Advertisement

Signaling of Nociceptors and Pain Perception: Impact of Age

  • Manjula VinayakEmail author
  • Ajeet Kumar Singh
Chapter

Abstract

Nociceptor is receptor of noxious stimulus, i.e., a stimulus that potentially leads to tissue damage. Signaling of nociceptors leads to pain perception. Thus, pain (hyperalgesia) is a signal of tissue damage. Acute hyperalgesia is sudden pain and is an essential constituent of protective system, whereas long persisting chronic hyperalgesia with no obvious use has generated great concern for physicians. Persistent chronic hyperalgesia is generally associated with long illness like diabetes, osteoarthritis, and cancer. Research in pain therapy has improved the quality of life to some extent; however, it is still a great challenge to overcome chronic hyperalgesia.

The challenge to treat chronic pain is even more difficult for elderly individuals as the elderly people over 65 constitute the fastest-growing group of people in today’s society due to decline in fertility and improvement in longevity. Although the normal aging process does not lead to chronic pain, these painful conditions are more frequent in elderly people than the younger ones. Therefore, the subfield of geriatric pain has grown dramatically over the last two decades. The literature supports that pain in older and younger adults differs in clinically and theoretically significant ways. Several unique characteristics of geriatric pain are proposed due to the possibility of nonuniform age-related variations in physiology and prolonged recovery from tissue and nerve injury. The discrepant findings of age-related increase/decrease or stability in pain require a concrete theoretical framework based on the molecular mechanism of hyperalgesia. Another challenge for the society is to tackle the psychosocial factors important in adjustment to chronic pain in older people. The present chapter reviews the signaling of nociceptors, various types of hyperalgesia with insight in the molecular mechanism, age-related patterns in pain, and challenges in assessment strategies to evaluate pain; and establishment of clinically relevant animal models as well as sociopsychological aspect of pain in old people. The chapter also presents avenues for future research.

Keywords

Nociceptive signaling Inflammation Ion channels Hyperalgesia Chronic pain Neuropathy 

Notes

Acknowledgments

Authors are thankful to DRDO, India, for financial support (grant no. ERIP/ER/1003851/M/01/1336). Partial financial support by DST-FIST and UGC-CAS program to the Department of Zoology, BHU, and UGC-UPE to BHU is also acknowledged.

