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  • Review Article
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Pain in ankylosing spondylitis: a neuro-immune collaboration

Nature Reviews Rheumatology volume 13, pages 410–420 (2017)Cite this article

Subjects

Key Points

  • Inflammatory mediators can directly and indirectly induce pain

  • Pain in ankylosing spondylitis (AS) is not strictly inflammatory and involves a neuropathic component

  • Brain abnormalities that underlie chronic pain can be detected in AS

  • An individual's sex affects the degree of neuro-immune involvement in pain, and sex differences in pain perception might contribute to sexual dimorphisms in AS presentation

  • Pain in AS might involve distinct molecular underpinnings and so strategies to treat pain might differ from those that target inflammation

Abstract

Clinicians have commonly differentiated chronic back pain into two broad subsets: namely, non-inflammatory (or mechanical) back pain and inflammatory back pain. As the terminology suggests, the latter category, in which ankylosing spondylitis (AS) is prominent, presupposes a close link between pain and inflammation. Advances in research into the genetics and immunology of AS have improved our understanding of the inflammatory processes involved in this disease, and have led to the development of potent anti-inflammatory biologic therapeutic agents. However, evidence from clinical trials and from biomarker and imaging studies in patients with AS indicate that pain and inflammation are not always correlated. Thus, the assumption that pain in AS is a reliable surrogate marker for inflammation might be an over-simplification. This Review provides an overview of current concepts relating to neuro-immune interactions in AS and summarizes research that reveals an increasingly complex interplay between the activation of the immune system and pain pathways in the nervous system. The different types of pain experienced by patients with AS, insights from brain imaging studies, neurological mechanisms of pain, sex bias in pain and how the immune system can modify pain in patients with AS are also discussed.

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Figure 1: Pain in ankylosing spondylitis.
Figure 2: The pathways that underlie neuropathic pain processing in female and male mice.
Figure 3: Pain pathways in health and during chronic inflammatory conditions.

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References

  1. Costello, M.-E. et al. Brief report: intestinal dysbiosis in ankylosing spondylitis. Arthritis Rheumatol. 67, 686–691 (2015).

    Article  PubMed  Google Scholar 

  2. Tsui, F. W., Tsui, H. W., Akram, A., Haroon, N. & Inman, R. D. The genetic basis of ankylosing spondylitis: new insights into disease pathogenesis. Appl. Clin. Genet. 7, 105–115 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Brown, M. A., Kenna, T. & Wordsworth, B. P. Genetics of ankylosing spondylitis — insights into pathogenesis. Nat. Rev. Rheumatol. 12, 81–91 (2015).

    Article  CAS  PubMed  Google Scholar 

  4. Cortes, A. et al. Major histocompatibility complex associations of ankylosing spondylitis are complex and involve further epistasis with ERAP1. Nat. Commun. 6, 7146 (2015).

    Article  PubMed  Google Scholar 

  5. Ranganathan, V., Gracey, E., Brown, M. A., Inman, R. D. & Haroon, N. Pathogenesis of ankylosing spondylitis — recent advances and future directions. Nat. Rev. Rheumatol. 13, 359–367 (2017).

    Article  CAS  PubMed  Google Scholar 

  6. Jethwa, H. & Bowness, P. The interleukin (IL)-23/IL-17 axis in ankylosing spondylitis: new advances and potentials for treatment. Clin. Exp. Immunol. 183, 30–36 (2016).

    Article  CAS  PubMed  Google Scholar 

  7. Taurog, J. D., Chhabra, A. & Colbert, R. A. Ankylosing spondylitis and axial spondyloarthritis. N. Engl. J. Med. 374, 2563–2574 (2016).

    Article  PubMed  Google Scholar 

  8. Sieper, J. & Poddubnyy, D. New evidence on the management of spondyloarthritis. Nat. Rev. Rheumatol. 12, 282–295 (2016).

    Article  CAS  PubMed  Google Scholar 

  9. Gracey, E. et al. Sexual dimorphism in the Th17 signature of ankylosing spondylitis. Arthritis Rheumatol. 68, 679–689 (2016).

    Article  CAS  PubMed  Google Scholar 

  10. Blachier, M. et al. Factors associated with radiographic lesions in early axial spondyloarthritis. Results from the DESIR cohort. Rheumatology (Oxford) 52, 1686–1693 (2013).

    Article  Google Scholar 

  11. Sieper, J. et al. Sarilumab for the treatment of ankylosing spondylitis: results of a phase II, randomised, double-blind, placebo-controlled study (ALIGN). Ann. Rheum. Dis. 74, 1051–1057 (2015).

    Article  CAS  PubMed  Google Scholar 

  12. Sieper, J., Porter-Brown, B., Thompson, L., Harari, O. & Dougados, M. Assessment of short-term symptomatic efficacy of tocilizumab in ankylosing spondylitis: results of randomised, placebo-controlled trials. Ann. Rheum. Dis. 73, 95–100 (2014).

    Article  CAS  PubMed  Google Scholar 

  13. Ji, R.-R., Chamessian, A. & Zhang, Y.-Q. Pain regulation by non-neuronal cells and inflammation. Science 354, 572–577 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Pinho-Ribeiro, F. A., Verri, W. A. & Chiu, I. M. Nociceptor sensory neuron–immune interactions in pain and inflammation. Trends Immunol. 38, 5–19 (2017).

