Skip to main content
SpringerLink
Log in

Pathophysiology of Chronic Pain

  • Chapter
  • First Online:
Advances in Chronic and Neuropathic Pain

Part of the book series: Contemporary Rheumatology ((CR))

  • 749 Accesses

Abstract

In this review we discussed normal physiology of pain; receptors, pathways and transmitters, to compare the normal with abnormal finding in chronic neuropathic pain. We demonstrated the possible new mechanisms explaining mechanisms of chronic pain with probable new coming pharmacological solutions and recent trials to introduce new drugs capable for reducing pain intensity to improve the quality of life. Glial cells in CNS showed an important role and component in central sensitization pathway. Long non-coding RNAs (lncRNA) and Cysteinyl-aspartate-specific proteases (CASPs) showed a high-level concentration in nervous systems in patients with chronic pain. Mitochondria also was found to be involved in chronic pain through reactive oxygen species (ROS). Blocking ATP pathways in mitochondria showed positive results. However, the absolute mechanism is not well understood, multiple theories have recommended many drugs with promising effects.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

Abbreviations

BDNF:

Brain-derived neurotrophic factor

Caspase-6:

Cysteine-aspartic acid protease-6

CNS:

Central nervous system

CSF-1:

Colony-stimulating factor-1

CX:

Connexin

DAMPs:

Damage-associated molecular patterns

GABA:

Gamma-aminobutyric acid

JAK-STAT:

Janus kinase/signal transducer and activator of the transcription

lncRNA:

Long non-coding RNAs

MMPs:

Matrix metalloproteinases

NMDA:

N-methyl-d-aspartate

PRR:

Pattern-recognition receptors

RAGE:

Advanced glycation end products

TNF:

Tumor necrosis factors

TRP:

Transient receptor potential channels

References

  1. Fornasari D. Pain mechanisms in patients with chronic pain. Clin Drug Investig. 2012;32(Suppl 1):45–52.

    CAS  PubMed  Google Scholar 

  2. Rapo-Pylkkö S, Haanpää M, Liira H. A one-year follow-up study of chronic pain in community-dwelling older adults with and without neuropathic pain. BMC Geriatr. 2017;17(1):152.

    PubMed  PubMed Central  Google Scholar 

  3. Huguet A, Miró J. The severity of chronic pediatric pain: an epidemiological study. J Pain. 2008;9(3):226–36.

    PubMed  Google Scholar 

  4. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet (London, England). 2017;390(10100):1211–59.

    Google Scholar 

  5. Mills SEE, Nicolson KP, Smith BH. Chronic pain: a review of its epidemiology and associated factors in population-based studies. Br J Anaesth. 2019;123(2):e273–83.

    PubMed  PubMed Central  Google Scholar 

  6. Pergolizzi J, Ahlbeck K, Aldington D, Alon E, Coluzzi F, Dahan A, et al. The development of chronic pain: physiological CHANGE necessitates a multidisciplinary approach to treatment. Curr Med Res Opin. 2013;29(9):1127–35.

    PubMed  PubMed Central  Google Scholar 

  7. Helme RD, Gibson S, Khalil Z. Neural pathways in chronic pain. Med J Aust. 1990;153(7):400–6.

    CAS  PubMed  Google Scholar 

  8. Nicholson B. Differential diagnosis: nociceptive and neuropathic pain. Am J Manag Care. 2006;12(9 Suppl):S256–62.

    PubMed  Google Scholar 

  9. Lallemend F, Ernfors P. Molecular interactions underlying the specification of sensory neurons. Trends Neurosci. 2012;35(6):373–81.

    CAS  PubMed  Google Scholar 

  10. Mantyh PW. Cancer pain and its impact on diagnosis, survival and quality of life. Nat Rev Neurosci. 2006;7(10):797–809.

    CAS  PubMed  Google Scholar 

  11. Schaible HG, Richter F, Ebersberger A, Boettger MK, Vanegas H, Natura G, et al. Joint pain. Exp Brain Res. 2009;196(1):153–62.

    PubMed  Google Scholar 

  12. Costigan M, Scholz J, Woolf CJ. Neuropathic pain: a maladaptive response of the nervous system to damage. Annu Rev Neurosci. 2009;32:1–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Zhang N, Oppenheim JJ. Crosstalk between chemokines and neuronal receptors bridges immune and nervous systems. J Leukoc Biol. 2005;78(6):1210–4.

    CAS  PubMed  Google Scholar 

  14. Kato J, Agalave NM, Svensson CI. Pattern recognition receptors in chronic pain: mechanisms and therapeutic implications. Eur J Pharmacol. 2016;788:261–73.