References

  1. 1.
    Basbaum AI, Jessell T (2000) The perception of pain. In: Kandel ER, Schwartz J, Jessell T (eds) Principles of neuroscience. Appleton and Lange, New York, pp 472–491Google Scholar
  2. 2.
    Ji RR, Samad TA, Jin SX, Schmoll R, Woolf CJ (2002) p38 MAPK activation by NGF in primary sensory neurons after inflammation increases TRPV1 levels and maintains heat hyperalgesia. Neuron 36(1):57–68PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Keen P, Harmar AJ, Spears F, Winter E (1982) Biosynthesis, axonal transport and turnover of neuronal substance P. Ciba Found Symp 91:145–164Google Scholar
  4. 4.
    Kashihara Y, Sakaguchi M, Kuno M (1989) Axonal transport and distribution of endogenous calcitonin gene-related peptide in rat peripheral nerve. J Neurosci 9(11):3796–3802PubMedCrossRefPubMedCentralGoogle Scholar
  5. 5.
    Ren K, Dubner R (2010) Interactions between the immune and nervous systems in pain. Nat Med 16:1267–1276PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Meyer RA, Ringkamp M, Campbell JN, Raja SN (2008) Peripheral mechanisms of cutaneous nociception. In: McMahon SB, Koltzenburg M (eds) Wall and Melzack’s textbook of pain. Elsevier, Philadelphia, pp 3–34Google Scholar
  7. 7.
    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):463–484PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Bingel U, Tracey I (2008) Imaging CNS modulation of pain in humans. Physiology (Bethesda) 23:371–380Google Scholar
  9. 9.
    Tracey I, Mantyh PW (2007) The cerebral signature for pain perception and its modulation. Neuron 55(3):377–391PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Singh AK, Vinayak M (2015) Curcumin attenuates CFA induced thermal hyperalgesia by modulation of antioxidant enzymes and down regulation of TNF-α, IL-1β and IL-6. Neurochem Res 40:463–472PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Singh AK, Vinayak M (2016) Anti-nociceptive effect of resveratrol during inflammatory hyperalgesia via differential regulation of pro-inflammatory mediators. Phytother Res 30(7):1164–1171PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Basbaum AI, Bautista DM, Scherrer G, Julius D (2009) Cellular and molecular mechanisms of pain. Cell 137:267–284CrossRefGoogle Scholar
  13. 13.
    Bandell M, Story GM, Hwang SW, Viswanath V, Eid SR, Petrus MJ, Earley TJ, Patapoutian A (2004) Noxious cold ion channel TRPA1 is activated by pungent compounds and bradykinin. Neuron 41:849–857PubMedCrossRefPubMedCentralGoogle Scholar
  14. 14.
    Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D (1997) The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389:816–824PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Jordt SE, Bautista DM, Chuang HH, McKemy DD, Zygmunt PM, Hogestatt ED, Meng ID, Julius D (2004) Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1. Nature 427:260–265PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    McKemy DD, Neuhausser WM, Julius D (2002) Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature 416:52–58PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Peier AM, Moqrich A, Hergarden AC, Reeve AJ, Andersson DA, Story GM, Earley TJ, Dragoni I, McIntyre P, Bevan S, Patapoutian A (2002) A TRP channel that senses cold stimuli and menthol. Cell 108:705–715PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Thielke S, Sale J, Reid MC (2012) Aging: are these 4 pain myths complicating care? J Fam Pract 61:666–670PubMedPubMedCentralGoogle Scholar
  19. 19.
    Gagliese L, Farrell MJ (2005) The neurobiology of aging, nociception and pain: an integration of animal and human experimental evidence. In: Gibson SJ, Weiner DK (eds) Pain in older persons. IASP Press, Seattle, pp 25–44Google Scholar
  20. 20.
    Yezierski RP (2012) The effects of age on pain sensitivity: preclinical studies. Pain Med 13:S27–S36PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Bergman E, Ulfhake B (1998) Loss of primary sensory neurons in the very old rat: neuron number estimates using the dissector method and confocal optical sectioning. J Comp Neurol 396(2):211–222PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Raut A, Ratka A (2009) Oxidative damage and sensitivity to nociceptive stimulus and opioids in aging rats. Neurobiol Aging 30:910–919PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Hess GD, Joseph JA, Roth GS (1981) Effect of age on sensitivity to pain and brain opiate receptors. Neurobiol Aging 1:49–55CrossRefGoogle Scholar
  24. 24.