    Article  CAS  PubMed  Google Scholar 

  15. Wu, Q., Inman, R. D. & Davis, K. D. Neuropathic pain in ankylosing spondylitis: a psychophysics and brain imaging study. Arthritis Rheum. 65, 1494–1503 (2013).

    Article  PubMed  Google Scholar 

  16. Braun, J. & Inman, R. Clinical significance of inflammatory back pain for diagnosis and screening of patients with axial spondyloarthritis. Ann. Rheum. Dis. 69, 1264–1268 (2010).

    Article  PubMed  Google Scholar 

  17. Nhan, D. T. & Caplan, L. Patient-reported outcomes in axial spondyloarthritis. Rheum. Dis. Clin. North Am. 42, 285–299 (2016).

    Article  PubMed  Google Scholar 

  18. Chen, C., Zhang, X., Xiao, L., Zhang, X. & Ma, X. Comparative effectiveness of biologic therapy regimens for ankylosing spondylitis: a systematic review and a network meta-analysis. Medicine (Baltimore) 95, e3060 (2016).

    Article  Google Scholar 

  19. Dagfinrud, H., Vollestad, N. K., Loge, J. H., Kvien, T. K. & Mengshoel, A. M. Fatigue in patients with ankylosing spondylitis: a comparison with the general population and associations with clinical and self-reported measures. Arthritis Rheum. 53, 5–11 (2005).

    Article  PubMed  Google Scholar 

  20. Brophy, S. et al. Fatigue in ankylosing spondylitis: treatment should focus on pain management. Semin. Arthritis Rheum. 42, 361–367 (2013).

    Article  PubMed  Google Scholar 

  21. Dernis-Labous, E., Messow, M. & Dougados, M. Assessment of fatigue in the management of patients with ankylosing spondylitis. Rheumatology (Oxford) 42, 1523–1528 (2003).

    Article  CAS  Google Scholar 

  22. Wu, Q., Inman, R. D. & Davis, K. D. Tumor necrosis factor inhibitor therapy in ankylosing spondylitis: differential effects on pain and fatigue and brain correlates. Pain 156, 297–304 (2015).

    Article  CAS  PubMed  Google Scholar 

  23. Bedaiwi, M. et al. Fatigue in ankylosing spondylitis and nonradiographic axial spondyloarthritis: analysis from a longitudinal observation cohort. J. Rheumatol. 42, 2354–2360 (2015).

    Article  CAS  PubMed  Google Scholar 

  24. Christie, A., Dagfinrud, H., Mowinckel, P. & Hagen, K. B. Variation in fatigue may be poorly explained by pain: results from a longitudinal, exploratory study. Rheumatol. Int. 36, 279–282 (2016).

    Article  PubMed  Google Scholar 

  25. Wu, Q., Inman, R. D. & Davis, K. D. Fatigue in ankylosing spondylitis is associated with the brain networks of sensory salience and attention. Arthritis Rheumatol. 66, 295–303 (2014).

    Article  PubMed  Google Scholar 

  26. Navarro- Compán, V. et al. Disease activity is longitudinally related to sacroiliac inflammation on MRI in male patients with axial spondyloarthritis: 2-years of the DESIR cohort. Ann. Rheum. Dis. 75, 874–878 (2016).

    Article  Google Scholar 

  27. Baraliakos, X. et al. Quantification of bone marrow edema by magnetic resonance imaging only marginally reflects clinical neck pain evaluation in rheumatoid arthritis and ankylosing spondylitis. J. Rheumatol. 43, 2131–2135 (2016).

    Article  CAS  PubMed  Google Scholar 

  28. Braun, J., Baraliakos, X., Hermann, K.-G. A., Xu, S. & Hsu, B. Serum C-reactive protein levels demonstrate predictive value for radiographic and magnetic resonance imaging outcomes in patients with active ankylosing spondylitis treated with golimumab. J. Rheumatol. 43, 1704–1712 (2016).

    Article  CAS  PubMed  Google Scholar 

  29. Wallis, D., Haroon, N., Ayearst, R., Carty, A. & Inman, R. D. Ankylosing spondylitis and nonradiographic axial spondyloarthritis: part of a common spectrum or distinct diseases? J. Rheumatol. 40, 2038–2041 (2013).

    Article  PubMed  Google Scholar 

  30. Wach, J., Letroublon, M.-C., Coury, F. & Tebib, J. G. Fibromyalgia in spondyloarthritis: effect on disease activity assessment in clinical practice. J. Rheumatol. 43, 2056–2063 (2016).

    Article  CAS  PubMed  Google Scholar 

  31. Bedaiwi, M. K. et al. Clinical efficacy of celecoxib compared to acetaminophen in chronic nonspecific low back pain: results of a randomized controlled trial. Arthritis Care Res. (Hoboken) 68, 845–852 (2016).

    Article  CAS  Google Scholar 

  32. Meesters, J. J. L. et al. The risk for depression in patients with ankylosing spondylitis: a population-based cohort study. Arthritis Res. Ther. 16, 418 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Van der Horst-Bruinsma, I. E., Zack, D. J., Szumski, A. & Koenig, A. S. Female patients with ankylosing spondylitis: analysis of the impact of gender across treatment studies. Ann. Rheum. Dis. 72, 1221–1224 (2013).

