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Nociception and role of immune system in pain

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Abstract

Both pain and inflammation are protective responses. However, these self-limiting conditions (with well-established negative feedback loops) become pathological if left uncontrolled. Both pain and inflammation can interact with each other in a multi-dimensional manner. These interactions are known to create an array of ‘difficult to manage’ pathologies. This review explains in detail the role of immune system and the related cells in peripheral sensitization and neurogenic inflammation. Various neuro-immune interactions are analyzed at peripheral, sensory and central nervous system levels. Innate immunity plays a critical role in central sensitization and in establishing acute pain as chronic condition. Moreover, inflammatory mediators also exhibit psychological effects, thus contributing towards the emotional elements associated with pain. However, there is also a considerable anti-inflammatory and analgesic role of immune system. This review also attempts to enlist various novel pharmacological approaches that exhibit their actions through modification of neuro-immune interface.

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References

  1. Baranauskas G, Nistri A (1998) Sensitization of pain pathways in the spinal cord: cellular mechanisms. Prog Neurobiol 54:349–365

    Article  CAS  PubMed  Google Scholar 

  2. Ren K, Dubner R (2010) Interactions between the immune and nervous systems in pain. Nature Med 16(11):1267–1276

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Hackel D, Pflücke D, Neumann A, Viebahn J, Mousa S, Wischmeyer E, Roewer N, Brack A, Rittner HL (2013) The connection of monocytes and reactive oxygen species in pain. PLoS ONE 8(5):2

    Article  Google Scholar 

  4. Schaible HG, Richter F (2004) Pathophysiology of pain. Langenbecks Arch Surg 389:237–243

    Article  PubMed  Google Scholar 

  5. Walker AK, Kavelaars A, Heijnen CJ, Dantzer R (2014) Neuroinflammation and comorbidity of pain and depression. Pharmacol Rev 66(1):80–101. doi:10.1124/pr.113.008144. Print 2014. Review. PubMed PMID: 24335193; PubMed Central PMCID: PMC3880465

  6. Singhal G, Jaehne EJ, Corrigan F, Toben C, Baune BT (2014) Inflammasomes in neuroinflammation and changes in brain function: a focused review. Front Neurosci 8:315. doi:10.3389/fnins.2014.00315. eCollection 2014. Review. PubMed PMID: 25339862; PubMed Central PMCID: PMC4188030

  7. Ren K, Torres R. (2009) Role of interleukin-1beta during pain and inflammation. Brain Res Rev 60(1):57–64. doi:10.1016/j.brainresrev.2008.12.020. Epub 2008 Dec 31. Review. PubMed PMID: 19166877; PubMed Central PMCID: PMC3076185

  8. Stannus OP, Jones G, Blizzard L, Cicuttini FM, Ding C (2013) Associations between serum levels of inflammatory markers and change in knee pain over 5 years in older adults: a prospective cohort study. Ann Rheum Dis 72(4):535–40. doi:10.1136/annrheumdis-2011-201047. Epub 2012 May 12. PubMed PMID: 22580582

  9. Otmishi P, Gordon J, El-Oshar S, Li H, Guardiola J, Saad M, Proctor M, Yu J (2008) Neuroimmune interaction in inflammatory diseases. Clin Med Circ Respirat Pulm Med 2:35–44. PubMed PMID: 21157520; PubMed Central PMCID: PMC2990232

  10. Eskandari F, Webster JI, Sternberg EM (2003) Review: neural immune pathways and their connection to inflammatory diseases. Arthritis Res Ther 5(6):251–265

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Cutolo M, Wilder RL (2000) Review: different roles for androgens and estrogens in the susceptibility to autoimmune rheumatic diseases. Rheum Dis Clin North Am 26(4):825–839

    Article  CAS  PubMed  Google Scholar 

  12. Olsen NJ, Kovacs WJ. Gonadal steroids and immunity. Endocr Rev. 1996 Aug;17(4):369–84. Review. PubMed PMID: 8854050

  13. Voscopoulos C, Lema M (2010) When does acute pain become chronic? Br J Anaesth 105(Suppl 1):i69–i85

    Article  PubMed  Google Scholar 

  14. Kin NW, Sanders VM (2006) Review: it takes nerve to tell T and B cells what to do. J Leukoc Biol 79(6):1093–1104

    Article  CAS  PubMed  Google Scholar 

  15. Wang H, Yu M, Ochani M, Amella CA, Tanovic M, Susarla S, Li JH, Wang H, 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):384–388

