, Mashal NM, Irwin MR (2009) An fMRI study of cytokine-induced depressed mood and social pain: the role of sex differences. NeuroImage 47(3):881–890. doi: 10.1016/j.neuroimage.2009.04.040 PubMedCrossRefGoogle Scholar
  53. Eisenberger NI, Berkman ET, Inagaki TK, Rameson LT, Mashal NM, Irwin MR (2010) Inflammation-induced anhedonia: endotoxin reduces ventral striatum responses to reward. Biol Psychiatry 68(8):748–754. doi: 10.1016/j.biopsych.2010.06.010 PubMedCrossRefGoogle Scholar
  54. Ekblom J, Jossan SS, Bergstrom M, Oreland L, Walum E, Aquilonius SM (1993) Monoamine oxidase-B in astrocytes. Glia 8(2):122–132. doi: 10.1002/glia.440080208 PubMedCrossRefGoogle Scholar
  55. Engler H, Nennesmo I, Kumlien E, Gambini JP, Lundberg P, Savitcheva I, Langstrom B (2012) Imaging astrocytosis with PET in Creutzfeldt-Jakob disease: case report with histopathological findings. Int J Clin Exp Med 5(2):201–207PubMedGoogle Scholar
  56. Engman J, Ahs F, Furmark T, Linnman C, Pissiota A, Appel L, Frans O, Langstrom B, Fredrikson M (2012) Age, sex and NK1 receptors in the human brain - A positron emission tomography study with [(11)C]GR205171. Eur Neuropsychopharmacol. doi: 10.1016/j.euroneuro.2011.12.005
  57. Fitzgibbon BM, Fairhall SL, Kirk IJ, Kalev-Zylinska M, Pui K, Dalbeth N, Keelan S, Robinson E, During M, McQueen FM (2008) Functional MRI in NPSLE patients reveals increased parietal and frontal brain activation during a working memory task compared with controls. Rheumatology (Oxford) 47(1):50–53. doi: 10.1093/rheumatology/kem287 CrossRefGoogle Scholar
  58. Folkersma H, Boellaard R, Yaqub M, Kloet RW, Windhorst AD, Lammertsma AA, Vandertop WP, van Berckel BN (2011) Widespread and prolonged increase in (R)-(11)C-PK11195 binding after traumatic brain injury. Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine 52(8):1235–1239. doi: 10.2967/jnumed.110.084061 Google Scholar
  59. Fowler JS, MacGregor RR, Wolf AP, Arnett CD, Dewey SL, Schlyer D, Christman D, Logan J, Smith M, Sachs H et al (1987) Mapping human brain monoamine oxidase A and B with 11C-labeled suicide inactivators and PET. Science 235(4787):481–485PubMedCrossRefGoogle Scholar
  60. Fowler JS, Wang GJ, Logan J, Xie S, Volkow ND, MacGregor RR, Schlyer DJ, Pappas N, Alexoff DL, Patlak C et al (1995) Selective reduction of radiotracer trapping by deuterium substitution: comparison of carbon-11-L-deprenyl and carbon-11-deprenyl-D2 for MAO B mapping. Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine 36(7):1255–1262Google Scholar
  61. Fowler JS, Logan J, Volkow ND, Wang GJ (2005) Translational neuroimaging: positron emission tomography studies of monoamine oxidase. Molecular Imaging and Biology: MIB: the Official Publication of the Academy of Molecular Imaging 7(6):377–387. doi: 10.1007/s11307-005-0016-1 CrossRefGoogle Scholar
  62. Frettloh J, Huppe M, Maier C (2006) Severity and specificity of neglect-like symptoms in patients with complex regional pain syndrome (CRPS) compared to chronic limb pain of other origins. Pain 124(1–2):184–189. doi: 10.1016/j.pain.2006.04.010 PubMedCrossRefGoogle Scholar
  63. Freund W, Wunderlich AP, Stuber G, Mayer F, Steffen P, Mentzel M, Weber F, Schmitz B (2010) Different activation of opercular and posterior cingulate cortex (PCC) in patients with complex regional pain syndrome (CRPS I) compared with healthy controls during perception of electrically induced pain: a functional MRI study. Clin J Pain 26 (4):339–347. doi: 10.1097/AJP.0b013e3181cb405 Google Scholar
  64. Freund W, Wunderlich AP, Stuber G, Mayer F, Steffen P, Mentzel M, Schmitz B, Weber F (2011) The role of periaqueductal gray and cingulate cortex during suppression of pain in complex regional pain syndrome. Clin J Pain 27(9):796–804. doi: 10.1097/AJP.0b013e31821d9063 PubMedCrossRefGoogle Scholar
  65. Gaba A, Grivennikov SI, Do MV, Stumpo DJ, Blackshear PJ, Karin M (2012) Cutting edge: IL-10-mediated tristetraprolin induction is part of a feedback loop that controls macrophage STAT3 activation and cytokine production. J Immunol. doi: 10.4049/jimmunol.1201126
  66. Galic MA, Riazi K, Pittman QJ (2012) Cytokines and brain excitability. Front Neuroendocrinol 33(1):116–125. doi: 10.1016/j.yfrne.2011.12.002 PubMedCrossRefGoogle Scholar