    Article  PubMed  Google Scholar 

  34. Lee, W. et al. Are there gender differences in severity of ankylosing spondylitis? Results from the PSOAS cohort. Ann. Rheum. Dis. 66, 633–638 (2007).

    Article  PubMed  Google Scholar 

  35. Karshikoff, B. et al. Modality and sex differences in pain sensitivity during human endotoxemia. Brain. Behav. Immun. 46, 35–43 (2015).

    Article  CAS  PubMed  Google Scholar 

  36. Dodds, K. N. et al. Glial contributions to visceral pain: implications for disease etiology and the female predominance of persistent pain. Transl Psychiatry 6, e888 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Mogil, J. S. & Chanda, M. L. The case for the inclusion of female subjects in basic science studies of pain. Pain 117, 1–5 (2005).

    Article  PubMed  Google Scholar 

  38. Rogachov, A. et al. Regional brain signal variability: a novel indicator of pain sensitivity and coping. Pain 157, 2483–2492 (2016).

    Article  PubMed  Google Scholar 

  39. Wang, G., Erpelding, N. & Davis, K. D. Sex differences in connectivity of the subgenual anterior cingulate cortex. Pain 155, 755–763 (2014).

    Article  PubMed  Google Scholar 

  40. Hashmi, J. A. & Davis, K. D. Deconstructing sex differences in pain sensitivity. Pain 155, 10–13 (2014).

    Article  PubMed  Google Scholar 

  41. Hashmi, J. A. & Davis, K. D. Women experience greater heat pain adaptation and habituation than men. Pain 145, 350–357 (2009).

    Article  PubMed  Google Scholar 

  42. Greenspan, J. D. et al. Studying sex and gender differences in pain and analgesia: a consensus report. Pain 132 (Suppl. 1), S26–S45 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  43. Sorge, R. E. et al. Different immune cells mediate mechanical pain hypersensitivity in male and female mice. Nat. Neurosci. 18, 1081–1083 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Sorge, R. E. et al. Spinal cord Toll-like receptor 4 mediates inflammatory and neuropathic hypersensitivity in male but not female mice. J. Neurosci. 31, 15450–15454 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Taves, S. et al. Spinal inhibition of p38 MAP kinase reduces inflammatory and neuropathic pain in male but not female mice: sex-dependent microglial signaling in the spinal cord. Brain. Behav. Immun. 55, 70–81 (2016).

    Article  CAS  PubMed  Google Scholar 

  46. Draleau, K. et al. Phenotypic identification of spinal cord-infiltrating CD4+ T lymphocytes in a murine model of neuropathic pain. J. Pain Relief Suppl. 3, 3 (2014).

    Google Scholar 

  47. Rosen, S., Ham, B. & Mogil, J. S. Sex differences in neuroimmunity and pain. J. Neurosci. Res. 95, 500–508 (2017).

    Article  CAS  PubMed  Google Scholar 

  48. Varkas, G. & Van den Bosch, F. NSAIDs in axial spondyloarthritis: to be continued...? Ann. Rheum. Dis. 75, 1423–1425 (2016).

    Article  CAS  PubMed  Google Scholar 

  49. Haroon, N., Kim, T.-H. & Inman, R. D. NSAIDs and radiographic progression in ankylosing spondylitis Bagging big game with small arms? Ann. Rheum. Dis. 71, 1593–1595 (2012).

    Article  PubMed  Google Scholar 

  50. Molto, A., Granger, B., Wendling, D., Dougados, M. & Gossec, L. Use of nonsteroidal anti-inflammatory drugs in early axial spondyloarthritis in daily practice: data from the DESIR cohort. Joint Bone Spine 84, 79–82 (2017).

    Article  CAS  PubMed  Google Scholar 

  51. Varkas, G. et al. Brief report: six-week treatment of axial spondyloarthritis patients with an optimal dose of nonsteroidal antiinflammatory drugs: early response to treatment in signal intensity on magnetic resonance imaging of the sacroiliac joints. Arthritis Rheumatol. 68, 672–678 (2016).

    Article  CAS  PubMed  Google Scholar 

  52. Sieper, J. & Poddubnyy, D. Axial spondyloarthritis. Lancet http://dx.doi.org/10.1016/S0140-6736(16)31591-4 (2017).

  53. Thompson, C., Davies, R. & Choy, E. Anti cytokine therapy in chronic inflammatory arthritis. Cytokine 86, 92–99 (2016).

    Article  CAS  PubMed  Google Scholar 

  54. Hess, A. et al. Blockade of TNF-α rapidly inhibits pain responses in the central nervous system. Proc. Natl Acad. Sci. USA 108, 3731–3736 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Haroon, N. et al. The impact of TNF-inhibitors on radiographic progression in ankylosing spondylitis. Arthritis Rheum. 65, 2645–2654 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Danve, A. & Deodhar, A. Treat to target in axial spondyloarthritis: what are the issues? Curr. Rheumatol. Rep. 19, 22 (2017).

