Skip to main content

Advertisement

SpringerLink
Log in

The Role of Peripheral Nociceptive Neurons in the Pathophysiology of Osteoarthritis Pain

  • Bone and Joint Pain (PW Mantyh and TJ Schnitzer, Section Editors)
  • Published:
Current Osteoporosis Reports Aims and scope Submit manuscript

Abstract

Knee osteoarthritis is characterized by progressive damage and remodeling of all tissues in the knee joint. Pain is the main symptom associated with knee osteoarthritis. Recent clinical and pre-clinical studies have provided novel insights into the mechanisms that drive the pain associated with joint destruction. In this narrative review, we describe current knowledge regarding the changes in the peripheral and central nervous systems that occur during the progression of osteoarthritis and discuss how therapeutic interventions may provide pain relief.

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

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Lawrence RC, Felson DT, Helmick CG, Arnold LM, Choi H, Deyo RA, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis Rheum. 2008;58(1):26–35.

    Article  PubMed Central  PubMed  Google Scholar 

  2. Murphy L, Schwartz TA, Helmick CG, Renner JB, Tudor G, Koch G, et al. Lifetime risk of symptomatic knee osteoarthritis. Arthritis Rheum. 2008;59(9):1207–13.

    Article  PubMed Central  PubMed  Google Scholar 

  3. Creamer P, Lethbridge-Cejku M, Hochberg MC. Factors associated with functional impairment in symptomatic knee osteoarthritis. Rheumatology (Oxford). 2000;39(5):490–6.

    Article  CAS  Google Scholar 

  4. Neogi T. The epidemiology and impact of pain in osteoarthritis. Osteoarthr Cart. 2013;21(9):1145–53.

    Article  CAS  Google Scholar 

  5. Hawker GA, Stewart L, French MR, Cibere J, Jordan JM, March L, et al. Understanding the pain experience in hip and knee osteoarthritis—an OARSI/OMERACT initiative. Osteoarthr Cart. 2008;16(4):415–22.

    Article  CAS  Google Scholar 

  6. Hochberg MC, Altman RD, April KT, Benkhalti M, Guyatt G, McGowan J, et al. American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee. Arthritis Care Res. 2012;64(4):465–74.

    Article  CAS  Google Scholar 

  7. Hunter DJ, Neogi T, Hochberg MC. Quality of osteoarthritis management and the need for reform in the US. Arthritis Care Res. 2011;63(1):31–8.

    Article  Google Scholar 

  8. Riddle DL, Perera RA, Stratford PW, Jiranek WA, Dumenci L. Progressing toward, and recovering from, knee replacement surgery: a five-year cohort study. Arthritis Rheum. 2013;65(12):3304–13.

    Article  PubMed  Google Scholar 

  9. United States Bone and Joint Initiative: The Burden of Musculoskeletal Diseases in the United States (BMUS) [Internet]. 2014 [cited June 6, 2015]. Available from: http://www.boneandjointburden.org.

  10. Loeser RF, Goldring SR, Scanzello CR, Goldring MB. Osteoarthritis: a disease of the joint as an organ. Arthritis Rheum. 2012;64(6):1697–707.

    Article  PubMed Central  PubMed  Google Scholar 

  11. Malfait AM, Schnitzer TJ. Towards a mechanism-based approach to pain management in osteoarthritis. Nat Rev Rheumatol. 2013;9(11):654–64.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Little CB, Zaki S. What constitutes an “animal model of osteoarthritis”—the need for consensus? Osteoarthr Cart. 2012;20(4):261–7.

    Article  CAS  Google Scholar 

  13. Malfait AM, Little CB, McDougall JJ. A commentary on modelling osteoarthritis pain in small animals. Osteoarthr Cart. 2013;21(9):1316–26.

    Article  CAS  Google Scholar 

  14. Malfait AM, Little CB. On the predictive utility of animal models of osteoarthritis. Arthritis Res Ther. In press.

  15. Bryden LA, Nicholson JR, Doods H, Pekcec A. Deficits in spontaneous burrowing behavior in the rat bilateral monosodium iodoacetate model of osteoarthritis: an objective measure of pain-related behavior and analgesic efficacy. Osteoarthr Cartil. In press.

