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Emerging Concepts of Pain Therapy Based on Neuronal Mechanisms

  • Chapter
Pain Control

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 227))

Abstract

Current pain treatment is successful in many patients, but nevertheless numerous problems have to be solved because still about 20 % of the people in the population suffer from chronic pain. A major aim of pain research is, therefore, to clarify the neuronal mechanisms which are involved in the generation and maintenance of different pain states and to identify the mechanisms which can be targeted for pain treatment. This volume on pain control addresses neuronal pain mechanisms at the peripheral, spinal, and supraspinal level which are thought to significantly contribute to pain and which may be the basis for the development of new treatment principles. This introductory chapter addresses the types of pain which are currently defined based on the etiopathologic considerations, namely physiologic nociceptive pain, pathophysiologic nociceptive pain, and neuropathic pain. It briefly describes the structures and neurons of the nociceptive system, and it addresses molecular mechanisms of nociception which may become targets for pharmaceutical intervention. It will provide a frame for the chapters which address a number of important topics. Such topics are the concept of hyperalgesic priming, the role of voltage-gated sodium channels and nerve growth factor (NGF) in different inflammatory and neuropathic pain states, the hyperalgesic effects of NGF in different tissues, the contribution of proteinase-activated receptors (PARs) to the development of pain in several chronic pain conditions, the role of spinal NO and of glial cell activation in the generation and maintenance of inflammatory and neuropathic pain, the potential role of spinal inhibitory interneurons, the endogenous endocannabinoid system, and the importance of nonneuronal immune mechanisms in opioid signaling in the control of pain, the influence of spinal mechanisms on the expression of peripheral inflammation, the role of the amygdala and their connections to the medial prefrontal cortex in pain states, the experimental methods to test central sensitization of the nociceptive system in humans, and differences and similarities of the neuronal systems of pain and itch. Finally it will be discussed that both the concentration on single key molecules of nociception and the interference with disease-related mediators may provide novel approaches of pain treatment.

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References

  • Arendt-Nielsen L (2015) Central sensitization in humans: assessment and pharmacology. In: Schaible H-G (ed) Pain control. Springer, Berlin, pp 79–102

    Google Scholar 

  • Bär K-J, Natura G, Telleria-Diaz A, Teschner P, Vogel R, Vasquez E, Schaible H-G, Ebersberger A (2004) Changes in the effect of spinal prostaglandin E2 during inflammation—prostaglandin E (EP1-EP4) receptors in spinal nociceptive processing of input from the normal or inflamed knee joint. J Neurosci 24:642–651

    Article  PubMed  Google Scholar 

  • Basbaum AI, Bautista DM, Scherrer G, Julius D (2009) Cellular and molecular mechanisms of pain. Cell 139:267–284

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Bennett D (2007) NGF, sensitization of nociceptors. In: Schmidt RF, Willis WD (eds) Encyclopedia of pain, vol 2. Springer, Berlin, pp 1338–1342

    Chapter  Google Scholar 

  • Breivik H, Beverly C, Ventafridda V, Cohen R, Gallacher D (2006) Survey of chronic pain in Europe: prevalence, impact on daily life, and treatment. Eur J Pain 10:287–333

    Article  PubMed  Google Scholar 

  • Brenn D, Richter F, Schaible H-G (2007) Sensitization of unmyelinated sensory fibres of the joint nerve to mechanical stimuli by interleukin-6 in the rat. An inflammatory mechanism of joint pain. Arthritis Rheum 56:351–359

    Article  CAS  PubMed  Google Scholar 

  • Bushnell MC, Ceko M, Low LA (2013) Cognitive and emotional control of pain and its disruption in chronic pain. Nat Rev Neurosci 14:502–511

    Article  CAS  PubMed  Google Scholar 

  • Cervero F (2009) Spinal cord hyperexcitability and its role in pain and hyperalgesia. Exp Brain Res 196:129–137

    Article  PubMed  Google Scholar 

  • Denk F, McMahon SB, Tracey I (2014) Pain vulnerability: a neurobiological perspective. Nat Neurosci 17:192–200

    Article  CAS  PubMed  Google Scholar 

  • Devor M (2009) Ectopic discharge in Aβ afferents as a source of neuropathic pain. Exp Brain Res 196:115–128

    Article  CAS  PubMed  Google Scholar 

  • Duvarci S, Pare D (2014) Amygdala microcircuits controlling learned fear. Neuron 82:966–980

    Article  CAS  PubMed  Google Scholar 

  • Gold MS (2008) Na+ channel blockers for the treatment of pain: context is everything, almost. Exp Neurol 210:1–6

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Gwilym SE, Filippini N, Douaud G, Carr AJ, Tracey I (2010) Thalamic atrophy associated with painful osteoarthritis of the hip is reversible after arthroplasty. Arthritis Rheum 62:2930–2940

    Article  PubMed  Google Scholar 

  • Habib AM, Wood JN, Cox JJ (2015) Sodium channels and pain. In: Schaible H-G (ed) Pain control. Springer, Berlin, pp 39–56