    Article  PubMed  Google Scholar 

  57. Toussirot, É. Biologics in spondyloarthritis: TNFα inhibitors and other agents. Immunotherapy 7, 669–681 (2015).

    Article  CAS  PubMed  Google Scholar 

  58. Baeten, D. et al. Secukinumab, an interleukin-17A inhibitor, in ankylosing spondylitis. N. Engl. J. Med. 373, 2534–2548 (2015).

    Article  CAS  PubMed  Google Scholar 

  59. Sieper, J. New treatment targets for axial spondyloarthritis. Rheumatology (Oxford) 55 (Suppl. 2), ii38–ii42 (2016).

    Article  Google Scholar 

  60. Van der Heijde, D. et al. 2016 update of the ASAS-EULAR management recommendations for axial spondyloarthritis. Ann. Rheum. Dis. 76, 978–991 (2017).

    Article  PubMed  Google Scholar 

  61. Grace, P. M. et al. Morphine paradoxically prolongs neuropathic pain in rats by amplifying spinal NLRP3 inflammasome activation. Proc. Natl Acad. Sci. USA 113, E3441–E3450 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Kistner, K. et al. Systemic desensitization through TRPA1 channels by capsazepine and mustard oil — a novel strategy against inflammation and pain. Sci. Rep. 6, 28621 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Garrison, S. R. & Stucky, C. L. The dynamic TRPA1 channel: a suitable pharmacological pain target? Curr. Pharm. Biotechnol. 12, 1689–1697 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Trevisan, G. et al. TRPA1 mediates trigeminal neuropathic pain in mice downstream of monocytes/macrophages and oxidative stress. Brain 139, 1361–1377 (2016).

    Article  PubMed  Google Scholar 

  65. Kress, M. et al. MicroRNAs in nociceptive circuits as predictors of future clinical applications. Front. Mol. Neurosci. 6, 33 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Leinders, M., Üçeyler, N., Pritchard, R. A., Sommer, C. & Sorkin, L. S. Increased miR-132-3p expression is associated with chronic neuropathic pain. Exp. Neurol. 283, 276–286 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Malfait, A.-M. & Miller, R. J. Emerging targets for the management of osteoarthritis pain. Curr. Osteoporos. Rep. 14, 260–268 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  68. Siniscalco, D., Giordano, C., Rossi, F., Maione, S. & de Novellis, V. Role of neurotrophins in neuropathic pain. Curr. Neuropharmacol. 9, 523–529 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Seminowicz, D. A. et al. Effective treatment of chronic low back pain in humans reverses abnormal brain anatomy and function. J. Neurosci. 31, 7540–7550 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Kucyi, A. & Davis, K. D. The dynamic pain connectome. Trends Neurosci. 38, 86–95 (2015).

    Article  CAS  PubMed  Google Scholar 

  71. Hubbard, C. S. et al. Altered brain structure and function correlate with disease severity and pain catastrophizing in migraine patients. eNeuro 1, e20.14 (2014).

    Article  PubMed  Google Scholar 

  72. Mathur, V. A. et al. Altered cognition-related brain activity and interactions with acute pain in migraine. Neuroimage Clin. 7, 347–358 (2015).

    Google Scholar 

  73. Apkarian, A. V. The brain in chronic pain: clinical implications. Pain Manag. 1, 577–586 (2011).

    Article  PubMed  Google Scholar 

  74. Napadow, V. et al. Intrinsic brain connectivity in fibromyalgia is associated with chronic pain intensity. Arthritis Rheum. 62, 2545–2555 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Baliki, M. N., Geha, P. Y., Apkarian, A. V. & Chialvo, D. R. Beyond feeling: chronic pain hurts the brain, disrupting the default-mode network dynamics. J. Neurosci. 28, 1398–1403 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Seminowicz, D. A. & Davis, K. D. Pain enhances functional connectivity of a brain network evoked by performance of a cognitive task. J. Neurophysiol. 97, 3651–3659 (2007).

    Article  PubMed  Google Scholar 

  77. Davis, K. D. & Moayedi, M. Central mechanisms of pain revealed through functional and structural MRI. J. Neuroimmune Pharmacol. 8, 518–534 (2013).

    Article  PubMed  Google Scholar 

  78. Goswami, R., Anastakis, D. J., Katz, J. & Davis, K. D. A longitudinal study of pain, personality, and brain plasticity following peripheral nerve injury. Pain 157, 729–739 (2016).

    Article  PubMed  Google Scholar 

  79. DeSouza, D. D., Davis, K. D. & Hodaie, M. Reversal of insular and microstructural nerve abnormalities following effective surgical treatment for trigeminal neuralgia. Pain 156, 1112–1123 (2015).

    PubMed  Google Scholar 

  80. Cˇeko, M. et al. Partial recovery of abnormal insula and dorsolateral prefrontal connectivity to cognitive networks in chronic low back pain after treatment. Hum. Brain Mapp. 36, 2075–2092 (2015).

    Article  Google Scholar 

  81. Moayedi, M. et al. Contribution of chronic pain and neuroticism to abnormal forebrain gray matter in patients with temporomandibular disorder. Neuroimage 55, 277–286 (2011).

    Article  PubMed  Google Scholar 

  82. Moayedi, M. et al. White matter brain and trigeminal nerve abnormalities in temporomandibular disorder. Pain 153, 1467–1477 (2012).