  16. Bove SE, Calcaterra SL, Brooker RM, Huber CM, Guzman RE, Juneau PL, et al. Weight bearing as a measure of disease progression and efficacy of anti-inflammatory compounds in a model of monosodium iodoacetate-induced osteoarthritis. Osteoarthr Cart. 2003;11(11):821–30.

    Article  CAS  Google Scholar 

  17. Combe R, Bramwell S, Field MJ. The monosodium iodoacetate model of osteoarthritis: a model of chronic nociceptive pain in rats? Neurosci Lett. 2004;370(2-3):236–40.

    Article  CAS  PubMed  Google Scholar 

  18. Sagar DR, Staniaszek LE, Okine BN, Woodhams S, Norris LM, Pearson RG, et al. Tonic modulation of spinal hyperexcitability by the endocannabinoid receptor system in a rat model of osteoarthritis pain. Arthritis Rheum. 2010;62(12):3666–76.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. van der Kraan PM, Vitters EL, van Beuningen HM, van de Putte LB, van den Berg WB. Degenerative knee joint lesions in mice after a single intra-articular collagenase injection. A new model of osteoarthritis. J Exp Pathol (Oxford). 1990;71(1):19–31.

    Google Scholar 

  20. van Lent PL, Blom AB, Schelbergen RF, Sloetjes A, Lafeber FP, Lems WF, et al. Active involvement of alarmins S100A8 and S100A9 in the regulation of synovial activation and joint destruction during mouse and human osteoarthritis. Arthritis Rheum. 2012;64(5):1466–76.

    Article  PubMed  Google Scholar 

  21. Cook AD, Pobjoy J, Steidl S, Durr M, Braine EL, Turner AL, et al. Granulocyte-macrophage colony-stimulating factor is a key mediator in experimental osteoarthritis pain and disease development. Arthritis Res Ther. 2012;14(5):R199.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Lee CH, Wen ZH, Chang YC, Huang SY, Tang CC, Chen WF, et al. Intra-articular magnesium sulfate (MgSO4) reduces experimental osteoarthritis and nociception: association with attenuation of N-methyl-D-aspartate (NMDA) receptor subunit 1 phosphorylation and apoptosis in rat chondrocytes. Osteoarthr Cart. 2009;17(11):1485–93.

    Article  CAS  Google Scholar 

  23. Bendele AM. Animal models of osteoarthritis. J Musculoskelet Neuronal Interact. 2001;1(4):363–76.

    CAS  PubMed  Google Scholar 

  24. Bove SE, Laemont KD, Brooker RM, Osborn MN, Sanchez BM, Guzman RE, et al. Surgically induced osteoarthritis in the rat results in the development of both osteoarthritis-like joint pain and secondary hyperalgesia. Osteoarthr Cart. 2006;14(10):1041–8.

    Article  CAS  Google Scholar 

  25. Mapp PI, Sagar DR, Ashraf S, Burston JJ, Suri S, Chapman V, et al. Differences in structural and pain phenotypes in the sodium monoiodoacetate and meniscal transection models of osteoarthritis. Osteoarthr Cart. 2013;21(9):1336–45.

    Article  CAS  Google Scholar 

  26. Glasson SS, Blanchet TJ, Morris EA. The surgical destabilization of the medial meniscus (DMM) model of osteoarthritis in the 129/SvEv mouse. Osteoarthr Cart. 2007;15(9):1061–9.

    Article  CAS  Google Scholar 

  27. Inglis JJ, McNamee KE, Chia SL, Essex D, Feldmann M, Williams RO, et al. Regulation of pain sensitivity in experimental osteoarthritis by the endogenous peripheral opioid system. Arthritis Rheum. 2008;58(10):3110–9.

    Article  CAS  PubMed  Google Scholar 

  28. Malfait AM, Ritchie J, Gil AS, Austin JS, Hartke J, Qin W, et al. ADAMTS-5 deficient mice do not develop mechanical allodynia associated with osteoarthritis following medial meniscal destabilization. Osteoarthr Cart. 2010;18(4):572–80.

