Skip to main content
SpringerLink
Log in

Central mechanisms in the maintenance of chronic widespread noninflammatory muscle pain

  • Published:
Current Pain and Headache Reports Aims and scope Submit manuscript

Abstract

Chronic widespread pain (CWP) conditions such as fibromyalgia and myofascial syndromes are characterized by generalized pain, tenderness, morning stiffness, disturbed sleep, and pronounced fatigue. However, CWP pathophysiology is still unclear. A number of hypotheses have been proposed as the underlying pathophysiology of CWP: muscular dysfunction/ischemia, central sensitization, and a deficit in endogenous pain-modulating systems. This article reviews the current and emerging literature about the pathophysiology and neurobiology of chronic widespread musculoskeletal pain. Widespread musculoskeletal pain results in changes in the central nervous system in human subjects and animal models. These changes likely reflect alterations in supraspinal modulation of nociception, and include increases in excitatory and decreases in inhibitory modulation pathways. These alterations in excitation and inhibition likely drive changes observed in the spinal cord to result in central sensitization, and the consequent pain and hyperalgesia.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

  1. Clauw DJ, Crofford LJ: Chronic widespread pain and fibromyalgia: what we know, and what we need to know? Best Pract Res Clin Rheumatol 2003, 17:685–701.

    Article  Google Scholar 

  2. Wolfe F, Smythe HA, Yunus MB, et al.: The American College of Rheumatology 1990 criteria for the classification of fibromyalgia. Report of the multicenter criteria committee. Arthritis Rheum 1990, 33:160–172.

    Article  PubMed  CAS  Google Scholar 

  3. Boissevain MD, McCain GA: Toward an integrated understanding of fibromyalgia syndrome. I. Medical and pathophysiological aspects. Pain 1991, 45:227–238.

    Article  PubMed  CAS  Google Scholar 

  4. Bengtsson A, Henriksson KG: The muscle in fibromyalgia—a review of Swedish studies. J Rheumatol Suppl 1989, 19:144–149.

    PubMed  CAS  Google Scholar 

  5. Henriksson KG, Bengtsson A: Fibromyalgia—a clinical entity? Can J Physiol Pharmacol 1991, 69:672–677.

    PubMed  CAS  Google Scholar 

  6. Staud R, Vierck CJ, Mauderli A, et al.: Abnormal temporal summation of second pain (wind-up) in patients with the fibromyalgia syndrome. Arthritis Rheum 1998, 41:S353.

    Google Scholar 

  7. Price DD, Staud R, Robinson ME, et al.: Enhanced temporal summation of second pain and its central modulation in fibromyalgia patients. Pain 2002, 99:49–59.

    Article  PubMed  Google Scholar 

  8. Kosek E, Ekholm J, Hansson P: Modulation of pressure pain thresholds during and following isometric contraction in patients with fibromyalgia and in healthy controls. Pain 1996, 64:415–423.

    Article  PubMed  CAS  Google Scholar 

  9. Julien N, Goffaux P, Arsenault P, et al.: Widespread pain in fibromyalgia is related to a deficit of endogenous pain inhibition. Pain 2005, 114:295–302.

    Article  PubMed  Google Scholar 

  10. Graven-Nielsen T, Aspegren KS, Henriksson KG, et al.: Ketamine reduces muscle pain, temporal summation, and referred pain in fibromyalgia patients. Pain 2000, 85:483–491.

    Article  PubMed  CAS  Google Scholar 

  11. Vierck CJ Jr, Staud R, Price DD, et al.: The effect of maximal exercise on temporal summation of second pain (windup) in patients with fibromyalgia syndrome. J Pain 2001, 2:334–344.

    Article  PubMed  Google Scholar 

  12. Staud R, Carl KE, Vierck CJ, et al.: Repetitive muscle stimuli result in enhanced wind-up of fibromyalgia patients. Arthritis Rheum 2001, 44:S395.

    Google Scholar 

  13. Sörensen J, Graven-Nielsen T, Henriksson KG, et al.: Hyperexcitability in fibromyalgia. J Rheumatol 1998, 25:152–155.

    PubMed  Google Scholar 

  14. Staud R, Vierck CJ, Cannon RL, et al.: Abnormal sensitization and temporal summation of second pain (wind-up) in patients with fibromyalgia syndrome. Pain 2001, 91:165–175.

    Article  PubMed  CAS  Google Scholar 

  15. Kosek E, Hansson P: Modulatory influence on somatosensory perception from vibration and heterotopic noxious conditioning stimulation (HNCS) in fibromyalgia patients and healthy subjects. Pain 1997, 70:41–51.