    Article  CAS  PubMed  Google Scholar 

  16. Momin A, McNaughton PA (2009) Regulation of firing frequency in nociceptive neurons by pro-inflammatory mediators. Experimental Brain Res 196:45–52

    Article  CAS  Google Scholar 

  17. Burnstock G (2009) Purinergic receptors and pain. Curr Pharm Des 15:1717–1735

    Article  CAS  PubMed  Google Scholar 

  18. Miller RJ, Jung H, Bhangoo SK et al (2009) Cytokine and chemokine regulation of sensory neuron function. Handb Exp Pharmacol 194:417–449

    Article  CAS  PubMed  Google Scholar 

  19. Watson JJ, Allen SJ, Dawbarn D (2008) Targeting nerve growth factor in pain: what is the therapeutic potential? BioDrugs 22:349–359

    Article  CAS  PubMed  Google Scholar 

  20. Chatterjea D, Martinov T (2014) Mast cells: versatile gatekeepers of pain. Mol Immunol. pii: S0161–5890(14)00054–6. doi:10.1016/j.molimm.2014.03.001. [Epub ahead of print]

  21. Shubayev VI et al (2006) TNFα-induced MMP-9 promotes macrophage recruitment into injured peripheral nerve. Mol Cell Neurosci 31:407–415

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Gómez-Nicola D, Valle-Argos B, Suardíaz M, Taylor JS, Nieto-Sampedro M (2008) Role of IL-15 in spinal cord and sciatic nerve after chronic constriction injury: regulation of macrophage and T-cell infiltration. J Neurochem 107:1741–1752

    Article  PubMed  Google Scholar 

  23. Richardson JD, Vasko MR (2002) Cellular mechanisms of neurogenic inflammation. J Pharmacol Exp Ther 302(3):839–845

    Article  CAS  PubMed  Google Scholar 

  24. Ginhoux F, Lim S, Hoeffel G, Low D, Huber T (2013) Origin and differentiation of microglia. Front Cell Neurosci 7:45

    Article  PubMed Central  PubMed  Google Scholar 

  25. Calvo M, Zhu N, Tsantoulas C, Ma Z, Grist J, Loeb JA, Bennett DL (2010) Neuregulin-ErbB signaling promotes microglial proliferation and chemotaxis contributing to microgliosis and pain after peripheral nerve injury. J Neurosci 30:5437–5450

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Kawasaki Y, Xu ZZ, Wang X, Park JY, Zhuang ZY, Tan PH, Gao YJ, Roy K, Corfas G, Lo EH, Ji RR (2008) Distinct roles of matrix metalloproteases in the early- and late-phase development of neuropathic pain. Nat Med 14:331–336

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Thalakoti S et al (2007) Neuron-glia signaling in trigeminal ganglion: implications for migraine pathology. Headache 47:1008–1023

    Article  PubMed Central  PubMed  Google Scholar 

  28. Zhang J, Shi XQ, Echeverry S, Mogil JS, De KY, Rivest S (2007) Expression of CCR2 in both resident and bone marrow-derived microglia plays a critical role in neuropathic pain. J Neurosci 27:12396–12406

    Article  CAS  PubMed  Google Scholar 

  29. Kim D, Kim MA, Cho IH, Kim MS, Lee S, Jo EK, Choi SY, Park K, Kim JS, Akira S, Na HS, Oh SB, Lee SJ (2007) A critical role of toll-like receptor 2 in nerve injury-induced spinal cord glial cell activation and pain hypersensitivity. J Biol Chem 282:14975–14983

    Article  CAS  PubMed  Google Scholar 

  30. Tsuda M, Masuda T, Kitano J, Shimoyama H, Tozaki-Saitoh H, Inoue K (2009) IFN-gamma receptor signaling mediates spinal microglia activation driving neuropathic pain. Proc Natl Acad Sci USA 106:8032–8037