    Google Scholar 

  • Hucho T, Levine JD (2007) Signaling pathways in sensitization: toward a nociceptor cell biology. Neuron 55:365–376

    Article  CAS  PubMed  Google Scholar 

  • Julius D (2013) TRP channels and pain. Annu Rev Cell Dev Biol 29:355–384

    Article  CAS  PubMed  Google Scholar 

  • Kandasamy R, Price TJ (2015) The pharmacology of nociceptor priming. In: Schaible H-G (ed) Pain control. Springer, Berlin, pp 15–37

    Google Scholar 

  • Kosek E, Ordeberg G (2000) Lack of pressure pain modulation by heterotopic noxious conditioning stimulation in patients with painful osteoarthritis before, but not following surgical pain relief. Pain 88:69–78

    Article  CAS  PubMed  Google Scholar 

  • Kulkarni B, Bentley DE, Elliott R, Julyan PJ, Boger E, Watson A, Boyle Y, El-Deredy W, Jones AKP (2007) Arthritic pain is processed in brain areas concerned with emotions and fear. Arthritis Rheum 56:1345–1354

    Article  CAS  PubMed  Google Scholar 

  • Kwan KY, Glazer JM, Corey DP, Rice FL, Stucky CL (2009) TRPA1 modulates mechanotransduction in cutaneous sensory neurons. J Neurosci 29:4808–4819

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Lane NE, Schnitzer TJ, Birbara CA, Mokhtarani M, Shelton DL, Smith MD, Brown MT (2010) Tanezumab for the treatment of pain from osteoarthritis of the knee. N Engl J Med 363:1521–1531

    Article  CAS  PubMed  Google Scholar 

  • Levine JD, Alessandri-Haber N (2007) TRP channels: targets for the relief of pain. Biochim Biophys Acta 1772:989–1003

    Article  CAS  PubMed  Google Scholar 

  • Lewis GN, Rice DA, McNair PJ (2012) Conditioned pain modulation in populations with chronic pain: a systematic review and meta-analysis. J Pain 13:936–944

    Article  PubMed  Google Scholar 

  • Linley JE, Rose K, Ooi L, Gamper N (2010) Understanding inflammatory pain: ion channels contributing to acute and chronic nociception. Pflugers Arch 459:657–669

    Article  CAS  PubMed  Google Scholar 

  • Malsch P, Andratsch M, Vogl C, Link AS, Alzheimer C, Brierley SM, Hughes PA, Kress M (2014) Deletion of interleukin-6 signal transducer gp130 in small sensory neurons attenuates mechanonociception and down-regulates mechanotransducer ion channel TRPA1. J Neurosci 34:9845–9856

    Article  PubMed Central  PubMed  Google Scholar 

  • McDougall JJ, Muley MM (2015) The role of proteases in pain. In: Schaible H-G (ed) Pain control. Springer, Berlin, pp 239–260

    Google Scholar 

  • McMahon SB, Malcangio M (2009) Current challenges in glia-pain biology. Neuron 64:46–54

    Article  CAS  PubMed  Google Scholar 

  • Mizumura K, Murase S (2015) Role of nerve growth factor in pain. In: Schaible H-G (ed) Pain control. Springer, Berlin, pp 57–77

    Google Scholar 

  • Natura G, Bär K-J, Eitner A, Böttger M, Richter F, Hensellek S, Ebersberger A, Leuchtweis J, Maruyama T, Hofmann GO, Halbhuber K-J, Schaible H-G (2013) Neuronal prostaglandin E2 receptor subtype EP3 mediates antinociception during inflammation. Proc Natl Acad Sci U S A 110:13648–13653

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Neugebauer V (2015) Amygdala pain mechanisms. In: Schaible H-G (ed) Pain control. Springer, Berlin, pp 261–284

    Google Scholar 

  • Old EA, Clark AK, Malcangio M (2015) The role of glia in the spinal cord in neuropathic and inflammatory pain. In: Schaible H-G (ed) Pain control. Springer, Berlin, pp 145–170

    Google Scholar 

  • Ossipov MH, Dussor GO, Porreca F (2010) Central modulation of pain. J Clin Invest 120:3779–3787

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Phillips K, Clauw DJ (2013) Central pain mechanisms in the rheumatic diseases. Arthritis Rheum 65:291–302

    Article  PubMed Central  PubMed  Google Scholar 

  • Richter F, Natura G, Loeser S, Schmidt K, Viisanen H, Schaible H-G (2010) Tumor necrosis factor-α (TNF-α) causes persistent sensitization of joint nociceptors for mechanical stimuli. Arthritis Rheum 62:3806–3814

    Article  CAS  PubMed  Google Scholar 

  • Richter F, Natura G, Ebbinghaus M, Segond von Banchet G, Hensellek S, König C, Bräuer R, Schaible H-G (2012) Interleukin-17 sensitizes joint nociceptors for mechanical stimuli and contributes to arthritic pain through neuronal IL-17 receptors in rodents. Arthritis Rheum 64:4125–4134