    Article  PubMed  CAS  Google Scholar 

  16. Staud R, Vierck CJ, Robinson ME, et al.: Effects of the N-methyl-D-aspartate receptor antagonist dextromethorphan on temporal summation of pain are similar in fibromyalgia patients and normal control subjects. J Pain 2005, 6:323–332.

    Article  PubMed  CAS  Google Scholar 

  17. Russell IJ, Orr MD, Littman B, et al.: Elevated cerebrospinal fluid levels of substance P in patients with the fibromyalgia syndrome. Arthritis Rheum 1994, 37:1593–1601.

    Article  PubMed  CAS  Google Scholar 

  18. Giovengo SL, Russell IJ, Larson AA: Increased concentrations of nerve growth factor in cerebrospinal fluid of patients with fibromyalgia. J Rheumatol 1999, 26:1564–1569.

    PubMed  CAS  Google Scholar 

  19. Vierck CJ Jr: Mechanisms underlying development of spatially distributed chronic pain (fibromyalgia). Pain 2006, 124:242–263.

    Article  PubMed  Google Scholar 

  20. Staud R, Rodriguez ME: Mechanisms of disease: pain in fibromyalgia syndrome. Nat Clin Pract Rheumatol 2006, 2:90–98.

    Article  PubMed  Google Scholar 

  21. Sluka KA, Kalra A, Moore SA: Unilateral intramuscular injections of acidic saline produce a bilateral, long-lasting hyperalgesia. Muscle Nerve 2001, 24:37–46.

    Article  PubMed  CAS  Google Scholar 

  22. Sluka KA: Stimulation of deep somatic tissue with capsaicin produces long-lasting mechanical allodynia and heat hypoalgesia that depends on early activation of the cAMP pathway. J Neurosci 2002, 22:5687–5693.

    PubMed  CAS  Google Scholar 

  23. Radhakrishnan R, Sluka KA: Spinal muscarinic receptors are activated during low or high frequency TENS-induced antihyperalgesia in rats. Neuropharmacology 2003, 45:1111–1119.

    Article  PubMed  CAS  Google Scholar 

  24. Skyba DA, King EW, Sluka KA: Effects of NMDA and non-NMDA ionotropic glutamate receptor antagonists on the development and maintenance of hyperalgesia induced by repeated intramuscular injection of acidic saline. Pain 2002, 98:69–78.

    Article  PubMed  CAS  Google Scholar 

  25. Skyba DA, Lisi TL, Sluka KA: Excitatory amino acid concentrations increase in the spinal cord dorsal horn after repeated intramuscular injection of acidic saline. Pain 2005, 119:142–149.

    Article  PubMed  CAS  Google Scholar 

  26. Hoeger-Bement MK, Sluka KA: Phosphorylation of CREB and mechanical hyperalgesia is reversed by blockade of the cAMP pathway in a time-dependent manner after repeated intramuscular acid injections. J Neurosci 2003, 23:5437–5445.

    PubMed  CAS  Google Scholar 

  27. Yokoyama T, Maeda Y, Audette KM, Sluka KA: Pregabalin reduces muscle and cutaneous hyperalgesia in two models of chronic muscle pain in rats. J Pain 2007, 8:422–429.

    Article  PubMed  CAS  Google Scholar 

  28. Tillu DV, Gebhart GF, Sluka KA: Descending facilitatory pathways from the RVM initiate and maintain bilateral hyperalgesia after muscle insult. Pain 2008, 136:331–339.

    Article  PubMed  CAS  Google Scholar 

  29. Nielsen AN, Mathiesen C, Blackburn-Munro G: Pharmacological characterisation of acid-induced muscle allodynia in rats. Eur J Pharmacol 2004, 487:93–103.

    Article  PubMed  CAS  Google Scholar 

  30. Sluka KA, Rohlwing JJ, Bussey RA, et al.: Chronic muscle pain induced by repeated acid injection is reversed by spinally administered mu-and delta-, but not kappa-, opioid receptor agonists. J Pharmacol Exp Ther 2002, 302:1146–1150.

    Article  PubMed  CAS  Google Scholar 

  31. Bement MK, Sluka KA: Low-intensity exercise reverses chronic muscle pain in the rat in a naloxone-dependent manner. Arch Phys Med Rehabil 2005, 86:1736–1740.

    Article  PubMed  Google Scholar 

  32. Busch AJ, Barber KA, Overend TJ, et al.: Exercise for treating fibromyalgia syndrome. Cochrane Database Syst Rev 2007, CD003786.