    CAS  PubMed  Google Scholar 

  15. Edwards RR, Cahalan C, Mensing G, Smith M, Haythornthwaite JA. Pain, catastrophizing, and depression in the rheumatic diseases. Nat Rev Rheumatol. 2011;7(4):216–24.

    CAS  PubMed  Google Scholar 

  16. Smart KM, Blake C, Staines A, Doody C. Self-reported pain severity, quality of life, disability, anxiety and depression in patients classified with ‘nociceptive’, ‘peripheral neuropathic’ and ‘central sensitisation’ pain. The discriminant validity of mechanisms-based classifications of low back (±leg) pain. Man Ther. 2012;17(2):119–25.

    PubMed  Google Scholar 

  17. Sandkühler J. Models and mechanisms of hyperalgesia and allodynia. Physiol Rev. 2009;89(2):707–58.

    PubMed  Google Scholar 

  18. Pedersen JL, Andersen OK, Arendt-Nielsen L, Kehlet H. Hyperalgesia and temporal summation of pain after heat injury in man. Pain. 1998;74(2–3):189–97.

    CAS  PubMed  Google Scholar 

  19. Pertovaara A, Almeida A. Chapter 13: Descending inhibitory systems. In: Handbook of clinical neurology, vol. 81. Amsterdam: Elsevier; 2006. p. 179–92.

    Google Scholar 

  20. Chen G, Zhang Y-Q, Qadri YJ, Serhan CN, Ji R-R. Microglia in pain: detrimental and protective roles in pathogenesis and resolution of pain. Neuron. 2018;100(6):1292–311.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Ji R-R, Berta T, Nedergaard M. Glia and pain: is chronic pain a gliopathy? Pain. 2013;154:S10–28.

    PubMed  PubMed Central  Google Scholar 

  22. Shi Y, Shu J, Liang Z, Yuan S, Tang SJ. EXPRESS: oligodendrocytes in HIV-associated pain pathogenesis. Mol Pain. 2016;12:1744806916656845.

    PubMed  PubMed Central  Google Scholar 

  23. Berta T, Park C-K, Xu Z-Z, Xie R-G, Liu T, Lü N, et al. Extracellular caspase-6 drives murine inflammatory pain via microglial TNF-α secretion. J Clin Invest. 2014;124(3):1173–86.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Abbadie C, Bhangoo S, De Koninck Y, Malcangio M, Melik-Parsadaniantz S, White FA. Chemokines and pain mechanisms. Brain Res Rev. 2009;60(1):125–34.

    CAS  PubMed  Google Scholar 

  25. Guan Z, Kuhn JA, Wang X, Colquitt B, Solorzano C, Vaman S, et al. Injured sensory neuron-derived CSF1 induces microglial proliferation and DAP12-dependent pain. Nat Neurosci. 2016;19(1):94–101.

    CAS  PubMed  Google Scholar 

  26. Ji R-R, Xu Z-Z, Gao Y-J. Emerging targets in neuroinflammation-driven chronic pain. Nat Rev Drug Discov. 2014;13(7):533–48.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Raghavendra V, Tanga F, DeLeo JA. Inhibition of microglial activation attenuates the development but not existing hypersensitivity in a rat model of neuropathy. J Pharmacol Exp Ther. 2003;306(2):624–30.

    CAS  PubMed  Google Scholar 

  28. Echeverry S, Shi XQ, Yang M, Huang H, Wu Y, Lorenzo LE, et al. Spinal microglia are required for long-term maintenance of neuropathic pain. Pain. 2017;158(9):1792–801.

    PubMed  Google Scholar 

  29. Sweitzer S, Schubert P, DeLeo J. Propentofylline, a glial modulating agent, exhibits antiallodynic properties in a rat model of neuropathic pain. J Pharmacol Exp Ther. 2001;297(3):1210–7.

    CAS  PubMed  Google Scholar 

  30. Walters ET. Neuroinflammatory contributions to pain after SCI: roles for central glial mechanisms and nociceptor-mediated host defense. Exp Neurol. 2014;258:48–61.

    CAS  PubMed  Google Scholar 

  31. Ellis A, Wieseler J, Favret J, Johnson KW, Rice KC, Maier SF, et al. Systemic administration of propentofylline, ibudilast, and (+)-naltrexone each reverses mechanical allodynia in a novel rat model of central neuropathic pain. J Pain. 2014;15(4):407–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Binshtok AM, Wang H, Zimmermann K, Amaya F, Vardeh D, Shi L, et al. Nociceptors are interleukin-1β sensors. J Neurosci. 2008;28(52):14062–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Takeda M, Kitagawa J, Takahashi M, Matsumoto S. Activation of interleukin-1β receptor suppresses the voltage-gated potassium currents in the small-diameter trigeminal ganglion neurons following peripheral inflammation. Pain. 2008;139(3):594–602.