    Wang S, Davis BM, Zwick M, Waxman SG, Albers KM (2006) Reduced thermal sensitivity and Nav1. 8 and TRPV1 channel expression in sensory neurons of aged mice. Neurobiol Aging 27:895–903PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Wang S, Albers KM (2009) Behavioral and cellular level changes in the aging somatosensory system. Ann NY Acad Sci 1170:745–749PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Chan SHH, Lai Y-Y (1982) Effects of aging on pain responses and analgesic efficacy of morphine and clonidine in rats. Expt Neurol 75:112–119CrossRefGoogle Scholar
  27. 27.
    Pickering G, Jourdan D, Millecamps M, Chapuy E, Alliot J, Eschalier A (2006) Age-related impact of neuropathic pain on animal behavior. Europ J Pain 10:749–755CrossRefGoogle Scholar
  28. 28.
    Iwata K, Fukuoka T, Londo E, Tsuboi Y, Tashiro A, Noguchi K, Masuda Y, Morimoto T, Kanda K (2002) Plastic changes in nociceptive transmission of the rat spinal cord with advancing age. J Neurophysiol 87:1086–1093PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Kitagawa J, Tsuboi Y, Ogawa A, Ren K, Hitomi S, Saitoh K, Takahashi O, Masuda Y, Harada T, Hanzawa N, Kanda K, Iwata K (2005) Involvement of dorsal column nucleus neurons in nociceptive transmission in aged rate. J Neurophysiol 94:4178–4187PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Zhang R-X, Lao L, Qiao JT, Ruda MA (2004) Effects of aging on hyperalgesia and spinal dynorphin expression in rats with peripheral inflammation. Br Res 999:135–141CrossRefGoogle Scholar
  31. 31.
    Gagliese L, Melzack R (1999) Age differences in the response to the formalin test in rats. Neurobiol of Aging. 20:699–707CrossRefGoogle Scholar
  32. 32.
    Iwata K, Kanda K, Tsuboi Y, Kitajima K, Sumino R (1995) Fos induction in the medullary dorsal horn and C1 segment of the spinal cord by acute inflammation in aged rats. Brain Res 24:127–139CrossRefGoogle Scholar
  33. 33.
    Yezierski RP, King CD, Morgan D, Carter CS, Vierck CJ (2010) Effects of age on thermal sensitivity in the rat. J Gerontol A Biol Sci Med Sci 65:353–362PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Novak JC, Lovell JA, Stuesse SL, Cruce WLR, McBurney DL, Crisp T (1999) Aging and neuropathic pain. Brain Res 833:308–310PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Crisp T, Giles JR, Cruce WLR, McBurney DL, Stuesse SL (2003) The effects of aging on thermal hyperalgesia and tactile-evoked allodynia using two models of peripheral mononeuropathy in the rat. Neurosci Lett 339:103–106PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Chung JM, Choi Y, Yoon YW, Na HS (1995) Effects of age on behavioral signs of neuropathic pain in an experimental rat model. Neurosci Lett 183:54–57PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    Kim YI, Na HS, Yoon YW, Hahm SH, KOKH HSK (1995) Mechanical allodynia is more strongly manifested in older rats in an experimental model of peripheral neuropathy. Neurosci Lett 199:158–160PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Galbavy W, Kaczocha M, Puopolo M, Liu L, Rebecchi MJ (2015) Neuroimmune and neuropathic responses of spinal cord and dorsal root ganglia in middle age. PLoS One 10(8):e0134394PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Bräscher AK, Becker S, Hoeppli ME, Schweinhardt P (2016) Different brain circuitries mediating controllable and uncontrollable pain. J Neurosci 36(18):5013–5025PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Farrell MJ (2012) Age-related changes in the structure and function of brain regions involved in pain processing. Pain Med 13(Suppl 2):S37–S43PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Ochoa J, Mair WG (1969) The normal sural nerve in man. II. Changes in the axons and Schwann cells due to ageing. Acta Neuropathol 13:217–239PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Hakour MC, Gibson SJ, Bradbeer M, Helme RD (1996) The effect of age on Aδ- and C-fibre thermal pain perception. Pain 64:143–152CrossRefGoogle Scholar
  43. 43.
    Kempsell AT, Fieber LA (2014) Behavioral aging is associated with reduced sensory neuron excitability in Aplysia californica. Front Aging Neurosci 6:84PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Watkins LR, Maier SF (2002) Beyond Neurons: evidence that immune and glial cells contribute to pathological pain states. Physiol Rev 82:981–1011PubMedCrossRefPubMedCentralGoogle Scholar
  45. 45.