  33. Yokoyama T, Lisi TL, Moore SA, et al.: Muscle fatigue increases the probability of developing hyperalgesia in mice. J Pain 2007, 8:692–699.

    Article  PubMed  Google Scholar 

  34. Reeh PW, Steen KH: Tissue acidosis in nociception and pain. Prog Brain Res 1996, 113:143–151.

    Article  PubMed  CAS  Google Scholar 

  35. Frey Law LA, Sluka KA, McMullen T, et al.: Acidic buffer induced muscle pain evokes referred pain and mechanical hyperalgesia in humans [abstract]. Presented at the 12th World Congress on Pain, International Association for the Study of Pain. Glasgow, Scotland; August 17–22, 2008.

  36. Graven-Nielsen T, Arendt-Nielsen L, Svensson P, et al.: Quantification of local and referred muscle pain in humans after sequential i.m. injections of hypertonic saline. Pain 1997, 69:111–117.

    Article  PubMed  CAS  Google Scholar 

  37. Graven-Nielsen T, Arendt-Nielsen L, Svensson P, et al.: Experimental muscle pain: a quantitative study of local and referred pain in humans following injection of hypertonic saline. J Musculoskelet Pain 1997, 5:49–69.

    Article  Google Scholar 

  38. Graven-Nielsen T, Arendt-Nielsen L, Svensson P, et al.: Stimulus-response functions in areas with experimentally induced referred muscle pain—a psychophysical study. Brain Res 1997, 744:121–128.

    Article  PubMed  CAS  Google Scholar 

  39. Dougherty PM, Willis WD: Enhanced responses of spinothalamic tract neurons to excitatory amino acids accompany capsaicin-induced sensitization in the monkey. J Neurosci 1992, 12:883–894.

    PubMed  CAS  Google Scholar 

  40. Sluka KA, Westlund KN: Spinal cord amino acid release and content in an arthritis model: the effects of pretreatment with non-NMDA, NMDA, and NK1 receptor antagonists. Brain Res 1993, 627:89–103.

    Article  PubMed  CAS  Google Scholar 

  41. Sluka KA, Price MP, Breese NM, et al.: Chronic hyperalgesia induced by repeated acid injections in muscle is abolished by the loss of ASIC3, but not ASIC1. Pain 2003, 106:229–239.

    Article  PubMed  CAS  Google Scholar 

  42. Sluka KA: Activation of the cAMP transduction cascade contributes to the mechanical hyperalgesia and allodynia induced by intradermal injection of capsaicin. Br J Pharmacol 1997, 122:1165–1173.

    Article  PubMed  CAS  Google Scholar 

  43. Dolan S, Nolan AM: Biphasic modulation of nociceptive processing by the cyclic AMP-protein kinase A signalling pathway in sheep spinal cord. Neurosci Lett 2001, 309:157–160.

    Article  PubMed  CAS  Google Scholar 

  44. Vadakkan KI, Wang H, Ko SW, et al.: Genetic reduction of chronic muscle pain in mice lacking calcium/calmodulin-stimulated adenylyl cyclases. Mol Pain 2006, 2:7.

    Article  PubMed  Google Scholar 

  45. Bement MK, Sluka KA: Co-localization of p-CREB and p-NR1 in spinothalamic neurons in a chronic muscle pain model. Neurosci Lett 2007, 418:22–27.

    Article  PubMed  CAS  Google Scholar 

  46. Sluka KA, Skyba DA, Hoeger Bement MK, et al.: Second messenger pathways in pain. In Molecular Pain. China: Higher Education Press, Springer; 2008.

    Google Scholar 

  47. Sluka KA, Audette KM: Activation of protein kinase C in the spinal cord produces mechanical hyperalgesia by activating glutamate receptors, but does not mediate chronic muscle-induced hyperalgesia. Mol Pain 2006, 2:13.

    Article  PubMed  CAS  Google Scholar 

  48. Watkins LR, Milligan ED, Maier SF: Glial activation: a driving force for pathological pain. Trends Neurosci 2001, 24:450–455.

    Article  PubMed  CAS  Google Scholar 

  49. Watkins LR, Maier SF: Beyond neurons: evidence that immune and glial cells contribute to pathological pain states. Physiol Rev 2002, 82:981–1011.

    PubMed  CAS  Google Scholar 

  50. Fu KY, Light AR, Matsushima GK, et al.: Microglial reactions after subcutaneous formalin injection into the rat hind paw. Brain Res 1999, 825:59–67.