    Article  CAS  Google Scholar 

  29. Miller RE, Tran PB, Das R, Ghoreishi-Haack N, Ren D, Miller RJ, et al. CCR2 chemokine receptor signaling mediates pain in experimental osteoarthritis. Proc Natl Acad Sci U S A. 2012;109(50):20602–7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Jackson MT, Moradi B, Zaki S, Smith MM, McCracken S, Smith SM, et al. Depletion of protease-activated receptor 2 but not protease-activated receptor 1 may confer protection against osteoarthritis in mice through extracartilaginous mechanisms. Arthritis Rheum. 2014;66(12):3337–48.

    Article  CAS  Google Scholar 

  31. Knights CB, Gentry C, Bevan S. Partial medial meniscectomy produces osteoarthritis pain-related behaviour in female C57BL/6 mice. Pain. 2012;153(2):281–92.

    Article  PubMed  Google Scholar 

  32. Samuel EP. The autonomic and somatic innervation of the articular capsule. Anat Rec. 1952;113(1):53–70.

    Article  CAS  PubMed  Google Scholar 

  33. Skoglund S. Anatomical and physiological studies of knee joint innervation in the cat. Acta Physiol Scand Suppl. 1956;36(124):1–101.

    CAS  PubMed  Google Scholar 

  34. Usoskin D, Furlan A, Islam S, Abdo H, Lonnerberg P, Lou D, et al. Unbiased classification of sensory neuron types by large-scale single-cell RNA sequencing. Nat Neurosci. 2015;18(1):145–53. This study demonstrates the diversity of sensory neurons and reveals new distinct sub-types of nociceptors.

    Article  CAS  PubMed  Google Scholar 

  35. Marchand F, Perretti M, McMahon SB. Role of the immune system in chronic pain. Nat Rev Neurosci. 2005;6(7):521–32.

    Article  CAS  PubMed  Google Scholar 

  36. Sokolove J, Lepus CM. Role of inflammation in the pathogenesis of osteoarthritis: latest findings and interpretations. Ther Adv Musculoskelet Dis. 2013;5(2):77–94.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Miller RJ, Jung H, Bhangoo SK, White FA. Cytokine and chemokine regulation of sensory neuron function. Handb Exp Pharmacol. 2009;194:417–49.

    Article  CAS  PubMed  Google Scholar 

  38. Miller RE, Miller RJ, Malfait AM. Osteoarthritis joint pain: the cytokine connection. Cytokine. 2014;70(2):185–93.

    Article  CAS  PubMed  Google Scholar 

  39. Liu-Bryan R, Terkeltaub R. Emerging regulators of the inflammatory process in osteoarthritis. Nat Rev Rheumatol. 2015;11(1):35–44.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Allette YM, Due MR, Wilson SM, Feldman P, Ripsch MS, Khanna R, et al. Identification of a functional interaction of HMGB1 with Receptor for Advanced Glycation End-products in a model of neuropathic pain. Brain Behav Immun. 2014.

  41. Liu T, Xu ZZ, Park CK, Berta T, Ji RR. Toll-like receptor 7 mediates pruritus. Nat Neurosci. 2010;13(12):1460–2.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  42. Qi J, Buzas K, Fan H, Cohen JI, Wang K, Mont E, et al. Painful pathways induced by TLR stimulation of dorsal root ganglion neurons. J Immunol. 2011;186(11):6417–26.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  43. Shibasaki M, Sasaki M, Miura M, Mizukoshi K, Ueno H, Hashimoto S, et al. Induction of high mobility group box-1 in dorsal root ganglion contributes to pain hypersensitivity after peripheral nerve injury. Pain. 2010;149(3):514–21.

    Article  CAS  PubMed  Google Scholar 

  44. Miller RE, Belmadani A, Ishihara S, Tran PB, Ren D, Miller RJ, Malfait AM. Damage-associated molecular patterns generated in osteoarthritis directly excite murine nociceptive neurons through toll-like receptor 4. Arthritis Rheum. In press.

  45. Walsh DA, Mapp PI, Kelly S. Calcitonin gene-related peptide in the joint: contributions to pain and inflammation. Br J Clin Pharmacol. 2015.