  67. Galli U, Gaab J, Ettlin DA, Ruggia F, Ehlert U, Palla S (2009) Enhanced negative feedback sensitivity of the hypothalamus-pituitary-adrenal axis in chronic myogenous facial pain. European Journal of Pain 13(6):600–605. doi: 10.1016/j.ejpain.2008.07.010 PubMedCrossRefGoogle Scholar
  68. Gao YJ, Ji RR (2010) Chemokines, neuronal-glial interactions, and central processing of neuropathic pain. Pharmacol Ther 126(1):56–68. doi: 10.1016/j.pharmthera.2010.01.002 PubMedCrossRefGoogle Scholar
  69. Garcia-Larrea L, Perchet C, Creac'h C, Convers P, Peyron R, Laurent B, Mauguiere F, Magnin M (2010) Operculo-insular pain (parasylvian pain): a distinct central pain syndrome. Brain: a Journal of Neurology 133(9):2528–2539. doi: 10.1093/brain/awq220 CrossRefGoogle Scholar
  70. Geha PY, Apkarian AV (2005) Brain imaging findings in neuropathic pain. Curr Pain Headache Rep 9(3):184–188PubMedCrossRefGoogle Scholar
  71. Geha PY, Baliki MN, Harden RN, Bauer WR, Parrish TB, Apkarian AV (2008) The brain in chronic CRPS pain: abnormal gray-white matter interactions in emotional and autonomic regions. Neuron 60(4):570–581PubMedCrossRefGoogle Scholar
  72. Gieteling EW, van Rijn MA, de Jong BM, Hoogduin JM, Renken R, van Hilten JJ, Leenders KL (2008) Cerebral activation during motor imagery in complex regional pain syndrome type 1 with dystonia. Pain 134 (3):302–309. doi: 10.1016/j.pain.2007.04.029 Google Scholar
  73. Gordh T, Chu H, Sharma HS (2006) Spinal nerve lesion alters blood-spinal cord barrier function and activates astrocytes in the rat. Pain 124(1–2):211–221PubMedCrossRefGoogle Scholar
  74. Gradl G, Finke B, Schattner S, Gierer P, Mittlmeier T, Vollmar B (2007) Continuous intra-arterial application of substance P induces signs and symptoms of experimental complex regional pain syndrome (CRPS) such as edema, inflammation and mechanical pain but no thermal pain. Neuroscience 148(3):757–765. doi: 10.1016/j.neuroscience.2007.06.024 PubMedCrossRefGoogle Scholar
  75. Gustin SM, Schwarz A, Birbaumer N, Sines N, Schmidt AC, Veit R, Larbig W, Flor H, Lotze M (2010) NMDA-receptor antagonist and morphine decrease CRPS-pain and cerebral pain representation. Pain 151 (1):69–76. doi: 10.1016/j.pain.2010.06.022 Google Scholar
  76. Hains LE, Loram LC, Weiseler JL, Frank MG, Bloss EB, Sholar P, Taylor FR, Harrison JA, Martin TJ, Eisenach JC, Maier SF, Watkins LR (2010) Pain intensity and duration can be enhanced by prior challenge: initial evidence suggestive of a role of microglial priming. The Journal of Pain: Official Journal of the American Pain Society 11(10):1004–1014. doi: 10.1016/j.jpain.2010.01.271 CrossRefGoogle Scholar
  77. Hannestad J, Gallezot JD, Schafbauer T, Lim K, Kloczynski T, Morris ED, Carson RE, Ding YS, Cosgrove KP (2012a) Endotoxin-induced systemic inflammation activates microglia: [(11)C]PBR28 positron emission tomography in nonhuman primates. NeuroImage 63(1):232–239. doi: 10.1016/j.neuroimage.2012.06.055 PubMedCrossRefGoogle Scholar
  78. Hannestad J, Subramanyam K, Dellagioia N, Planeta-Wilson B, Weinzimmer D, Pittman B, Carson RE (2012b) Glucose metabolism in the insula and cingulate is affected by systemic inflammation in humans. Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine 53(4):601–607. doi: 10.2967/jnumed.111.097014 Google Scholar
  79. Hao S, Liu S, Zheng X, Zheng W, Ouyang H, Mata M, Fink DJ (2011) The role of TNFalpha in the periaqueductal gray during naloxone-precipitated morphine withdrawal in rats. Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology 36(3):664–676. doi: 10.1038/npp.2010.197 CrossRefGoogle Scholar
  80. Harke H, Gretenkort P, Ladleif HU, Rahman S, Harke O (2001) The response of neuropathic pain and pain in complex regional pain syndrome I to carbamazepine and sustained-release morphine in patients pretreated with spinal cord stimulation: a double-blinded randomized study. Anesth Analg 92(2):488–495PubMedCrossRefGoogle Scholar
  81. Harris EJ, Schimka KE, Carlson RM (2012) Complex regional pain syndrome of the pediatric lower extremity: a retrospective review. J Am Podiatr Med Assoc 102(2):99–104PubMedGoogle Scholar
  82. Harrison NA, Brydon L, Walker C, Gray MA, Steptoe A, Critchley HD (2009a) Inflammation causes mood changes through alterations in subgenual cingulate activity and mesolimbic connectivity. Biol Psychiatry 66(5):407–414. doi: 10.1016/j.biopsych.2009.03.015 PubMedCrossRefGoogle Scholar