    Article  PubMed  Google Scholar 

  83. Chen, J. Y.-W., Blankstein, U., Diamant, N. E. & Davis, K. D. White matter abnormalities in irritable bowel syndrome and relation to individual factors. Brain Res. 1392, 121–131 (2011).

    Article  CAS  PubMed  Google Scholar 

  84. Blankstein, U., Chen, J., Diamant, N. E. & Davis, K. D. Altered brain structure in irritable bowel syndrome: potential contributions of pre-existing and disease-driven factors. Gastroenterology 138, 1783–1789 (2010).

    Article  PubMed  Google Scholar 

  85. Kucyi, A. et al. Enhanced medial prefrontal-default mode network functional connectivity in chronic pain and its association with pain rumination. J. Neurosci. 34, 3969–3975 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Weissman-Fogel, I. et al. Abnormal cortical activity in patients with temporomandibular disorder evoked by cognitive and emotional tasks. Pain 152, 384–396 (2011).

    Article  CAS  PubMed  Google Scholar 

  87. Hemington, K. S., Wu, Q., Kucyi, A., Inman, R. D. & Davis, K. D. Abnormal cross-network functional connectivity in chronic pain and its association with clinical symptoms. Brain Struct. Funct. 221, 4203–4219 (2016).

    Article  CAS  PubMed  Google Scholar 

  88. Purves, D. et al. (ed.) Neuroscience 2nd edn. (Sinauer Associates, 2001).

    Google Scholar 

  89. Dubin, A. E. & Patapoutian, A. Nociceptors: the sensors of the pain pathway. J. Clin. Invest. 120, 3760–3772 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Gold, M. S. & Gebhart, G. F. Nociceptor sensitization in pain pathogenesis. Nat. Med. 16, 1248–1257 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Li, W.-W. et al. Substance P signaling controls mast cell activation, degranulation, and nociceptive sensitization in a rat fracture model of complex regional pain syndrome. Anesthesiology 116, 882–895 (2012).

    Article  CAS  PubMed  Google Scholar 

  92. Kim, C. F. & Moalem-Taylor, G. Interleukin-17 contributes to neuroinflammation and neuropathic pain following peripheral nerve injury in mice. J. Pain 12, 370–383 (2011).

    Article  CAS  PubMed  Google Scholar 

  93. Davis, K. D., Meyer, R. A. & Campbell, J. N. Chemosensitivity and sensitization of nociceptive afferents that innervate the hairy skin of monkey. J. Neurophysiol. 69, 1071–1081 (1993).

    Article  CAS  PubMed  Google Scholar 

  94. Schaible, H. G. & Grubb, B. D. Afferent and spinal mechanisms of joint pain. Pain 55, 5–54 (1993).

    Article  CAS  PubMed  Google Scholar 

  95. Schaible, H.-G. Nociceptive neurons detect cytokines in arthritis. Arthritis Res. Ther. 16, 470 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Cervero, F. & Laird, J. M. A. Understanding the signaling and transmission of visceral nociceptive events. J. Neurobiol. 61, 45–54 (2004).

    Article  CAS  PubMed  Google Scholar 

  97. Felson, D. T. The sources of pain in knee osteoarthritis. Curr. Opin. Rheumatol. 17, 624–628 (2005).

    Article  PubMed  Google Scholar 

  98. Mantyh, P. W. The neurobiology of skeletal pain. Eur. J. Neurosci. 39, 508–519 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  99. Cavanaugh, J. M., Lu, Y., Chen, C. & Kallakuri, S. Pain generation in lumbar and cervical facet joints. J. Bone Joint Surg. Am. 88 (Suppl. 2), 63–67 (2006).

    PubMed  Google Scholar 

  100. Szadek, K., Hoogland, P., Zuurmond, W., Delange, J. & Perez, R. Nociceptive nerve fibers in the sacroiliac joint in humans. Reg. Anesth. Pain Med. 33, 36–43 (2008).

    Article  PubMed  Google Scholar 

  101. Palsson, T. S. & Graven-Nielsen, T. Experimental pelvic pain facilitates pain provocation tests and causes regional hyperalgesia. Pain 153, 2233–2240 (2012).

    Article  PubMed  Google Scholar 

  102. Rio, E. et al. The pain of tendinopathy: physiological or pathophysiological? Sport. Med. 44, 9–23 (2014).

    Article  Google Scholar 

  103. McCleskey, E. W. & Gold, M. S. Ion channels of nociception. Annu. Rev. Physiol. 61, 835–856 (1999).

    Article  CAS  PubMed  Google Scholar 

  104. Benarroch, E. E. Ion channels in nociceptors: recent developments. Neurology 84, 1153–1164 (2015).

    Article  PubMed  Google Scholar 

  105. Moore, C. et al. UVB radiation generates sunburn pain and affects skin by activating epidermal TRPV4 ion channels and triggering endothelin-1 signaling. Proc. Natl Acad. Sci. USA 110, E3225–E3234 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  106. Khodorova, A., Montmayeur, J.-P. & Strichartz, G. Endothelin receptors and pain. J. Pain 10, 4–28 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Ranade, S. S. et al. Piezo2 is the major transducer of mechanical forces for touch sensation in mice. Nature 516, 121–125 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Cekic, C. & Linden, J. Purinergic regulation of the immune system. Nat. Rev. Immunol. 16, 177–192 (2016).