    Weyer AD, Zappia KJ, Garrison SR, O’Hara CL, Dodge AK, Stucky CL (2016) Nociceptor sensitization depends on age and pain chronicity. eNeuro 3(1):ENEURO.0115-15.2015PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Skaper SD, Giusti P, Facci L (2012) Microglia and mast cells: Two tracks on the road to neuroinflammation. FASEB J 26:3103–3117PubMedCrossRefPubMedCentralGoogle Scholar
  47. 47.
    Bicket MC, Mao J (2015) Chronic pain in older adults. Anesthesiol Clin 33(3):577–590PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    St Sauver JL, Warner DO, Yawn BP, Jacobson DJ, McGree ME, Pankratz JJ, Melton LJ 3rd, Roger VL, Ebbert JO, Rocca WA (2013) Why patients visit their doctors: assessing the most prevalent conditions in a defined American population. Mayo Clin Proc 88:56–67PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Patel KV, Guralnik JM, Dansie EJ, Turk DC (2013) Prevalence and impact of pain among older adults in the United States: findings from the 2011 National Health and Aging Trends Study. Pain 154(12):2649–2657PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    Young MJ, Boulton AJ, MacLeod AF, Williams DR, Sonksen PH (1993) A multicentre study of the prevalence of diabetic peripheral neuropathy in the United Kingdom hospital clinic population. Diabetologia 36(2):150–154PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Cruz-Almeida Y, Aguirre M, Sorenson HL, Tighe P, Wallet SM, Riley JL (2015) Age differences in cytokine expression under conditions of health using experimental pain models. Exp Gerontol 72:150–156PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Woods JA, Wilund KR, Martin SA, Kistler BM (2012) Exercise, inflammation and aging. Aging Dis 3(1):130–140PubMedPubMedCentralGoogle Scholar
  53. 53.
    Loeser RF (2011) Aging and osteoarthritis. Curr Opin Rheumatol 23(5):492–496PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Dimitroulas T, Duarte RV, Behura A, Kitas GD, Raphael JH (2014) Neuropathic pain in osteoarthritis: a review of pathophysiological mechanisms and implications for treatment. Semin Arthritis Rheum 44(2):145–154PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Sharma L, Kapoor D, Issa S (2006) Epidemiology of osteoarthritis: an update. Curr Opin Rheumatol 18:147–156PubMedCrossRefPubMedCentralGoogle Scholar
  56. 56.
    Schaible HG (2012) Mechanisms of chronic pain in osteoarthritis. Curr Rheumatol Rep 14:549–556PubMedCrossRefPubMedCentralGoogle Scholar
  57. 57.
    Loeser RF, Collins JA, Diekman BO (2016) Ageing and the pathogenesis of osteoarthritis. Nat Rev Rheumatol 12(7):412–420PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Henrotin YE, Bruckner P, Pujol JP (2003) The role of reactive oxygen species in homeostasis and degradation of cartilage. Osteoarthritis Cartilage 11:747–755PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    Valdes AM, Suokas AK, Doherty SA, Jenkins W, Doherty M (2014) History of knee surgery is associated with higher prevalence of neuropathic pain-like symptoms in patients with severe osteoarthritis of the knee. Semin Arthritis Rheum 43:588–592PubMedCrossRefPubMedCentralGoogle Scholar
  60. 60.
    Ohtori S, Orita S, Yamashita M, Ishikawa T, Ito T, Shigemura T et al (2012) Existence of a neuropathic pain component in patients with osteoarthritis of the knee. Yonsei Med J 53:801–805PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Duarte RV, Raphael JH, Dimitroulas T, Sparkes E, Southall JL, Ashford RL, Kitas GD (2014) Osteoarthritis pain has a significant neuropathic component: an exploratory in vivo patient model. Rheumatol Int 34:315–320PubMedCrossRefPubMedCentralGoogle Scholar
  62. 62.
    Varija D, Kumar KP, Reddy KP, Reddy VK (2008) Prolonged constriction of sciatic nerve affecting oxidative stressors & antioxidant enzymes in rat. Indian J Med Res 129:587–592Google Scholar
  63. 63.
    Pickering G (2014) Antiepileptics for post-herpetic neuralgia in the elderly: current and future prospects. Drugs Aging 31(9):653–660PubMedCrossRefPubMedCentralGoogle Scholar
  64. 64.
    Opsstelten W, Mauritz JW, deWit NJ, Van Vijck AJM, Stalman WAB, Van Essen GA (2002) Herpes Zoster and postherpetic neuralgia: incidence and risk indicators using a general practice research database. Fam Pract 19(5):471–475CrossRefGoogle Scholar
  65. 65.
    Kost R, Straus S (1996) Postherpetic neuralgia-pathogenesis, treatment and prevention. N Eng J Med 332(1):32–42CrossRefGoogle Scholar
  66. 66.