  83. Harrison NA, Brydon L, Walker C, Gray MA, Steptoe A, Dolan RJ, Critchley HD (2009b) Neural origins of human sickness in interoceptive responses to inflammation. Biol Psychiatry 66(5):415–422. doi: 10.1016/j.biopsych.2009.03.007 PubMedCrossRefGoogle Scholar
  84. Hart BL (1988) Biological basis of the behavior of sick animals. Neurosci Biobehav Rev 12(2):123–137PubMedCrossRefGoogle Scholar
  85. Hatashita S, Sekiguchi M, Kobayashi H, Konno S, Kikuchi S (2008) Contralateral neuropathic pain and neuropathology in dorsal root ganglion and spinal cord following hemilateral nerve injury in rats. Spine 33(12):1344–1351. doi: 10.1097/BRS.0b013e3181733188 PubMedCrossRefGoogle Scholar
  86. Heinisch S, Palma J, Kirby LG (2011) Interactions between chemokine and mu-opioid receptors: anatomical findings and electrophysiological studies in the rat periaqueductal grey. Brain, Behavior, and Immunity 25(2):360–372. doi: 10.1016/j.bbi.2010.10.020 PubMedCrossRefGoogle Scholar
  87. Hess A, Axmann R, Rech J, Finzel S, Heindl C, Kreitz S, Sergeeva M, Saake M, Garcia M, Kollias G, Straub RH, Sporns O, Doerfler A, Brune K, Schett G (2011) Blockade of TNF-alpha rapidly inhibits pain responses in the central nervous system. Proc Natl Acad Sci U S A 108(9):3731–3736. doi: 10.1073/pnas.1011774108 PubMedCrossRefGoogle Scholar
  88. Hossaini M, Sarac C, Jongen JL, Holstege JC (2011) Spinal glycinergic and GABAergic neurons expressing C-fos after capsaicin stimulation are increased in rats with contralateral neuropathic pain. Neuroscience 196:265–275. doi: 10.1016/j.neuroscience.2011.08.050 PubMedCrossRefGoogle Scholar
  89. Inagaki TK, Muscatell KA, Irwin MR, Cole SW, Eisenberger NI (2012) Inflammation selectively enhances amygdala activity to socially threatening images. NeuroImage 59(4):3222–3226. doi: 10.1016/j.neuroimage.2011.10.090 PubMedCrossRefGoogle Scholar
  90. Janig W, Baron R (2002) Complex regional pain syndrome is a disease of the central nervous system. Clin Auton Res 12 (3):150–164Google Scholar
  91. Jha MK, Jeon S, Suk K (2012) Glia as a link between neuroinflammation and neuropathic pain. Immune Netw 12(2):41–47. doi: 10.4110/in.2012.12.2.41 PubMedCrossRefGoogle Scholar
  92. Johansson A, Engler H, Blomquist G, Scott B, Wall A, Aquilonius SM, Langstrom B, Askmark H (2007) Evidence for astrocytosis in ALS demonstrated by [11C](L)-deprenyl-D2 PET. J Neurol Sci 255(1–2):17–22. doi: 10.1016/j.jns.2007.01.057 PubMedCrossRefGoogle Scholar
  93. Judenhofer MS, Wehrl HF, Newport DF, Catana C, Siegel SB, Becker M, Thielscher A, Kneilling M, Lichy MP, Eichner M, Klingel K, Reischl G, Widmaier S, Rocken M, Nutt RE, Machulla HJ, Uludag K, Cherry SR, Claussen CD, Pichler BJ (2008) Simultaneous PET-MRI: a new approach for functional and morphological imaging. Nature Medicine 14(4):459–465PubMedCrossRefGoogle Scholar
  94. Karnath HO, Baier B, Nagele T (2005) Awareness of the functioning of one's own limbs mediated by the insular cortex? The Journal of Neuroscience: the Official Journal of the Society for Neuroscience 25(31):7134–7138. doi: 10.1523/JNEUROSCI.1590-05.2005 CrossRefGoogle Scholar
  95. Kelly S, Dunham JP, Donaldson LF (2007) Sensory nerves have altered function contralateral to a monoarthritis and may contribute to the symmetrical spread of inflammation. Eur J Neurosci 26(4):935–942. doi: 10.1111/j.1460-9568.2007.05737.x PubMedCrossRefGoogle Scholar
  96. Kilpatrick LA, Zald DH, Pardo JV, Cahill LF (2006) Sex-related differences in amygdala functional connectivity during resting conditions. NeuroImage 30(2):452–461PubMedCrossRefGoogle Scholar
  97. Kim CF, Moalem-Taylor G (2011) Detailed characterization of neuro-immune responses following neuropathic injury in mice. Brain Research 1405:95–108. doi: 10.1016/j.brainres.2011.06.022 PubMedCrossRefGoogle Scholar
  98. Kim SK, Eto K, Nabekura J (2012) Synaptic structure and function in the mouse somatosensory cortex during chronic pain: in vivo two-photon imaging. Neural Plasticity 2012:640259. doi: 10.1155/2012/640259
  99. Klega A, Eberle T, Buchholz HG, Maus S, Maihofner C, Schreckenberger M, Birklein F (2010) Central opioidergic neurotransmission in complex regional pain syndrome. Neurology 75(2):129–136. doi: 10.1212/WNL.0b013e3181e7ca2e PubMedCrossRefGoogle Scholar