    Article  CAS  PubMed  Google Scholar 

  109. Chiu, I. M., von Hehn, C. A. & Woolf, C. J. Neurogenic inflammation and the peripheral nervous system in host defense and immunopathology. Nat. Neurosci. 15, 1063–1067 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Nicotra, L., Loram, L. C., Watkins, L. R. & Hutchinson, M. R. Toll-like receptors in chronic pain. Exp. Neurol. 234, 316–329 (2012).

    Article  CAS  PubMed  Google Scholar 

  111. Meseguer, V. et al. TRPA1 channels mediate acute neurogenic inflammation and pain produced by bacterial endotoxins. Nat. Commun. 5, 783–801 (2014).

    Article  CAS  Google Scholar 

  112. Liu, T., Xu, Z.-Z., Park, C.-K., Berta, T. & Ji, R.-R. Toll-like receptor 7 mediates pruritus. Nat. Neurosci. 13, 1460–1462 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Xu, Z.-Z. et al. Inhibition of mechanical allodynia in neuropathic pain by TLR5-mediated A-fiber blockade. Nat. Med. 21, 1326–1331 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Das, N. et al. HMGB1 activates proinflammatory signaling via TLR5 leading to allodynia. Cell Rep. 17, 1128–1140 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Parsadaniantz, S. M., Rivat, C., Rostène, W. & Goazigo, A. R.-L. Opioid and chemokine receptor crosstalk: a promising target for pain therapy? Nat. Rev. Neurosci. 16, 69–78 (2015).

    Article  CAS  Google Scholar 

  116. Zhou, Y.-Q. et al. Interleukin-6: an emerging regulator of pathological pain. J. Neuroinflamm. 13, 141 (2016).

    Article  CAS  Google Scholar 

  117. Üçeyler, N., Riediger, N., Kafke, W. & Sommer, C. Differential gene expression of cytokines and neurotrophic factors in nerve and skin of patients with peripheral neuropathies. J. Neurol. 262, 203–212 (2015).

    Article  CAS  PubMed  Google Scholar 

  118. Eskander, M. A. et al. Persistent nociception triggered by nerve growth factor (NGF) is mediated by TRPV1 and oxidative mechanisms. J. Neurosci. 35, 8593–8603 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Grace, P. M., Hutchinson, M. R., Maier, S. F. & Watkins, L. R. Pathological pain and the neuroimmune interface. Nat. Rev. Immunol. 14, 217–231 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Vincent, L. et al. Mast cell activation contributes to sickle cell pathobiology and pain in mice. Blood 122, 1853–1862 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Vicuña, L. et al. The serine protease inhibitor SerpinA3N attenuates neuropathic pain by inhibiting T cell–derived leukocyte elastase. Nat. Med. 21, 518–523 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Wu, X.-B. et al. CXCL13/CXCR5 enhances sodium channel Nav1.8 current density via p38 MAP kinase in primary sensory neurons following inflammatory pain. Sci. Rep. 6, 34836 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Latremoliere, A. & Woolf, C. J. Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J. Pain 10, 895–926 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  124. Meeus, M. & Nijs, J. Central sensitization: a biopsychosocial explanation for chronic widespread pain in patients with fibromyalgia and chronic fatigue syndrome. Clin. Rheumatol. 26, 465–473 (2007).

    Article  PubMed  Google Scholar 

  125. Porreca, F., Ossipov, M. H. & Gebhart, G. F. Chronic pain and medullary descending facilitation. Trends Neurosci. 25, 319–325 (2002).

    Article  CAS  PubMed  Google Scholar 

  126. Dickenson, A. H., Chapman, V. & Green, G. M. The pharmacology of excitatory and inhibitory amino acid-mediated events in the transmission and modulation of pain in the spinal cord. Gen. Pharmacol. Vasc. Syst. 28, 633–638 (1997).

    Article  CAS  Google Scholar 

  127. Tsuda, M. et al. P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury. Nature 424, 778–783 (2003).

    Article  CAS  PubMed  Google Scholar 

  128. Coull, J. A. M. et al. BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 438, 1017–1021 (2005).

    Article  CAS  PubMed  Google Scholar 

  129. Beggs, S., Trang, T. & Salter, M. W. P2X4R+ microglia drive neuropathic pain. Nat. Neurosci. 15, 1068–1073 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Trang, T., Beggs, S., Wan, X. & Salter, M. W. P2X4-receptor-mediated synthesis and release of brain-derived neurotrophic factor in microglia is dependent on calcium and p38-mitogen-activated protein kinase activation. J. Neurosci. 29, 3518–3528 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  132. Liu, X. J. et al. Treatment of inflammatory and neuropathic pain by uncoupling Src from the NMDA receptor complex. Nat. Med. 14, 1325–1332 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Salter, M. W. & Kalia, L. V. Src kinases: a hub for NMDA receptor regulation. Nat. Rev. Neurosci. 5, 317–328 (2004).

    Article  CAS  PubMed  Google Scholar 

  134. Keller, A. F., Beggs, S., Salter, M. W. & De Koninck, Y. Transformation of the output of spinal lamina I neurons after nerve injury and microglia stimulation underlying neuropathic pain. Mol. Pain 3, 27 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Chavan, S. S. & Tracey, K. J. Essential neuroscience in immunology. J. Immunol. 198, 3389–3397 (2017).