    Article  PubMed  CAS  Google Scholar 

  51. Sweitzer SM, Colburn RW, Rutkowski M, et al.: Acute peripheral inflammation induces moderate glial activation and spinal IL-1beta expression that correlates with pain behavior in the rat. Brain Res 1999, 829:209–221.

    Article  PubMed  CAS  Google Scholar 

  52. Ledeboer A, Mahoney JH, Milligan ED, et al.: Spinal cord glia and interleukin-1 do not appear to mediate persistent allodynia induced by intramuscular acidic saline in rats. J Pain 2006, 7:757–767.

    Article  PubMed  CAS  Google Scholar 

  53. Willis WD, Sluka KA, Rees H, et al.: Cooperative mechanisms of neurotransmitter action in central nervous sensitization. Prog Brain Res 1996, 110:151–166.

    Article  PubMed  CAS  Google Scholar 

  54. Terayama R, Dubner R, Ren K: The roles of NMDA receptor activation and nucleus reticularis gigantocellularis in the time-dependent changes in descending inhibition after inflammation. Pain 2002, 97:171–181.

    Article  PubMed  CAS  Google Scholar 

  55. Vera-Portocarrero LP, Xie JY, Kowal J, et al.: Descending facilitation from the rostral ventromedial medulla maintains visceral pain in rats with experimental pancreatitis. Gastroenterology 2006, 130:2155–2164.

    Article  PubMed  Google Scholar 

  56. Vera-Portocarrero LP, Zhang ET, Ossipov MH, et al.: Descending facilitation from the rostral ventromedial medulla maintains nerve injury-induced central sensitization. Neuroscience 2006, 140:1311–1320.

    Article  PubMed  CAS  Google Scholar 

  57. Staud R, Robinson ME, Vierck CJ Jr, et al.: Diffuse noxious inhibitory controls (DNIC) attenuate temporal summation of second pain in normal males but not in normal females or fibromyalgia patients. Pain 2003, 101:167–174.

    Article  PubMed  Google Scholar 

  58. Sluka KA, Radhakrishnan R, Benson CJ, et al.: ASIC3 in muscle mediates mechanical, but not heat, hyperalgesia associated with muscle inflammation. Pain 2007, 129:102–112.

    Article  PubMed  Google Scholar 

  59. Ikeuchi M, Kolker SJ, Burnes LA, et al.: Role of ASIC3 in the primary and secondary hyperalgesia produced by joint inflammation in mice. Pain 2008 Mar 13 (Epub ahead of print).

  60. Chen CC, Zimmer A, Sun WH, et al.: A role for ASIC3 in the modulation of high-intensity pain stimuli. Proc Natl Acad Sci U S A 2002, 99:8992–8997.

    PubMed  CAS  Google Scholar 

  61. Mogil JS, Breese NM, Witty MF, et al.: Transgenic expression of a dominant-negative ASIC3 subunit leads to increased sensitivity to mechanical and inflammatory stimuli. J Neurosci 2005, 25:9893–9901.

    Article  PubMed  CAS  Google Scholar 

  62. Snider WD: Functions of the neurotrophins during nervous system development: what the knockouts are teaching us. Cell 1994, 77:627–638.

    Article  PubMed  Google Scholar 

  63. Nagano M, Suzuki H: Quantitative analyses of expression of GDNF and neurotrophins during postnatal development in rat skeletal muscles. Neurosci Res 2003, 45:391–399.

    Article  PubMed  CAS  Google Scholar 

  64. McMahon SB, Armanini MP, Ling LH, Philips HS: Expression and co-expression of Trk receptors in subpopulations of adult primary sensory neurons projecting to identified peripheral targets. Neuron 1994, 12:1161–1171.

    Article  PubMed  CAS  Google Scholar 

  65. Gandhi R, Ryals JM, Wright DE: Neurotrophin-3 reverses chronic mechanical hyperalgesia induced by intramuscular acid injection. J Neurosci 2004, 24:9405–9413.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Physical Therapy and Rehabilitation Science, 1-242 MEB, University of Iowa, Iowa City, IA, 52252, USA

    Kathleen A. Sluka

Authors
  1. Josimari M. DeSantana
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kathleen A. Sluka
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kathleen A. Sluka.

Rights and permissions

Reprints and permissions

About this article

Cite this article

DeSantana, J.M., Sluka, K.A. Central mechanisms in the maintenance of chronic widespread noninflammatory muscle pain. Current Science Inc 12, 338–343 (2008). https://doi.org/10.1007/s11916-008-0057-7

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11916-008-0057-7

Keywords

Search

Navigation