  100. Kolb L, Lang C, Seifert F, Maihofner C (2012) Cognitive correlates of "neglect-like syndrome" in patients with complex regional pain syndrome. Pain 153(5):1063–1073. doi: 10.1016/j.pain.2012.02.014 PubMedCrossRefGoogle Scholar
  101. Kong J, Loggia ML, Zyloney C, Tu P, Laviolette P, Gollub RL (2010) Exploring the brain in pain: activations, deactivations and their relation. Pain 148(2):257–267PubMedCrossRefGoogle Scholar
  102. Kramer HH (2012) Immunological aspects of the Complex Regional Pain Syndrome (CRPS). Curr Pharm DesGoogle Scholar
  103. Kramer HH, Eberle T, Uceyler N, Wagner I, Klonschinsky T, Muller LP, Sommer C, Birklein F (2011) TNF-alpha in CRPS and 'normal' trauma–significant differences between tissue and serum. Pain 152(2):285–290. doi: 10.1016/j.pain.2010.09.024 PubMedCrossRefGoogle Scholar
  104. Kreisl WC, Fujita M, Fujimura Y, Kimura N, Jenko KJ, Kannan P, Hong J, Morse CL, Zoghbi SS, Gladding RL, Jacobson S, Oh U, Pike VW, Innis RB (2010) Comparison of [(11)C]-(R)-PK 11195 and [(11)C]PBR28, two radioligands for translocator protein (18 kDa) in human and monkey: implications for positron emission tomographic imaging of this inflammation biomarker. NeuroImage 49(4):2924–2932. doi: 10.1016/j.neuroimage.2009.11.056 PubMedCrossRefGoogle Scholar
  105. Kreisl WC, Jenko KJ, Hines CS, Hyoung Lyoo C, Corona W, Morse CL, Zoghbi SS, Hyde T, Kleinman JE, Pike VW, McMahon FJ, Innis RB (2012) A genetic polymorphism for translocator protein 18 kDa affects both in vitro and in vivo radioligand binding in human brain to this putative biomarker of neuroinflammation. Journal of Cerebral Blood Flow and Metabolism: Official Journal of the International Society of Cerebral Blood Flow and Metabolism. doi: 10.1038/jcbfm.2012.131
  106. Krishnadas R, Cavanagh J (2012) Depression: an inflammatory illness? J Neurol Neurosurg Psychiatry 83(5):495–502. doi: 10.1136/jnnp-2011-301779 PubMedCrossRefGoogle Scholar
  107. Kullmann JS, Grigoleit JS, Lichte P, Kobbe P, Rosenberger C, Banner C, Wolf OT, Engler H, Oberbeck R, Elsenbruch S, Bingel U, Forsting M, Gizewski ER, Schedlowski M (2012) Neural response to emotional stimuli during experimental human endotoxemia. Human Brain Mapping. doi: 10.1002/hbm.22063
  108. Kurth F, Zilles K, Fox PT, Laird AR, Eickhoff SB (2010) A link between the systems: functional differentiation and integration within the human insula revealed by meta-analysis. Brain Struct Funct 214(5–6):519–534. doi: 10.1007/s00429-010-0255-z PubMedCrossRefGoogle Scholar
  109. Lamont K, Chin M, Kogan M (2011) Mirror box therapy: seeing is believing. Explore (NY) 7(6):369–372. doi: 10.1016/j.explore.2011.08.002 CrossRefGoogle Scholar
  110. Lavisse S, Guillermier M, Herard AS, Petit F, Delahaye M, Van Camp N, Ben Haim L, Lebon V, Remy P, Dolle F, Delzescaux T, Bonvento G, Hantraye P, Escartin C (2012) Reactive astrocytes overexpress TSPO and are detected by TSPO positron emission tomography imaging. The Journal of Neuroscience: the Official Journal of the Society for Neuroscience 32(32):10809–10818. doi: 10.1523/JNEUROSCI.1487-12.2012 CrossRefGoogle Scholar
  111. Lebel A, Becerra L, Wallin D, Moulton EA, Morris S, Pendse G, Jasciewicz J, Stein M, Aiello-Lammens M, Grant E, Berde C, Borsook D (2008) fMRI reveals distinct CNS processing during symptomatic and recovered complex regional pain syndrome in children. Brain: a Journal of Neurology 131(Pt 7):1854–1879. doi: 10.1093/brain/awn123 CrossRefGoogle Scholar
  112. LeBlanc BW, Zerah ML, Kadasi LM, Chai N, Saab CY (2011) Minocycline injection in the ventral posterolateral thalamus reverses microglial reactivity and thermal hyperalgesia secondary to sciatic neuropathy. Neurosci Lett 498(2):138–142. doi: 10.1016/j.neulet.2011.04.077 PubMedCrossRefGoogle Scholar
  113. Liang DY, Li X, Shi X, Sun Y, Sahbaie P, Li WW, Clark JD (2012) The complement component C5a receptor mediates pain and inflammation in a postsurgical pain model. Pain 153(2):366–372. doi: 10.1016/j.pain.2011.10.032 PubMedCrossRefGoogle Scholar
  114. Linnman C, Appel L, Furmark T, Soderlund A, Gordh T, Langstrom B, Fredrikson M (2010) Ventromedial prefrontal neurokinin 1 receptor availability is reduced in chronic pain. Pain 149(1):64–70PubMedCrossRefGoogle Scholar