    Article  CAS  PubMed  Google Scholar 

  136. Shen, H., Goodall, J. C. & Hill Gaston, J. S. Frequency and phenotype of peripheral blood Th17 cells in ankylosing spondylitis and rheumatoid arthritis. Arthritis Rheum. 60, 1647–1656 (2009).

    Article  CAS  PubMed  Google Scholar 

  137. Smolen, J. S. et al. Treating spondyloarthritis, including ankylosing spondylitis and psoriatic arthritis, to target: recommendations of an international task force. Ann. Rheum. Dis. 73, 6–16 (2014).

    Article  PubMed  Google Scholar 

  138. Task Force on Taxonomy of the International Association for the Study of Pain. Classification of chronic pain. Descriptions of chronic pain syndromes and definitions of pain terms. IASP https://www.iasp-pain.org/files/Content/ContentFolders/Publications2/FreeBooks/Classification-of-Chronic-Pain.pdf (1994).

  139. International Association for the Study of Pain. IASP taxonomy. IASP http://www.iasp-pain.org/Taxonomy (2002).

  140. Williams, A. C. & Craig, K. D. Updating the definition of pain. Pain 157, 2420–2423 (2016).

    Article  PubMed  Google Scholar 

  141. Bonica, J. (ed.) The Management of Pain (Lea & Febiger, 1953).

    Google Scholar 

  142. Treede, R.-D. et al. A classification of chronic pain for ICD-11. Pain 156, 1 (2015).

    Article  Google Scholar 

  143. Freynhagen, R., Tölle, T. R., Gockel, U. & Baron, R. The painDETECT project — far more than a screening tool on neuropathic pain. Curr. Med. Res. Opin. 32, 1033–1057 (2016).

    Article  PubMed  Google Scholar 

  144. Hawker, G. A., Mian, S., Kendzerska, T. & French, M. Measures of adult pain: Visual Analog Scale for Pain (VAS Pain), Numeric Rating Scale for Pain (NRS Pain), McGill Pain Questionnaire (MPQ), Short-Form McGill Pain Questionnaire (SF-MPQ), Chronic Pain Grade Scale (CPGS), Short Form-36 Bodily Pain Scale (SF-36 BPS), and Measure of Intermittent and Constant Osteoarthritis Pain (ICOAP). Arthritis Care Res. (Hoboken) 63, S240–S252 (2011).

    Article  Google Scholar 

  145. Melzack, R. The McGill Pain Questionnaire: major properties and scoring methods. Pain 1, 277–299 (1975).

    Article  CAS  PubMed  Google Scholar 

  146. Garrett, S. et al. A new approach to defining disease status in ankylosing spondylitis: the Bath Ankylosing Spondylitis Disease Activity Index. J. Rheumatol. 21, 2286–2291 (1994).

    CAS  PubMed  Google Scholar 

  147. Yarnitsky, D., Granot, M. & Granovsky, Y. Pain modulation profile and pain therapy: between pro- and antinociception. Pain 155, 663–665 (2014).

    Article  PubMed  Google Scholar 

  148. Tjølsen, A., Lund, A., Berge, O. G. & Hole, K. An improved method for tail-flick testing with adjustment for tail-skin temperature. J. Neurosci. Methods 26, 259–265 (1989).

    Article  PubMed  Google Scholar 

  149. Hargreaves, K., Dubner, R., Brown, F., Flores, C. & Joris, J. A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain 32, 77–88 (1988).

    Article  CAS  PubMed  Google Scholar 

  150. Chaplan, S. R., Bach, F. W., Pogrel, J. W., Chung, J. M. & Yaksh, T. L. Quantitative assessment of tactile allodynia in the rat paw. J. Neurosci. Methods 53, 55–63 (1994).

    Article  CAS  PubMed  Google Scholar 

  151. Sotocinal, S. G. et al. The Rat Grimace Scale: a partially automated method for quantifying pain in the laboratory rat via facial expressions. Mol. Pain 7, 55 (2011).

    PubMed  PubMed Central  Google Scholar 

  152. Sufka, K. J. Conditioned place preference paradigm: a novel approach for analgesic drug assessment against chronic pain. Pain 58, 355–366 (1994).

    Article  CAS  PubMed  Google Scholar 

  153. Daou, I. et al. Remote optogenetic activation and sensitization of pain pathways in freely moving mice. J. Neurosci. 33, 18631–18640 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Keystone, E. C., Schorlemmer, H. U., Pope, C. & Allison, A. C. Zymosan-induced arthritis: a model of chronic proliferative arthritis following activation of the alternative pathway of complement. Arthritis Rheum. 20, 1396–1401 (1977).

    Article  CAS  PubMed  Google Scholar 

  155. Courteix, C., Eschalier, A. & Lavarenne, J. Streptozocin-induced diabetic rats: behavioural evidence for a model of chronic pain. Pain 53, 81–88 (1993).

    Article  CAS  PubMed  Google Scholar 

  156. Guan, Z. et al. Injured sensory neuron-derived CSF1 induces microglial proliferation and DAP12-dependent pain. Nat. Neurosci. 19, 94–101 (2016).