  46. Zhang RX, Ren K, Dubner R. Osteoarthritis pain mechanisms: basic studies in animal models. Osteoarthr Cart. 2013;21(9):1308–15.

    Article  Google Scholar 

  47. Mantyh PW, Koltzenburg M, Mendell LM, Tive L, Shelton DL. Antagonism of nerve growth factor-TrkA signaling and the relief of pain. Anesthesiology. 2011;115(1):189–204.

    Article  PubMed Central  PubMed  Google Scholar 

  48. Lane NE, Schnitzer TJ, Birbara CA, Mokhtarani M, Shelton DL, Smith MD, et al. Tanezumab for the treatment of pain from osteoarthritis of the knee. N Engl J Med. 2010;363(16):1521–31.

    Article  CAS  PubMed  Google Scholar 

  49. Iannone F, De Bari C, Dell’Accio F, Covelli M, Patella V, Lo Bianco G, et al. Increased expression of nerve growth factor (NGF) and high affinity NGF receptor (p140 TrkA) in human osteoarthritic chondrocytes. Rheumatology (Oxford). 2002;41(12):1413–8.

    Article  CAS  Google Scholar 

  50. Ashraf S, Mapp PI, Burston J, Bennett AJ, Chapman V, Walsh DA. Augmented pain behavioural responses to intra-articular injection of nerve growth factor in two animal models of osteoarthritis. Ann Rheum Dis. 2014;73(9):1710–8.

    Article  PubMed Central  PubMed  Google Scholar 

  51. McNamee KE, Burleigh A, Gompels LL, Feldmann M, Allen SJ, Williams RO, et al. Treatment of murine osteoarthritis with TrkAd5 reveals a pivotal role for nerve growth factor in non-inflammatory joint pain. Pain. 2010;149(2):386–92.

    Article  CAS  PubMed  Google Scholar 

  52. Sagar DR, Nwosu L, Walsh DA, Chapman V. Dissecting the contribution of knee joint NGF to spinal nociceptive sensitization in a model of OA pain in the rat. Osteoarthr Cart. 2015;23(6):906–13.

    Article  CAS  Google Scholar 

  53. Malik-Hall M, Dina OA, Levine JD. Primary afferent nociceptor mechanisms mediating NGF-induced mechanical hyperalgesia. Eur J Neurosci. 2005;21(12):3387–94.

    Article  PubMed  Google Scholar 

  54. Shelton DL, Zeller J, Ho WH, Pons J, Rosenthal A. Nerve growth factor mediates hyperalgesia and cachexia in auto-immune arthritis. Pain. 2005;116(1-2):8–16.

    Article  CAS  PubMed  Google Scholar 

  55. Sabsovich I, Wei T, Guo TZ, Zhao R, Shi X, Li X, et al. Effect of anti-NGF antibodies in a rat tibia fracture model of complex regional pain syndrome type I. Pain. 2008;138(1):47–60.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  56. Ishikawa G, Koya Y, Tanaka H, Nagakura Y. Long-term analgesic effect of a single dose of anti-NGF antibody on pain during motion without notable suppression of joint edema and lesion in a rat model of osteoarthritis. Osteoarthr Cart. 2015;23(6):925–32. A single dose of anti-NGF antibody early in the MIA model resulted in long-term improvement in gait imbalance despite no improvement in inflammation.

    Article  CAS  Google Scholar 

  57. Dib-Hajj SD, Cummins TR, Black JA, Waxman SG. Sodium channels in normal and pathological pain. Annu Rev Neurosci. 2010;33:325–47.

    Article  CAS  PubMed  Google Scholar 

  58. Rahman W, Dickenson AH. Osteoarthritis-dependent changes in antinociceptive action of Nav1.7 and Nav1.8 sodium channel blockers: an in vivo electrophysiological study in the rat. Neuroscience. 2015;295:103-16. Blocking the voltage-gated sodium channels Na v 1.7 and Na v 1.8 resulted in decreased dorsal horn neuronal responses to a variety of mechanical and thermal stimuli in the MIA model.