  115. Linnman C, Beucke JC, Jensen KB, Gollub RL, Kong J (2012a) Sex similarities and differences in pain-related periaqueductal gray connectivity. Pain 153(2):444–454. doi: 10.1016/j.pain.2011.11.006 PubMedCrossRefGoogle Scholar
  116. Linnman C, Moulton EA, Barmettler G, Becerra L, Borsook D (2012b) Neuroimaging of the periaqueductal gray: state of the field. NeuroImage 60(1):505–522. doi: 10.1016/j.neuroimage.2011.11.095 PubMedCrossRefGoogle Scholar
  117. Loix S, De Kock M, Henin P (2011) The anti-inflammatory effects of ketamine: state of the art. Acta Anaesthesiol Belg 62(1):47–58PubMedGoogle Scholar
  118. Lossinsky AS, Shivers RR (2004) Structural pathways for macromolecular and cellular transport across the blood-brain barrier during inflammatory conditions. Review. Histol Histopathol 19(2):535–564PubMedGoogle Scholar
  119. Low AK, Ward K, Wines AP (2007) Pediatric complex regional pain syndrome. J Pediatr Orthop 27(5):567–572. doi: 10.1097/BPO.0b013e318070cc4d PubMedCrossRefGoogle Scholar
  120. Maier SF, Wiertelak EP, Martin D, Watkins LR (1993) Interleukin-1 mediates the behavioral hyperalgesia produced by lithium chloride and endotoxin. Brain research 623(2):321–324PubMedCrossRefGoogle Scholar
  121. Maihofner C, Forster C, Birklein F, Neundorfer B, Handwerker HO (2005a) Brain processing during mechanical hyperalgesia in complex regional pain syndrome: a functional MRI study. Pain 114(1–2):93–103. doi: 10.1016/j.pain.2004.12.001 PubMedCrossRefGoogle Scholar
  122. Maihofner C, Handwerker HO, Neundorfer B, Birklein F (2005b) Mechanical hyperalgesia in complex regional pain syndrome: a role for TNF-alpha? Neurology 65(2):311–313. doi: 10.1212/01.wnl.0000168866.62086.8f PubMedCrossRefGoogle Scholar
  123. Maihofner C, Handwerker HO, Birklein F (2006) Functional imaging of allodynia in complex regional pain syndrome. Neurology 66(5):711–717. doi: 10.1212/01.wnl.0000200961.49114.39 PubMedCrossRefGoogle Scholar
  124. Maihofner C, Baron R, DeCol R, Binder A, Birklein F, Deuschl G, Handwerker HO, Schattschneider J (2007) The motor system shows adaptive changes in complex regional pain syndrome. Brain : a journal of neurology 130 (Pt 10):2671–2687. doi: 10.1093/brain/awm131
  125. Maleki J, LeBel AA, Bennett GJ, Schwartzman RJ (2000) Patterns of spread in complex regional pain syndrome, type I (reflex sympathetic dystrophy). Pain 88(3):259–266PubMedCrossRefGoogle Scholar
  126. Maleki N, Becerra L, Brawn J, McEwen B, Burstein R, Borsook D (2012) Common hippocampal structural and functional changes in migraine. Brain Struct Funct. doi: 10.1007/s00429-012-0437-y
  127. Marinus J, Moseley GL, Birklein F, Baron R, Maihofner C, Kingery WS, van Hilten JJ (2011) Clinical features and pathophysiology of complex regional pain syndrome. Lancet Neurol 10(7):637–648. doi: 10.1016/S1474-4422(11)70106-5 PubMedCrossRefGoogle Scholar
  128. Messay B, Lim A, Marsland AL (2012) Current understanding of the bi-directional relationship of major depression with inflammation. Biology of Mood & Anxiety Disorders 2(1):4. doi: 10.1186/2045-5380-2-4 CrossRefGoogle Scholar
  129. Miller KL, Stagg CJ, Douaud G, Jbabdi S, Smith SM, Behrens TE, Jenkinson M, Chance SA, Esiri MM, Voets NL, Jenkinson N, Aziz TZ, Turner MR, Johansen-Berg H, McNab JA (2011) Diffusion imaging of whole, post-mortem human brains on a clinical MRI scanner. NeuroImage 57(1):167–181. doi: 10.1016/j.neuroimage.2011.03.070 PubMedCrossRefGoogle Scholar
  130. Milligan ED, Watkins LR (2009) Pathological and protective roles of glia in chronic pain. Nat Rev Neurosci 10(1):23–36. doi: 10.1038/nrn2533 PubMedCrossRefGoogle Scholar
  131. Moseley GL (2004) Why do people with complex regional pain syndrome take longer to recognize their affected hand? Neurology 62(12):2182–2186PubMedCrossRefGoogle Scholar
  132. Moulton EA, Keaser ML, Gullapalli RP, Maitra R, Greenspan JD (2006) Sex differences in the cerebral BOLD signal response to painful heat stimuli. Am J Physiol 291(2):R257–R267Google Scholar
  133. Mutso AA, Radzicki D, Baliki MN, Huang L, Banisadr G, Centeno MV, Radulovic J, Martina M, Miller RJ, Apkarian AV (2012) Abnormalities in hippocampal functioning with persistent pain. The Journal of Neuroscience: the Official Journal of the Society for Neuroscience 32(17):5747–5756. doi: 10.1523/JNEUROSCI.0587-12.2012 CrossRefGoogle Scholar