    Article  CAS  PubMed  Google Scholar 

  • Rodriguez-Raecke R, Niemeier A, Ihle K, Ruether W, May A (2009) Brain gray matter decrease in chronic pain is the consequence and not the cause of pain. J Neurosci 29:13746–13750

    Article  CAS  PubMed  Google Scholar 

  • Sandkühler J (2000) Learning and memory in pain pathways. Pain 88:113–118

    Article  PubMed  Google Scholar 

  • Schaible H-G, Richter F (2004) Pathophysiology of pain. Langenbecks Arch Surg 389:237–243

    Article  PubMed  Google Scholar 

  • Schaible H-G, Straub RH (2014) Function of the sympathetic supply in acute and chronic experimental joint inflammation. Auton Neurosci 182:55–64

    Article  PubMed  Google Scholar 

  • Schaible H-G, Richter F, Ebersberger A, Boettger MK, Vanegas H, Natura G, Vazquez E, Segond von Banchet G (2009) Joint pain. Exp Brain Res 196:153–162

    Article  PubMed  Google Scholar 

  • Schaible H-G, Segond von Banchet G, Boettger MK, Bräuer R, Gajda M, Richter F, Hensellek S, Brenn D, Natura G (2010) The role of proinflammatory cytokines in the generation and maintenance of joint pain. Ann N Y Acad Sci 1193:60–69

    Article  CAS  PubMed  Google Scholar 

  • Schaible H-G, Ebersberger A, Natura G (2011) Update on peripheral mechanisms of pain: beyond prostaglandins and cytokines. Arthritis Res Ther 13:21

    Article  Google Scholar 

  • Schmelz M (2015) Itch and pain differences and commonalities. In: Schaible H-G (ed) Pain control. Springer, Berlin, pp 285–300

    Google Scholar 

  • Schmidtko A (2015) Nitric oxide mediated pain processing in the spinal cord. In: Schaible H-G (ed) Pain control. Springer, Berlin, pp 103–117

    Google Scholar 

  • Segond von Banchet G, Boettger MK, König C, Iwakura Y, Bräuer R, Schaible H-G (2013) Neuronal IL-17 receptor upregulates TRPV4 but not TRPV1 receptors in DRG neurons and mediates mechanical but not thermal hyperalgesia. Mol Cell Neurosci 52:152–160

    Article  CAS  PubMed  Google Scholar 

  • Sommer C, Kress M (2004) Recent findings on how proinflammatory cytokines cause pain: peripheral mechanisms in inflammatory and neuropathic hyperalgesia. Neurosci Lett 361:184–187

    Article  CAS  PubMed  Google Scholar 

  • Sorkin LS (2015) Modulation of peripheral inflammation by the spinal cord. In: Schaible H-G (ed) Pain control. Springer, Berlin, pp 191–206

    Google Scholar 

  • Stein C, Clark JD, Oh U, Vasko MR, Wilcox GL, Overland AC, Vanderah TW, Spencer RH (2009) Peripheral mechanisms of pain and analgesia. Brain Res Rev 60:90–113

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Thomas J, Mustafa S, Johnson J, Nicotra L, Hutchinson M (2015) The relationship between opioids and immune signalling in the spinal cord. In: Schaible H-G (ed) Pain control. Springer, Berlin, pp 207–238

    Google Scholar 

  • Todd AJ (2015) Plasticity of inhibition in the spinal cord. In: Schaible H-G (ed) Pain control. Springer, Berlin, pp 171–190

    Google Scholar 

  • Treede RD, Kenshalo DR, Gracely RH, Jones A (1999) The cortical representation of pain. Pain 79:105–111

    Article  CAS  PubMed  Google Scholar 

  • Üceyler N, Schäfers M, Sommer C (2009) Mode of action of cytokines on nociceptive neurons. Exp Brain Res 196:67–78

    Article  PubMed  Google Scholar 

  • Vanegas H, Schaible H-G (2004) Descending control of persistent pain: inhibitory or facilitatory? Brain Res Rev 46:295–309

    Article  PubMed  Google Scholar 

  • Vogt BA (2005) Pain and emotion. Interactions in subregions of the cingulate cortex. Nat Rev Neurosci 6:533–544

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Waldburger JM, Firestein GS (2010) Regulation of peripheral inflammation by the central nervous system. Curr Rheumatol Rep 12:370–378

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Waxman SG, Zamponi GW (2014) Regulating excitability of peripheral afferents: emerging ion channel targets. Nat Neurosci 17:153–163

    Article  CAS  PubMed  Google Scholar 

  • Woodhams SG, Sagar DR, Burston JJ, Chapman V (2015) The role of the endocannabinoid system in pain. In: Schaible H-G (ed) Pain control. Springer, Berlin, pp 119–143

    Google Scholar 

  • Woolf CJ, Salter MW (2000) Neuronal plasticity: increasing the gain in pain. Science 288:1765–1768

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Hans-Georg Schaible .

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Schaible, HG. (2015). Emerging Concepts of Pain Therapy Based on Neuronal Mechanisms. In: Schaible, HG. (eds) Pain Control. Handbook of Experimental Pharmacology, vol 227. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-46450-2_1

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