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Kawasaki Y, Zhang L, Cheng JK, Ji RR (2008) Cytokine mechanisms of central sensitization: distinct and overlapping role of interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha in regulating synaptic and neuronal activity in the superficial spinal cord. J Neurosci 28:5189–5194

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Sweitzer SM, White KA, Dutta C, DeLeo JA (2002) The differential role of spinal MHC class II and cellular adhesion molecules in peripheral inflammatory versus neuropathic pain in rodents. J Neuroimmunol 125:82–93

    Article  CAS  PubMed  Google Scholar 

  33. Cao L, Palmer CD, Malon JT, De Leo JA (2009) Critical role of microglial CD40 in the maintenance of mechanical hypersensitivity in a murine model of neuropathic pain. Eur J Immunol 39:3562–3569

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Thalakoti S et al (2007) Neuron-glia signaling in trigeminal ganglion: implications for migraine pathology. Headache 47:1008–1023

    Article  PubMed Central  PubMed  Google Scholar 

  35. Vit JP, Ohara PT, Bhargava A, Kelley K, Jasmin L (2008) Silencing the Kir4.1 potassium channel subunit in satellite glial cells of the rat trigeminal ganglion results in pain-like behavior in the absence of nerve injury. J Neurosci 28:4161–4171

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Capuano A et al (2009) Proinflammatory-activated trigeminal satellite cells promote neuronal sensitization: relevance for migraine pathology. Mol Pain 5:43

    Article  PubMed Central  PubMed  Google Scholar 

  37. Mifflin KA, Kerr BJ (2014) The transition from acute to chronic pain: understanding how different biological systems interact. Can J Anaesth 61(2):112–122

    Article  PubMed  Google Scholar 

  38. Kronfol Z, Remick DG (2000) Cytokines and the brain: implications for clinical psychiatry. Am J Psychiatry 157(5):683–694

    Article  CAS  PubMed  Google Scholar 

  39. Oka Y et al (2007) Interleukin-6 is a candidate molecule that transmits inflammatory information to the CNS. Neuroscience 145:530–538

    Article  CAS  PubMed  Google Scholar 

  40. Wei F, Guo W, Zou S, Ren K, Dubner R (2008) Supraspinal glial-neuronal interactions contribute to descending pain facilitation. J Neurosci 28:10482–10495

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. Guo W et al (2007) Glial-cytokine-neuronal interactions underlying the mechanisms of persistent pain. J Neurosci 27:6006–6018

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  42. Ahrens C, Schiltenwolf M, Wang H (2012) Cytokines in psychoneuroendocrine immunological context of nonspecific musculoskeletal pain. Schmerz 26(4):383–388

    Article  CAS  PubMed  Google Scholar 

  43. Jessop DS et al (2010) Endomorphins in rheumatoid arthritis, osteoarthritis, and experimental arthritis. Ann NY Acad Sci 1193:117–122

    Article  PubMed  Google Scholar 

  44. Khodorova A et al (2003) Endothelin-B receptor activation triggers an endogenous analgesic cascade at sites of peripheral injury. Nat Med 9:1055–1061

    Article  CAS  PubMed  Google Scholar 

  45. Stein C (1993) Peripheral mechanisms of opioid analgesia. Anesth Analg 76:182–191

    Article  CAS  PubMed  Google Scholar 

  46. Serhan CN, Chiang N, Van Dyke TE (2008) Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators. Nat Rev Immunol 8:349–361

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  47. Serhan CN (2005) Lipoxins and aspirin-triggered 15-epi-lipoxins are the first lipid mediators of endogenous anti-inflammation and resolution. Prostaglandins Leukot Essent Fatty Acids 73:141–162

    Article  CAS  PubMed  Google Scholar 

  48. Svensson CI, Zattoni M, Serhan CN (2007) Lipoxins and aspirin-triggered lipoxin inhibit inflammatory pain processing. J Exp Med 204:245–252

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  49. Yoo S, Lim JY, Hwang SW (2013) Resolvins: endogenously-Generated Potent Painkilling Substances and their Therapeutic Perspectives. Curr Neuropharmacol 11(6):664–676