  134. O'Connor MF, Irwin MR, Wellisch DK (2009) When grief heats up: pro-inflammatory cytokines predict regional brain activation. NeuroImage 47(3):891–896. doi: 10.1016/j.neuroimage.2009.05.049 PubMedCrossRefGoogle Scholar
  135. Park JY, Ahn RS (2012) Hypothalamic-pituitary-adrenal axis function in patients with complex regional pain syndrome type 1. Psychoneuroendocrinology 37(9):1557–1568. doi: 10.1016/j.psyneuen.2012.02.016 PubMedCrossRefGoogle Scholar
  136. Paulson PE, Minoshima S, Morrow TJ, Casey KL (1998) Gender differences in pain perception and patterns of cerebral activation during noxious heat stimulation in humans. Pain 76(1–2):223–229PubMedCrossRefGoogle Scholar
  137. Pavlov VA, Tracey KJ (2006) Controlling inflammation: the cholinergic anti-inflammatory pathway. Biochem Soc Trans 34(Pt 6):1037–1040. doi: 10.1042/BST0341037 PubMedGoogle Scholar
  138. Peltz E, Seifert F, Lanz S, Muller R, Maihofner C (2011) Impaired hand size estimation in CRPS. The Journal of Pain: Official Journal of the American Pain Society 12(10):1095–1101. doi: 10.1016/j.jpain.2011.05.001 CrossRefGoogle Scholar
  139. Pleger B, Ragert P, Schwenkreis P, Forster AF, Wilimzig C, Dinse H, Nicolas V, Maier C, Tegenthoff M (2006) Patterns of cortical reorganization parallel impaired tactile discrimination and pain intensity in complex regional pain syndrome. NeuroImage 32 (2):503–510. doi: 10.1016/j.neuroimage.2006.03.045
  140. Polimeni JR, Fischl B, Greve DN, Wald LL (2010) Laminar analysis of 7T BOLD using an imposed spatial activation pattern in human V1. NeuroImage 52(4):1334–1346. doi: 10.1016/j.neuroimage.2010.05.005 PubMedCrossRefGoogle Scholar
  141. Raghavendra V, Tanga FY, DeLeo JA (2004) Complete Freunds adjuvant-induced peripheral inflammation evokes glial activation and proinflammatory cytokine expression in the CNS. Eur J Neurosci 20(2):467–473. doi: 10.1111/j.1460-9568.2004.03514.x PubMedCrossRefGoogle Scholar
  142. Reinersmann A, Haarmeyer GS, Blankenburg M, Frettloh J, Krumova EK, Ocklenburg S, Maier C (2010) Left is where the L is right. Significantly delayed reaction time in limb laterality recognition in both CRPS and phantom limb pain patients. Neurosci Lett 486(3):240–245. doi: 10.1016/j.neulet.2010.09.062 PubMedCrossRefGoogle Scholar
  143. Ren K, Dubner R (2010) Interactions between the immune and nervous systems in pain. Nature Medicine 16(11):1267–1276. doi: 10.1038/nm.2234 PubMedCrossRefGoogle Scholar
  144. Robinson G, Cohen H, Goebel A (2011) A case of complex regional pain syndrome with agnosia for object orientation. Pain 152(7):1674–1681. doi: 10.1016/j.pain.2011.02.010 PubMedCrossRefGoogle Scholar
  145. Rosenkranz MA, Busse WW, Johnstone T, Swenson CA, Crisafi GM, Jackson MM, Bosch JA, Sheridan JF, Davidson RJ (2005) Neural circuitry underlying the interaction between emotion and asthma symptom exacerbation. Proc Natl Acad Sci U S A 102(37):13319–13324. doi: 10.1073/pnas.0504365102 PubMedCrossRefGoogle Scholar
  146. Rosenkranz MA, Busse WW, Sheridan JF, Crisafi GM, Davidson RJ (2012) Are there neurophenotypes for asthma? Functional brain imaging of the interaction between emotion and inflammation in asthma. PLoS One 7(8):e40921. doi: 10.1371/journal.pone.0040921 PubMedCrossRefGoogle Scholar
  147. Saab CY, Hains BC (2009) Remote neuroimmune signaling: a long-range mechanism of nociceptive network plasticity. Trends Neurosci 32(2):110–117. doi: 10.1016/j.tins.2008.11.004 PubMedCrossRefGoogle Scholar
  148. Santillo AF, Gambini JP, Lannfelt L, Langstrom B, Ulla-Marja L, Kilander L, Engler H (2011) In vivo imaging of astrocytosis in Alzheimer's disease: an (1)(1)C-L-deuteriodeprenyl and PIB PET study. Eur J Nucl Med Mol Imaging 38(12):2202–2208. doi: 10.1007/s00259-011-1895-9 PubMedCrossRefGoogle Scholar
  149. Schinkel C, Gaertner A, Zaspel J, Zedler S, Faist E, Schuermann M (2006) Inflammatory mediators are altered in the acute phase of posttraumatic complex regional pain syndrome. Clin J Pain 22(3):235–239. doi: 10.1097/01.ajp.0000169669.70523.f0 PubMedCrossRefGoogle Scholar
  150. Schinkel C, Scherens A, Koller M, Roellecke G, Muhr G, Maier C (2009) Systemic inflammatory mediators in post-traumatic complex regional pain syndrome (CRPS I) - longitudinal investigations and differences to control groups. Eur J Med Res 14(3):130–135PubMedCrossRefGoogle Scholar