    Garry EM, Delaney A, Anderson HA, Sirinathsinghji EC, Clapp RH, Martin WJ, Kinchington PR, Krah DL, Abbadie C, Fleetwood-Walker SM (2005) Varicella zoster virus induces neuropathic changes in dorsal root ganglia and behavioral reflex sensitization that is attenuated by gabapentin or sodium channel blocking drugs. Pain 118(1–2):97–111PubMedCrossRefPubMedCentralGoogle Scholar
  67. 67.
    Baron R, Binder A, Wasner G (2010) Neuropathic pain: diagnosis, pathophysiological mechanisms and treatment. Lancet Neurol 9(8):807–819PubMedCrossRefPubMedCentralGoogle Scholar
  68. 68.
    Fields H, Rowbotham M, Baron R (1998) Postherpetic neuralgia: irritable nociceptors and deafferentation. Neurobiol Dis 5(4):209–227PubMedCrossRefPubMedCentralGoogle Scholar
  69. 69.
    Dunn KM, Hestbaek L, Cassidy JD (2013) Low back pain across the life course. Best Pract Res Clin Rheumatol 27(5):591–600PubMedCrossRefPubMedCentralGoogle Scholar
  70. 70.
    Dionne CE, Dunn KM, Croft PR (2006) Does back pain prevalence really decrease with increasing age? A systematic review. Age Ageing 35(3):229–234PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    Ito K, Creemers L (2013) Mechanisms of intervertebral disk degeneration/injury and pain: a review. Global Spine J 3(3):145–152.  https://doi.org/10.1055/s-0033-1347300 CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Martin RR, Hadjistavropoulos T, McCreary DR (2005) Fear of pain and fear of falling among younger and older adults with musculoskeletal pain conditions. Pain Res Manag 10(4):211–219PubMedCrossRefPubMedCentralGoogle Scholar
  73. 73.
    Hübscher M, Vogt L, Schmidt K, Fink M, Banzer W (2010) Perceived pain, fear of falling and physical function in women with osteoporosis. Gait Posture 32(3):383–385PubMedCrossRefPubMedCentralGoogle Scholar
  74. 74.
    Kaye AD, Baluch A, Scott JT (2010) Pain management in the elderly population: a review. Ochsner J 10(3):179–187PubMedPubMedCentralGoogle Scholar
  75. 75.
    Mol ME, van Boxtel MP, Willems D, Jolles J (2006) Do subjective memory complaints predict cognitive dysfunction over time? A six-year follow-up of the Maastricht Aging Study. Int J Geriatr Psychiatry 21(5):432–441PubMedCrossRefPubMedCentralGoogle Scholar
  76. 76.
    Weiner DK, Rudy TE (2002) Attitudinal barriers to effective treatment of persistent pain in nursing home residents. J Am Geriatr Soc 50(12):2035–2040PubMedCrossRefPubMedCentralGoogle Scholar
  77. 77.
    Jennings EM, Okine BN, Roche M, Finn DP (2014) Stress-induced hyperalgesia. Prog Neurobiol 121:1–18PubMedCrossRefPubMedCentralGoogle Scholar
  78. 78.
    Ploghaus A, Narain C, Beckmann CF, Clare S, Bantick S, Wise R, Matthews PM, Rawlins JN, Tracey I (2001) Exacerbation of pain by anxiety is associated with activity in a hippocampal network. J Neurosci 21:9896–9903PubMedCrossRefPubMedCentralGoogle Scholar
  79. 79.
    Rhudy JL, Meagher MW (2000) Fear and anxiety: divergent effects on human pain thresholds. Pain 84:65–75PubMedCrossRefPubMedCentralGoogle Scholar
  80. 80.
    Gamaro GD, Xavier MH, Denardin JD, Pilger JA, Ely DR, Ferreira MB, Dalmaz C (1998) The effects of acute and repeated restraint stress on the nociceptive response in rats. Physiol Behav 63:693–697PubMedCrossRefPubMedCentralGoogle Scholar
  81. 81.
    Yeon KY, Kim SA, Kim YH, Lee MK, Ahn DK, Kim HJ, Kim JS, Jung SJ, Oh SB (2010) Curcumin produces an anti- hyperalgesic effect via antagonism of TRPV1. J Dent Res 89:170–174PubMedCrossRefPubMedCentralGoogle Scholar
  82. 82.
    McKeown JL (2015) Pain management issues for the geriatric surgical patient. Anesthesiol Clin 33(3):563–576PubMedCrossRefPubMedCentralGoogle Scholar
  83. 83.
    Bowden JL, McNulty PA (2013) Age-related changes in cutaneous sensation in the healthy human hand. Age (Dordr) 35:1077–1089CrossRefGoogle Scholar
  84. 84.
    Tracy B, Sean Morrison R (2013) Pain management in older adults. Clin Ther 35:1659–1668PubMedCrossRefPubMedCentralGoogle Scholar
  85. 85.
    Gibson SJ, Lussier D (2012) Prevalence and relevance of pain in older persons. Pain Med 13:S23–S26PubMedCrossRefPubMedCentralGoogle Scholar
  86. 86.
    Jones MR, Ehrhardt KP, Ripoll JG, Sharma B, Padnos IW, Kaye RJ, Kaye AD (2016) Pain in the elderly. Curr Pain Headache Rep 20:23PubMedCrossRefPubMedCentralGoogle Scholar
  87. 87.
    Helme RD, Katz B, Gibson S, Corran T (1989) Can psychometric tools be used to analyse pain in a geriatric population. Clin Exp Neurol 26:113–117PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  1. 1.Biochemistry & Molecular Biology Laboratory, Department of Zoology, Institute of ScienceBanaras Hindu UniversityVaranasiIndia

Personalised recommendations