  59. Schuelert N, McDougall JJ. Involvement of Nav 1.8 sodium ion channels in the transduction of mechanical pain in a rodent model of osteoarthritis. Arthritis Res Ther. 2012;14(1):R5.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  60. Ren K, Dubner R. Interactions between the immune and nervous systems in pain. Nat Med. 2010;16(11):1267–76.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  61. Massier J, Eitner A, von Banchet GS, Schaible HG. Effects of differently activated rodent macrophages on sensory neurons. Arthritis Rheumatol: Implications for arthritic pain; 2015.

    Google Scholar 

  62. Dye SF, Vaupel GL, Dye CC. Conscious neurosensory mapping of the internal structures of the human knee without intraarticular anesthesia. Am J Sports Med. 1998;26(6):773–7.

    CAS  PubMed  Google Scholar 

  63. Mapp PI, Walsh DA. Mechanisms and targets of angiogenesis and nerve growth in osteoarthritis. Nat Rev Rheumatol. 2012;8(7):390–8.

    Article  CAS  PubMed  Google Scholar 

  64. Suri S, Gill SE, Massena de Camin S, Wilson D, McWilliams DF, Walsh DA. Neurovascular invasion at the osteochondral junction and in osteophytes in osteoarthritis. Ann Rheum Dis. 2007;66(11):1423–8.

    Article  PubMed Central  PubMed  Google Scholar 

  65. Walsh DA, Bonnet CS, Turner EL, Wilson D, Situ M, McWilliams DF. Angiogenesis in the synovium and at the osteochondral junction in osteoarthritis. Osteoarthr Cart. 2007;15(7):743–51.

    Article  CAS  Google Scholar 

  66. Walsh DA, McWilliams DF, Turley MJ, Dixon MR, Franses RE, Mapp PI, et al. Angiogenesis and nerve growth factor at the osteochondral junction in rheumatoid arthritis and osteoarthritis. Rheumatology (Oxford). 2010;49(10):1852–61.

    Article  CAS  Google Scholar 

  67. Ashraf S, Wibberley H, Mapp PI, Hill R, Wilson D, Walsh DA. Increased vascular penetration and nerve growth in the meniscus: a potential source of pain in osteoarthritis. Ann Rheum Dis. 2011;70(3):523–9.

    Article  PubMed  Google Scholar 

  68. Fukuta S, Kuge A, Korai F. Clinical significance of meniscal abnormalities on magnetic resonance imaging in an older population. Knee. 2009;16(3):187–90.

    Article  PubMed  Google Scholar 

  69. Fukuta S, Masaki K, Korai F. Prevalence of abnormal findings in magnetic resonance images of asymptomatic knees. J Orthop Sci. 2002;7(3):287–91.

    Article  PubMed  Google Scholar 

  70. Del Valle ME, Harwin SF, Maestro A, Murcia A, Vega JA. Immunohistochemical analysis of mechanoreceptors in the human posterior cruciate ligament: a demonstration of its proprioceptive role and clinical relevance. J Arthroplasty. 1998;13(8):916–22.

    Article  PubMed  Google Scholar 

  71. Franchi A, Zaccherotti G, Aglietti P. Neural system of the human posterior cruciate ligament in osteoarthritis. J Arthroplasty. 1995;10(5):679–82.

    Article  CAS  PubMed  Google Scholar 

  72. Eitner A, Pester J, Nietzsche S, Hofmann GO, Schaible HG. The innervation of synovium of human osteoarthritic joints in comparison with normal rat and sheep synovium. Osteoarthr Cart. 2013;21(9):1383–91.

    Article  CAS  Google Scholar 

  73. Stoppiello LA, Mapp PI, Wilson D, Hill R, Scammell BE, Walsh DA. Structural associations of symptomatic knee osteoarthritis. Arthritis Rheum. 2014;66(11):3018–27. This study shows that increased levels of synovitis and synovial levels of NGF are associated with symptomatic as compared to asymptomatic OA.

    Article  Google Scholar 

  74. Buma P, Verschuren C, Versleyen D, Van der Kraan P, Oestreicher AB. Calcitonin gene-related peptide, substance P and GAP-43/B-50 immunoreactivity in the normal and arthrotic knee joint of the mouse. Histochemistry. 1992;98(5):327–39.