  151. Schneider P, Weber-Fahr W, Schweinfurth N, Ho YJ, Sartorius A, Spanagel R, Pawlak CR (2012) Central metabolite changes and activation of microglia after peripheral interleukin-2 challenge. Brain, Behavior, and Immunity 26(2):277–283. doi: 10.1016/j.bbi.2011.09.011 PubMedCrossRefGoogle Scholar
  152. Schreiber KL, Beitz AJ, Wilcox GL (2008) Activation of spinal microglia in a murine model of peripheral inflammation-induced, long-lasting contralateral allodynia. Neurosci Lett 440(1):63–67. doi: 10.1016/j.neulet.2008.05.044 PubMedCrossRefGoogle Scholar
  153. Schwartzman RJ, Erwin KL, Alexander GM (2009a) The natural history of complex regional pain syndrome. Clin J Pain 25(4):273–280. doi: 10.1097/AJP.0b013e31818ecea5 PubMedCrossRefGoogle Scholar
  154. Schwartzman RJ, Patel M, Grothusen JR, Alexander GM (2009b) Efficacy of 5-day continuous lidocaine infusion for the treatment of refractory complex regional pain syndrome. Pain Med 10(2):401–412. doi: 10.1111/j.1526-4637.2009.00573.x PubMedCrossRefGoogle Scholar
  155. Seifert F, Kiefer G, DeCol R, Schmelz M, Maihofner C (2009) Differential endogenous pain modulation in complex-regional pain syndrome. Brain: a Journal of Neurology 132(Pt 3):788–800. doi: 10.1093/brain/awn346 CrossRefGoogle Scholar
  156. Shackman AJ, Salomons TV, Slagter HA, Fox AS, Winter JJ, Davidson RJ (2011) The integration of negative affect, pain and cognitive control in the cingulate cortex. Nat Rev Neurosci 12(3):154–167PubMedCrossRefGoogle Scholar
  157. Sharma A, Agarwal S, Broatch J, Raja SN (2009) A web-based cross-sectional epidemiological survey of complex regional pain syndrome. Reg Anesth Pain Med 34(2):110–115. doi: 10.1097/AAP.0b013e3181958f90 PubMedCrossRefGoogle Scholar
  158. Skaper SD, Giusti P, Facci L (2012) Microglia and mast cells: two tracks on the road to neuroinflammation. FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology 26(8):3103–3117. doi: 10.1096/fj.11-197194 CrossRefGoogle Scholar
  159. Slavich GM, Way BM, Eisenberger NI, Taylor SE (2010) Neural sensitivity to social rejection is associated with inflammatory responses to social stress. Proc Natl Acad Sci U S A 107(33):14817–14822. doi: 10.1073/pnas.1009164107 PubMedCrossRefGoogle Scholar
  160. Smith TO (2005) How effective is physiotherapy in the treatment of complex regional pain syndrome type I? A review of the literature. Musculoskeletal Care 3(4):181–200. doi: 10.1002/msc.9 PubMedCrossRefGoogle Scholar
  161. Straube T, Schmidt S, Weiss T, Mentzel HJ, Miltner WH (2009) Sex differences in brain activation to anticipated and experienced pain in the medial prefrontal cortex. Hum Brain Mapp 30(2):689–698PubMedCrossRefGoogle Scholar
  162. Strong JA, Xie W, Coyle DE, Zhang JM (2012) Microarray analysis of rat sensory Ganglia after local inflammation implicates novel cytokines in pain. PLoS One 7(7):e40779. doi: 10.1371/journal.pone.0040779 PubMedCrossRefGoogle Scholar
  163. Szabo I, Chen XH, Xin L, Adler MW, Howard OM, Oppenheim JJ, Rogers TJ (2002) Heterologous desensitization of opioid receptors by chemokines inhibits chemotaxis and enhances the perception of pain. Proc Natl Acad Sci U S A 99(16):10276–10281. doi: 10.1073/pnas.102327699 PubMedCrossRefGoogle Scholar
  164. Takeda K, Muramatsu M, Chikuma T, Kato T (2009) Effect of memantine on the levels of neuropeptides and microglial cells in the brain regions of rats with neuropathic pain. J Mol Neurosci 39(3):380–390. doi: 10.1007/s12031-009-9224-5 PubMedCrossRefGoogle Scholar
  165. Tal M (1999) A role for inflammation in chronic pain. Curr Rev Pain 3(6):440–446PubMedCrossRefGoogle Scholar
  166. Thacker MA, Clark AK, Bishop T, Grist J, Yip PK, Moon LD, Thompson SW, Marchand F, McMahon SB (2009) CCL2 is a key mediator of microglia activation in neuropathic pain states. European Journal of Pain 13(3):263–272. doi: 10.1016/j.ejpain.2008.04.017 PubMedCrossRefGoogle Scholar
  167. Tracey KJ (2007) Physiology and immunology of the cholinergic antiinflammatory pathway. J Clin Invest 117(2):289–296. doi: 10.1172/JCI30555 PubMedCrossRefGoogle Scholar
  168. Uceyler N, Eberle T, Rolke R, Birklein F, Sommer C (2007) Differential expression patterns of cytokines in complex regional pain syndrome. Pain 132(1–2):195–205. doi: 10.1016/j.pain.2007.07.031 PubMedCrossRefGoogle Scholar