    CAS  PubMed  Google Scholar 

  34. Gustafson-Vickers SL, Van Lu B, Lai AY, Todd KG, Ballanyi K, Smith PA. Long-term actions of interleukin-1β on delay and tonic firing neurons in rat superficial dorsal horn and their relevance to central sensitization. Mol Pain. 2008;4:63.

    PubMed  PubMed Central  Google Scholar 

  35. Kawasaki Y, Zhang L, Cheng J-K, Ji R-R. Cytokine mechanisms of central sensitization: distinct and overlapping role of interleukin-1β, interleukin-6, and tumor necrosis factor-α in regulating synaptic and neuronal activity in the superficial spinal cord. J Neurosci. 2008;28(20):5189–94.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Zhang R-X, Li A, Liu B, Wang L, Ren K, Zhang H, et al. IL-1ra alleviates inflammatory hyperalgesia through preventing phosphorylation of NMDA receptor NR-1 subunit in rats. Pain. 2008;135(3):232–9.

    CAS  PubMed  Google Scholar 

  37. Milligan ED, O’Connor KA, Nguyen KT, Armstrong CB, Twining C, Gaykema RP, et al. Intrathecal HIV-1 envelope glycoprotein gp120 induces enhanced pain states mediated by spinal cord proinflammatory cytokines. J Neurosci. 2001;21(8):2808–19.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Gabay E, Wolf G, Shavit Y, Yirmiya R, Tal M. Chronic blockade of interleukin-1 (IL-1) prevents and attenuates neuropathic pain behavior and spontaneous ectopic neuronal activity following nerve injury. Eur J Pain. 2011;15(3):242–8.

    CAS  PubMed  Google Scholar 

  39. Chen G, Park C-K, Xie R-G, Berta T, Nedergaard M, Ji R-R. Connexin-43 induces chemokine release from spinal cord astrocytes to maintain late-phase neuropathic pain in mice. Brain. 2014;137(8):2193–209.

    PubMed  PubMed Central  Google Scholar 

  40. Wang H, Cao Y, Chiang C-Y, Dostrovsky JO, Sessle BJ. The gap junction blocker carbenoxolone attenuates nociceptive behavior and medullary dorsal horn central sensitization induced by partial infraorbital nerve transection in rats. Pain. 2014;155(2):429–35.

    CAS  PubMed  Google Scholar 

  41. Ji R-R, Xu Z-Z, Wang X, Lo EH. Matrix metalloprotease regulation of neuropathic pain. Trends Pharmacol Sci. 2009;30(7):336–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Kawasaki Y, Xu Z-Z, Wang X, Park JY, Zhuang Z-Y, Tan P-H, et al. Distinct roles of matrix metalloproteases in the early- and late-phase development of neuropathic pain. Nat Med. 2008;14(3):331–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Diatchenko L, Nackley AG, Tchivileva IE, Shabalina SA, Maixner W. Genetic architecture of human pain perception. Trends Genet. 2007;23(12):605–13.

    CAS  PubMed  Google Scholar 

  44. Liu H, Yao YM, Yu Y, Dong N, Yin HN, Sheng ZY. Role of Janus kinase/signal transducer and activator of transcription pathway in regulation of expression and inflammation-promoting activity of high mobility group box protein 1 in rat peritoneal macrophages. Shock. 2007;27(1):55–60.

    PubMed  Google Scholar 

  45. Salaffi F, Giacobazzi G, Di Carlo M. Chronic pain in inflammatory arthritis: mechanisms, metrology, and emerging targets—a focus on the JAK-STAT pathway. Pain Res Manag. 2018;2018:8564215.

    PubMed  PubMed Central  Google Scholar 

  46. Taylor RC, Cullen SP, Martin SJ. Apoptosis: controlled demolition at the cellular level. Nat Rev Mol Cell Biol. 2008;9(3):231–41.

    CAS  PubMed  Google Scholar 

  47. Berta T, Lee JE, Park CK. Unconventional role of caspase-6 in spinal microglia activation and chronic pain. Mediat Inflamm. 2017;2017:9383184.

    Google Scholar 

  48. Li Z, Li X, Chen X, Li S, Ho IHT, Liu X, et al. Emerging roles of long non-coding RNAs in neuropathic pain. Cell Prolif. 2019;52(1):e12528.