    Article  CAS  PubMed  Google Scholar 

  75. Murakami K, Nakagawa H, Nishimura K, Matsuo S. Changes in peptidergic fiber density in the synovium of mice with collagenase-induced acute arthritis. Can J Physiol Pharmacol. 2015:1-7.

  76. Fernihough J, Gentry C, Bevan S, Winter J. Regulation of calcitonin gene-related peptide and TRPV1 in a rat model of osteoarthritis. Neurosci Lett. 2005;388(2):75–80.

    Article  CAS  PubMed  Google Scholar 

  77. Ferreira-Gomes J, Adaes S, Sarkander J, Castro-Lopes JM. Phenotypic alterations of neurons that innervate osteoarthritic joints in rats. Arthritis Rheum. 2010;62(12):3677–85.

    Article  PubMed  Google Scholar 

  78. Ivanavicius SP, Blake DR, Chessell IP, Mapp PI. Isolectin B4 binding neurons are not present in the rat knee joint. Neuroscience. 2004;128(3):555–60.

    Article  CAS  PubMed  Google Scholar 

  79. Burgi K, Cavalleri MT, Alves AS, Britto LR, Antunes VR, Michelini LC. Tyrosine hydroxylase immunoreactivity as indicator of sympathetic activity: simultaneous evaluation in different tissues of hypertensive rats. Am J Physiol Regul Integr Comp Physiol. 2011;300(2):R264–71.

    Article  CAS  PubMed  Google Scholar 

  80. Li L, Rutlin M, Abraira VE, Cassidy C, Kus L, Gong S, et al. The functional organization of cutaneous low-threshold mechanosensory neurons. Cell. 2011;147(7):1615–27.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  81. Mease PJ, Hanna S, Frakes EP, Altman RD. Pain mechanisms in osteoarthritis: understanding the role of central pain and current approaches to its treatment. J Rheumatol. 2011;38(8):1546–51.

    Article  CAS  PubMed  Google Scholar 

  82. Woolf CJ. Central sensitization: implications for the diagnosis and treatment of pain. Pain. 2011;152(3 Suppl):S2–15.

    Article  PubMed Central  PubMed  Google Scholar 

  83. Lee Y, Pai M, Brederson JD, Wilcox D, Hsieh G, Jarvis MF, et al. Monosodium iodoacetate-induced joint pain is associated with increased phosphorylation of mitogen activated protein kinases in the rat spinal cord. Mol Pain. 2011;7:39.

    Article  PubMed Central  PubMed  Google Scholar 

  84. Murphy SL, Phillips K, Williams DA, Clauw DJ. The role of the central nervous system in osteoarthritis pain and implications for rehabilitation. Curr Rheumatol Rep. 2012;14(6):576–82.

    Article  CAS  PubMed  Google Scholar 

  85. Fingleton C, Smart K, Moloney N, Fullen BM, Doody C. Pain sensitization in people with knee osteoarthritis: a systematic review and meta-analysis. Osteoarthr Cartil. 2015.

  86. Lluch E, Torres R, Nijs J, Van Oosterwijck J. Evidence for central sensitization in patients with osteoarthritis pain: a systematic literature review. Eur J Pain. 2014;18(10):1367–75.

    Article  CAS  PubMed  Google Scholar 

  87. Graven-Nielsen T, Wodehouse T, Langford RM, Arendt-Nielsen L, Kidd BL. Normalization of widespread hyperesthesia and facilitated spatial summation of deep-tissue pain in knee osteoarthritis patients after knee replacement. Arthritis Rheum. 2012;64(9):2907–16.

    Article  CAS  PubMed  Google Scholar 

  88. Kosek E, Ordeberg G. Lack of pressure pain modulation by heterotopic noxious conditioning stimulation in patients with painful osteoarthritis before, but not following, surgical pain relief. Pain. 2000;88(1):69–78.