    Article  CAS  PubMed  Google Scholar 

  157. Hildebrand, M. E. et al. Potentiation of synaptic GluN2B NMDAR currents by Fyn kinase is gated through BDNF-mediated disinhibition in spinal pain processing. Cell Rep. 17, 2753–2765 (2016).

    Article  CAS  PubMed  Google Scholar 

  158. Shubayev, V. I., Strongin, A. Y. & Yaksh, T. L. Role of myelin auto-antigens in pain: a female connection. Neural Regen. Res. 11, 890–891 (2016).

    PubMed  PubMed Central  Google Scholar 

  159. Costigan, M. et al. T-cell infiltration and signaling in the adult dorsal spinal cord is a major contributor to neuropathic pain-like hypersensitivity. J. Neurosci. 29, 14415–14422 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Cao, L. & DeLeo, J. A. CNS-infiltrating CD4+ T lymphocytes contribute to murine spinal nerve transection-induced neuropathic pain. Eur. J. Immunol. 38, 448–458 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors would like to acknowledge support in the form of grants from the Canadian Institute of Health Research (CIHR) and the Mayday Fund (to K.D.).

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Authors and Affiliations

  1. Krembil Research Institute, Toronto Western Hospital, University Health Network, 399 Bathurst Street, Toronto, M5T 2S8, Ontario, Canada

    Katayoon Bidad, Eric Gracey, Kasey S. Hemington, Karen D. Davis & Robert D. Inman

  2. Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences, 62 Dr Gharib Street, Keshavarz Boulevard, 14194, Tehran, Iran

    Katayoon Bidad

  3. Department of Immunology, Medical Sciences Building, University of Toronto, 1 King's College Circle, Toronto, M5S 1A8, Ontario, Canada

    Eric Gracey & Robert D. Inman

  4. Institute of Medical Science, Medical Sciences Building, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, M5S 1A8, Ontario, Canada

    Kasey S. Hemington, Karen D. Davis & Robert D. Inman

  5. University of Toronto Centre for the Study of Pain, 155 College Street, Toronto, M5T 1P8, Ontario, Canada

    Kasey S. Hemington, Josiane C. S. Mapplebeck & Karen D. Davis

  6. Department of Physiology, Medical Sciences Building, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, M5S 1A8, Ontario, Canada

    Josiane C. S. Mapplebeck

  7. The Hospital for Sick Children, 555 University Avenue, Toronto, M5G 1X8, Ontario, Canada

    Josiane C. S. Mapplebeck

  8. Department of Surgery, University of Toronto, 149 College Street, Toronto, M5T 1P5, Ontario, Canada

    Karen D. Davis

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All authors researched the data for the article, provided substantial contributions to discussions of its content, wrote the article and undertook review and/or editing of the manuscript before submission.

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PowerPoint slides

Glossary

Dysbiosis

A microbial imbalance associated with disease that is typified by a loss of protective bacteria and a gain of pathogenic bacteria.

Inflammatory back pain

A chronic pain of more than 3 months that has a relatively young age of onset (<45 years); morning stiffness is a major symptom associated with inflammation, and unlike mechanical back pain, inflammatory back pain is improved by movement rather than rest.

Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)

A patient-reported outcome that incorporates pain, fatigue and stiffness.

Sensorimotor network

A set of brain regions that includes the primary somatosensory and primary motor cortices; the activity of these regions is related to sensory and/or motor function, and is typically evoked by sensory stimuli or motor tasks.

Salience network

A set of brain regions that function to detect and respond to salient stimuli, such as those that are of value or importance, or simply those that are more prominent than other stimuli.

Inflammatory pain

Pain occurring following an injury or in a disease that involves the release of inflammatory agents that activate and/or sensitize nociceptors.

Allodynia

Pain that is evoked by stimuli that are not normally painful, such as a light touch, gentle heat or mild cooling.

Central sensitization

Enhanced response of the neurons in the central nervous system to normal stimuli.

Functional brain networks

Sets of brain regions for which activity is correlated over time.

Default mode network

A set of brain regions that have ongoing activity during a so-called resting state; this network is thought to monitor ones internal and external environment, and then become suppressed when the individual needs to respond to a situation.

Functional MRI (fMRI)

An MRI-based technique that is used to identify areas of evoked brain responses (for example, responses to a task or stimulus).

Functional connectivity

The degree to which the brain activity in certain regions fluctuates together over time.

PainDETECT screening tool

A screening tool that is used to evaluate the likelihood of the presence of a neuropathic pain component in patients with chronic pain using a questionnaire comprising seven questions that evaluate the quality of pain, sensitivity to light touch or mild temperature, numbness, pain radiation and the temporal pattern of pain.

Mixed Pain

Pain that has multiple components; for example, in ankylosing spondylitis there might be elements of both neuropathic pain and inflammatory pain.

Peripheral sensitization

Increased sensitivity of nociceptors to stimulation resulting from tissue injury.

Hyperalgesia

An increased amount of pain that is evoked by a stimulus that is normally painful.

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Bidad, K., Gracey, E., Hemington, K. et al. Pain in ankylosing spondylitis: a neuro-immune collaboration. Nat Rev Rheumatol 13, 410–420 (2017). https://doi.org/10.1038/nrrheum.2017.92

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