  169. Vallejo R, Tilley DM, Vogel L, Benyamin R (2010) The role of glia and the immune system in the development and maintenance of neuropathic pain. Pain Practice: the Official Journal of World Institute of Pain 10(3):167–184. doi: 10.1111/j.1533-2500.2010.00367.x CrossRefGoogle Scholar
  170. van de Beek WJ, Remarque EJ, Westendorp RG, van Hilten JJ (2001) Innate cytokine profile in patients with complex regional pain syndrome is normal. Pain 91(3):259–261PubMedCrossRefGoogle Scholar
  171. van de Meent H, Oerlemans M, Bruggeman A, Klomp F, van Dongen R, Oostendorp R, Frolke JP (2011) Safety of "pain exposure" physical therapy in patients with complex regional pain syndrome type 1. Pain 152(6):1431–1438. doi: 10.1016/j.pain.2011.02.032 PubMedCrossRefGoogle Scholar
  172. van de Vusse AC, Stomp-van den Berg SG, Kessels AH, Weber WE (2004) Randomised controlled trial of gabapentin in Complex Regional Pain Syndrome type 1 [ISRCTN84121379]. BMC Neurol 4:13. doi: 10.1186/1471-2377-4-13 PubMedCrossRefGoogle Scholar
  173. van Rijn MA, Marinus J, Putter H, Bosselaar SR, Moseley GL, van Hilten JJ (2011) Spreading of complex regional pain syndrome: not a random process. Journal of Neural Transmission 118(9):1301–1309. doi: 10.1007/s00702-011-0601-1 PubMedCrossRefGoogle Scholar
  174. Vega-Avelaira D, McKelvey R, Hathway G, Fitzgerald M (2012) The emergence of adolescent onset pain hypersensitivity following neonatal nerve injury. Molecular Pain 8(1):30. doi: 10.1186/1744-8069-8-30 PubMedCrossRefGoogle Scholar
  175. Viscomi MT, Florenzano F, Latini L, Molinari M (2009) Remote cell death in the cerebellar system. Cerebellum (London, England) 8(3):184–191. doi: 10.1007/s12311-009-0107-7 CrossRefGoogle Scholar
  176. Vlaeyen JW, Linton SJ (2012) Fear-avoidance model of chronic musculoskeletal pain: 12 years on. Pain 153(6):1144–1147. doi: 10.1016/j.pain.2011.12.009 PubMedCrossRefGoogle Scholar
  177. Walsh NP, Gleeson M, Shephard RJ, Woods JA, Bishop NC, Fleshner M, Green C, Pedersen BK, Hoffman-Goetz L, Rogers CJ, Northoff H, Abbasi A, Simon P (2011) Position statement. Part one: Immune function and exercise. Exerc Immunol Rev 17:6–63PubMedGoogle Scholar
  178. Wang H, Sun H, Della Penna K, Benz RJ, Xu J, Gerhold DL, Holder DJ, Koblan KS (2002) Chronic neuropathic pain is accompanied by global changes in gene expression and shares pathobiology with neurodegenerative diseases. Neuroscience 114(3):529–546PubMedCrossRefGoogle Scholar
  179. Watkins LR, Milligan ED, Maier SF (2001) Glial activation: a driving force for pathological pain. Trends Neurosci 24(8):450–455PubMedCrossRefGoogle Scholar
  180. Watts D, Kremer MJ (2011) Complex regional pain syndrome: a review of diagnostics, pathophysiologic mechanisms, and treatment implications for certified registered nurse anesthetists. Aana J 79(6):505–510PubMedGoogle Scholar
  181. Woolf CJ (2011) Central sensitization: implications for the diagnosis and treatment of pain. Pain 152(3 Suppl):S2–S15. doi: 10.1016/j.pain.2010.09.030 PubMedCrossRefGoogle Scholar
  182. Wright JL, Merchant RE (1992) Histopathological effects of intracerebral injections of human recombinant tumor necrosis factor-alpha in the rat. Acta Neuropathol 85(1):93–100PubMedCrossRefGoogle Scholar
  183. Yabuuchi K, Maruta E, Minami M, Satoh M (1996) Induction of interleukin-1 beta mRNA in the hypothalamus following subcutaneous injections of formalin into the rat hind paws. Neurosci Lett 207(2):109–112PubMedCrossRefGoogle Scholar
  184. Yoon SY, Patel D, Dougherty PM (2012) Minocycline blocks lipopolysaccharide induced hyperalgesia by suppression of microglia but not astrocytes. Neuroscience. doi: 10.1016/j.neuroscience.2012.06.024
  185. Zhang H, Yoon SY, Dougherty PM (2012) Evidence that spinal astrocytes but not microglia contribute to the pathogenesis of paclitaxel-induced painful neuropathy. The Journal of Pain: Official Journal of the American Pain Society. doi: 10.1016/j.jpain.2011.12.002
  186. Zhuo M, Wu G, Wu LJ (2011) Neuronal and microglial mechanisms of neuropathic pain. Mol Brain 4:31. doi: 10.1186/1756-6606-4-31 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  1. 1.P.A.I.N. Group, Departments Anesthesiology, Perioperative and Pain Medicine and RadiologyBoston Children’s Hospital, Harvard Medical SchoolBostonUSA

Personalised recommendations