    Article  CAS  PubMed  Google Scholar 

  89. Orita S, Ishikawa T, Miyagi M, Ochiai N, Inoue G, Eguchi Y, et al. Pain-related sensory innervation in monoiodoacetate-induced osteoarthritis in rat knees that gradually develops neuronal injury in addition to inflammatory pain. BMC Musculoskelet Disord. 2011;12:134.

    Article  PubMed Central  PubMed  Google Scholar 

  90. Sagar DR, Burston JJ, Hathway GJ, Woodhams SG, Pearson RG, Bennett AJ, et al. The contribution of spinal glial cells to chronic pain behaviour in the monosodium iodoacetate model of osteoarthritic pain. Mol Pain. 2011;7:88.

    Article  PubMed Central  PubMed  Google Scholar 

  91. Thakur M, Rahman W, Hobbs C, Dickenson AH, Bennett DL. Characterisation of a peripheral neuropathic component of the rat monoiodoacetate model of osteoarthritis. PLoS One. 2012;7(3):e33730.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  92. Ogbonna AC, Clark AK, Gentry C, Hobbs C, Malcangio M. Pain-like behaviour and spinal changes in the monosodium iodoacetate model of osteoarthritis in C57Bl/6 mice. Eur J Pain. 2013;17(4):514–26.

    Article  CAS  PubMed  Google Scholar 

  93. Ivanavicius SP, Ball AD, Heapy CG, Westwood FR, Murray F, Read SJ. Structural pathology in a rodent model of osteoarthritis is associated with neuropathic pain: increased expression of ATF-3 and pharmacological characterisation. Pain. 2007;128(3):272–82.

    Article  CAS  PubMed  Google Scholar 

  94. Pomonis JD, Boulet JM, Gottshall SL, Phillips S, Sellers R, Bunton T, et al. Development and pharmacological characterization of a rat model of osteoarthritis pain. Pain. 2005;114(3):339–46.

    Article  CAS  PubMed  Google Scholar 

  95. Fernihough J, Gentry C, Malcangio M, Fox A, Rediske J, Pellas T, et al. Pain related behaviour in two models of osteoarthritis in the rat knee. Pain. 2004;112(1-2):83–93.

    Article  PubMed  Google Scholar 

Download references

Compliance with Ethics Guidelines

Conflict of Interest

Rachel Miller was supported by the US National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) (F32AR062927).

Anne-Marie Malfait (R01AR064251 and R01AR060364) and Richard Miller (R01AR064251) were supported by NIAMS.

Phuong Tran has no conflicts of interest to disclose.

Padmanabhan Raghu has no conflicts of interest to disclose.

Alia Obeidat has no conflicts of interest to disclose.

Shingo Ishihara has no conflicts of interest to disclose.

Human and Animal Rights and Informed Consent

This article contains no studies with human or animal subjects performed by any of the authors.

Author information

Authors and Affiliations

  1. Department of Internal Medicine, Division of Rheumatology, Rush University Medical Center, 1611 W. Harrison St, Suite 510, Chicago, IL, 60612, USA

    Rachel E. Miller, Phuong B. Tran, Padmanabhan Raghu, Shingo Ishihara & Anne-Marie Malfait

  2. Department of Biochemistry, Rush University Medical Center, 1611 W. Harrison St, Suite 510, Chicago, IL, 60612, USA

    Rachel E. Miller, Alia M Obeidat & Anne-Marie Malfait

  3. Department of Pharmacology, Northwestern University, Lurie 8-125, 303 E. Superior St, Chicago, IL, 60611, USA

    Richard J. Miller

Authors
  1. Rachel E. Miller
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Phuong B. Tran
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alia M Obeidat
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Padmanabhan Raghu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shingo Ishihara
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Richard J. Miller
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Anne-Marie Malfait
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anne-Marie Malfait.

Additional information

This article is part of the Topical Collection on Bone and Joint Pain

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Miller, R.E., Tran, P.B., Obeidat, A.M. et al. The Role of Peripheral Nociceptive Neurons in the Pathophysiology of Osteoarthritis Pain. Curr Osteoporos Rep 13, 318–326 (2015). https://doi.org/10.1007/s11914-015-0280-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11914-015-0280-1

Keywords

Search

Navigation