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. Xu ZZ, Liu XJ, Berta T, Park CK, Lü N, Serhan CN, Ji RR (2013) Neuroprotectin/protectin D1 protects against neuropathic pain in mice after nerve trauma. Ann Neurol 74(3):490–5. doi:10.1002/ana.23928. Epub 2013 Sep 4

  51. Zylka MJ et al (2008) Prostatic acid phosphatase is an ectonucleotidase and suppresses pain by generating adenosine. Neuron 60:111–122

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  52. Chen Y et al (2008) Activation of P2X7 receptors in glial satellite cells reduces pain through downregulation of P2X3 receptors in nociceptive neurons. Proc Natl Acad Sci USA 105:16773–16778

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  53. Grace PM, Hutchinson MR, Maier SF, Watkins LR (2014) Pathological pain and the neuroimmune interface. Nat Rev Immunol 14:217–231. doi:10.1038/nri3621

    Article  CAS  PubMed  Google Scholar 

  54. Yoon SY, Patel D, Dougherty PM (2012) Minocycline blocks lipopolysaccharide induced hyperalgesia by suppression of microglia but not astrocytes. Neuroscience 221:214–224

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  55. Listing J et al (2005) Infections in patients with rheumatoid arthritis treated with biologic agents. Arthritis Rheum 52:L3403–L3412

    Article  Google Scholar 

  56. Torres R et al (2009) Hyperalgesia, synovitis and multiple biomarkers of inflammation are suppressed by interleukin 1 inhibition in a novel animal model of gouty arthritis. Ann Rheum Dis 68:1602–1608

    Article  CAS  PubMed  Google Scholar 

  57. Soderquist RG et al (2010) Release of plasmid DNA encoding IL-10 from PLGA microparticles facilitates long-term reversal of neuropathic pain following a single intrathecal administration. Pharm Res 27:841–854

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  58. Serrano A, Paré M, McIntosh F, Elmes SJ, Martino G, Jomphe C, Lessard E, Lembo PM, Vaillancourt F, Perkins MN, Cao CQ (2010) Blocking spinal CCR2 with AZ889 reversed hyperalgesia in a model of neuropathic pain. Mol Pain 6:90

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  59. Biswas K, Aya T, Qian W, Peterkin TA, Chen JJ, Human J, Hungate RW, Kumar G, Arik L, Lester-Zeiner D, Biddlecome G, Manning BH, Sun H, Dong H, Huang M, Loeloff R, Johnson EJ, Askew BC (2008) Aryl sulfones as novel bradykinin B1 receptor antagonists for treatment of chronic pain. Bioorg Med Chem Lett 17:4764–4769

    Article  Google Scholar 

  60. Clark AK, Wodarski R, Guida F, Sasso O, Malcangio M (2010) Cathepsin S release from primary cultured microglia is regulated by the P2X7 receptor. Glia 14:1710–1726

    Article  Google Scholar 

  61. Clark AK, Yip PK, Grist J, Gentry C, Staniland AA, Marchand F, Dehvari M, Wotherspoon G, Winter J, Ullah J, Bevan S, Malcangio M (2007) Inhibition of spinal microglial cathepsin S for the reversal of neuropathic pain. Proc Natl Acad Sci USA 104(25):10655–10660

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  62. Ting E et al (2008) Role of complement C5a in mechanical inflammatory hypernociception: potential use of C5a receptor antagonists to control inflammatory pain. Br J Pharmacol 153:1043–1053

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  63. Abdelmoaty S, Wigerblad G, Bas DB, Codeluppi S, Fernandez-Zafra T, El-Awady el-S, Moustafa Y, Abdelhamid Ael-D, Brodin E, Svensson CI (2013) Spinal actions of lipoxin A4 and 17(R)-resolvin D1 attenuate inflammation-induced mechanical hypersensitivity and spinal TNF release. PLoS ONE 8(9):e75543

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  64. Block BM, Hurley RW, Raja SN (2004) Mechanism-based therapies for pain. Drug News Perspect 17(3):172–186

    Article  CAS  PubMed  Google Scholar 

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Verma, V., Sheikh, Z. & Ahmed, A.S. Nociception and role of immune system in pain. Acta Neurol Belg 115, 213–220 (2015). https://doi.org/10.1007/s13760-014-0411-y

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