    PubMed  Google Scholar 

  49. Wu W, Ji X, Zhao Y. Emerging roles of long non-coding RNAs in chronic neuropathic pain. Front Neurosci. 2019;13:1097.

    PubMed  PubMed Central  Google Scholar 

  50. Li C, Lei Y, Tian Y, Xu S, Shen X, Wu H, et al. The etiological contribution of GABAergic plasticity to the pathogenesis of neuropathic pain. Mol Pain. 2019;15:1744806919847366.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. von Hehn CA, Baron R, Woolf CJ. Deconstructing the neuropathic pain phenotype to reveal neural mechanisms. Neuron. 2012;73(4):638–52.

    Google Scholar 

  52. Ulmann L, Hatcher JP, Hughes JP, Chaumont S, Green PJ, Conquet F, et al. Up-regulation of P2X4 receptors in spinal microglia after peripheral nerve injury mediates BDNF release and neuropathic pain. J Neurosci. 2008;28(44):11263–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Coull JA, Beggs S, Boudreau D, Boivin D, Tsuda M, Inoue K, et al. BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature. 2005;438(7070):1017–21.

    CAS  PubMed  Google Scholar 

  54. Inoue K. Purinergic signaling in microglia in the pathogenesis of neuropathic pain. Proc Jpn Acad Ser B Phys Biol Sci. 2017;93(4):174–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Sui BD, Xu TQ, Liu JW, Wei W, Zheng CX, Guo BL, et al. Understanding the role of mitochondria in the pathogenesis of chronic pain. Postgrad Med J. 2013;89(1058):709–14.

    CAS  PubMed  Google Scholar 

  56. Kim HY, Chung JM, Chung K. Increased production of mitochondrial superoxide in the spinal cord induces pain behaviors in mice: the effect of mitochondrial electron transport complex inhibitors. Neurosci Lett. 2008;447(1):87–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Joseph EK, Levine JD. Mitochondrial electron transport in models of neuropathic and inflammatory pain. Pain. 2006;121(1–2):105–14.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Faculty of Medicine, Alexandria University, Alexandria, Egypt

    Kirellos Said Abbas

  2. Department of Physical Medicine, Rheumatology and Rehabilitation, Tanta University Hospitals and Faculty of Medicine, Tanta University, Tanta, Egypt

    Abdallah El-Sayed Allam

  3. Morphological Madrid Research Center (MoMaRC), Madrid, Spain

    Abdallah El-Sayed Allam & Felice Galluccio

  4. Division of Rheumatology, Medical-Geriatric Department, University Hospital AOU Careggi, Florence, Italy

    Felice Galluccio

  5. Departement of Physical Medicine and Rehabilitation, Mohammed VI University hospital Oujda , Immuno Hematology and Cellular Therapy Laboratory, Faculty of Medicine of oujda, Mohammed First University of Oujda, Mohammed VI University hospital Oujda and Faculty of Medicine Mohammed First University of oujda, Oujda, Morocco

    Ahmed Amine El OUMRI

  6. King Abdullah University Hospital, Jordan University of Science and Technology, Irbid, Jordan

    Abdullah AlKharabsheh

  7. Anesthesia and Interventional Pain Medicine, Cleveland Clinic, Abu Dhabi, UAE

    Ammar Salti

  8. Anesthesiology - Cleveland Clinic Lerner College of Medicine - Case Western Reserve University, Cleveland, OH, USA

    Ammar Salti

Authors
  1. Kirellos Said Abbas
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Abdallah El-Sayed Allam
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Felice Galluccio
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ahmed Amine El OUMRI
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Abdullah AlKharabsheh
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ammar Salti
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. SMARTMD Philippines, Centuria Medical MakatiMakati City, Philippines

    Jeimylo de Castro

  2. Institute Medical Sciences, Canterbury Christ Church University, Canterbury, Kent, UK

    Yasser El Miedany

Rights and permissions

Reprints and permissions

Copyright information

© 2022 The Author(s), under exclusive license to Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Abbas, K.S., Allam, A.ES., Galluccio, F., El OUMRI, A.A., AlKharabsheh, A., Salti, A. (2022). Pathophysiology of Chronic Pain. In: de Castro, J., El Miedany, Y. (eds) Advances in Chronic and Neuropathic Pain. Contemporary Rheumatology. Springer, Cham. https://doi.org/10.1007/978-3-031-10687-3_3

Download citation

  • DOI: https://doi.org/10.1007/978-3-031-10687-3_3

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-031-10686-6

  • Online ISBN: 978-3-031-10687-3

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation