New Developments in the Pathophysiology of Genital Pain: Role of Central Sensitization

Abstract

Medically unexplained chronic vulvar pain, or vulvodynia, is a common condition that affects many aspects of a woman’s life. The most common subtype of vulvodynia is provoked vestibulodynia (PVD), and recent research has demonstrated that its pathophysiology likely involves both peripheral and central dysregulation. In this review, the phenomenon of central sensitization is specifically described and linked to relevant findings in the PVD literature. Recommendations for further research in the area of vulvodynia are made, in particular, the examination of other vulvodynia subtypes and of subtypes within the PVD samples. In addition, support is given for the validation of an existing animal model of provoked vulvar pain in order to understand further spinal involvement and also mechanisms involved in the genesis and persistence of this condition.

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References

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

  1. 1.

    Damsted-Petersen C, Boyer SC, Pukall CF. Current perspectives in vulvodynia. Womens Health. 2009;5(4):423–36.

    Google Scholar 

  2. 2.••

    Fugl-Meyer KS, Bohm-Starke N, Damsted Petersen C, Fugl-Meyer A, Parish S, Giraldi A. Standard operating procedures for female genital sexual pain. J Sex Med. 2013;10:83–93. This review paper supports a comprehensive somato-psychological multidisciplinary approach to female genital sexual pain disorders.

    PubMed  Article  Google Scholar 

  3. 3.

    Haefner HK. Report of the International Society for the Study of Vulvovaginal Disease terminology and classification of vulvodynia. J Low Genit Tract Dis. 2007;11(1):48–9.

    PubMed  Article  Google Scholar 

  4. 4.

    Moyal-Barracco M, Lynch PJ. 2003 ISSVD terminology and classification of vulvodynia: A historical perspective. J Reprod Med. 2004;49(10):772–7.

    PubMed  Google Scholar 

  5. 5.

    Harlow BL, Wise LA, Stewart EG. Prevalence and predictors of chronic lower genital tract discomfort. Am J Obstet Gynecol. 2001;185(3):545–50.

    CAS  PubMed  Article  Google Scholar 

  6. 6.

    Bergeron S, Binik YM, Khalifé S, Pagidas K, Glazer HI. Vulvar vestibulitis syndrome: Reliability of diagnosis and evaluation of current diagnostic criteria. Obstet Gynecol. 2001;98(1):45–51.

    CAS  PubMed  Article  Google Scholar 

  7. 7.

    Deliveliotou A, Creatsas G. Anatomy of the vulva. In: Farage MA, Maibach HI, editors. The Vulva. New York.: Informa Healthcare USA Inc; 2006. p. 1–8.

    Google Scholar 

  8. 8.

    Krantz KE. Innervation of the human vulva and vagina: A microscopic study. Obstet Gynecol. 1958;12:382–96.

    CAS  PubMed  Google Scholar 

  9. 9.

    Bohm-Starke N, Hilliges M, Flaconer C, Rylander E. Increased intraepithelial innervation in women with vulvar vestibulitis syndrome. Gynecol Obstet Invest. 1998;46(4):256–60.

    CAS  PubMed  Article  Google Scholar 

  10. 10.

    Kinsey AC, Pomeroy WB, Martin CE, Gebhard PM. Sexual Behaviour in the human Female. Philadelphia and London: W.B. Saunders Company; 1953.

    Google Scholar 

  11. 11.

    Pukall CF, Bergeron S, Goldfinger C. Vulvodynia: A review of pathophysiological factors and treatment options. Basic Clin Med. 2008;28(4):421–36.

    Google Scholar 

  12. 12.

    Latremoliere A, Woolf CJ. Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J Pain. 2009;10(9):895–926.

    PubMed Central  PubMed  Article  Google Scholar 

  13. 13.

    Devor M. Ectopic discharge in Abeta afferents as a source of neuropathic pain. Exp Brain Res. 2009;196(1):115–28.

    CAS  PubMed  Article  Google Scholar 

  14. 14.

    Baron R, Hans G, Dickenson A (2013) Peripheral input and its importance for central sensitization. Ann Neurol.; epub ahead of print.

  15. 15.

    De Koninck Y. Altered chloride homeostasis in neurological disorders: a new target. Curr Opin Pharmacol. 2007;7(1):93–9.

    PubMed  Article  Google Scholar 

  16. 16.

    Milligan ED, Watkins LR. Pathological and protective roles of glia in chronic pain. Nat Rev Neurosci. 2009;10(1):23–36.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  17. 17.

    Gao YJ, Ji RR. Chemokines, neuronal-glial interactions, and central processing of neuropathic pain. Pharmacol Ther. 2010;126(1):56–68.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  18. 18.

    Trang T, Beggs S, Salter MW. Brain-derived neurotrophic factor from microglia: a molecular substrate for neuropathic pain. Neuron Glia Biol. 2011;7(1):99–108.

    PubMed Central  PubMed  Article  Google Scholar 

  19. 19.

    Woolf CJ, Chong MS. Preemptive analgesia—treating postoperative pain by preventing the establishment of central sensitization. Anesth Analg. 1993;77(2):362–79.

    CAS  PubMed  Article  Google Scholar 

  20. 20.

    Levine J, Taiwo Y. Inflammatory pain. In: Wall PD, Melzack R, editors. Textbook of pain. 3rd ed. London, England: Churchill Livingstone; 1994. p. 45–56.

    Google Scholar 

  21. 21.

    Fields HL, Rowbatham M, Baron R. Postherpetic neuralgia: Irritable nociceptors and deafferentation. Neurobiol Dis. 1998;5:209–27.

    CAS  PubMed  Article  Google Scholar 

  22. 22.

    Woolf CJ. Central sensitization: implications for the diagnosis and treatment of pain. Pain. 201;152(3 Suppl):S2-15.

  23. 23.

    Cervero F, Laird JM, García-Nicas E. Secondary hyperalgesia and presynaptic inhibition: an update. Eur J Pain. 2003;7(4):345–51.

    PubMed  Article  Google Scholar 

  24. 24.

    Craig AD, Bushnell MC, Zhang ET, Blomqvist A. A thalamic nucleus specific for pain and temperature sensation. Nature. 1994;372:770–3.

    CAS  PubMed  Article  Google Scholar 

  25. 25.

    Becerra L, Breiter HC, Wise R, Gonzalez RG, Borsook D. Reward circuitry activation by noxious thermal stimuli. Neuron. 2001;32(5):927–46.

    CAS  PubMed  Article  Google Scholar 

  26. 26.

    Baliki MN, Geha PY, Fields HL, Apkarian AV. Predicting value of pain and analgesia: nucleus accumbens response to noxious stimuli changes in the presence of chronic pain. Neuron. 2010;66(1):149–60.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  27. 27.

    Li XY, Ko HG, Chen T, Descalzi G, Koga K, Wang H, et al. Alleviating neuropathic pain hypersensitivity by imhibiting PKMzeta in the anterior cingulate cortex. Science. 2010;330:1400–4.

    CAS  PubMed  Article  Google Scholar 

  28. 28.

    Bushnell MC, Ceko M, Low LA. Cognitive and emotional control of pain and its disruption in chronic pain. Nat Rev Neurosci. 2013;14(7):502–11.

    CAS  PubMed  Article  Google Scholar 

  29. 29.

    Galan A, Laird JM, Cervero F. In vivo recruitment by painful stimuli of AMPA receptor subunits to the plasma membrane of spinal cord neurons. Pain. 2004;112(3):315–23.

    CAS  PubMed  Article  Google Scholar 

  30. 30.

    D'Mello R, Marchand F, Pezet S, McMahon SB, Dickenson AH. Perturbing PSD-95 interactions with NR2B-subtype receptors attenuates spinal nociceptive plasticity and neuropathic pain. Mol Ther. 2011;19(10):1780–92.

    PubMed  Article  Google Scholar 

  31. 31.

    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;438:1017–21.

    CAS  PubMed  Article  Google Scholar 

  32. 32.

    Crozier RA, Bi C, Han YR, Plummer MR. BDNF modulation of NMDA receptors is activity dependent. J Neurophysiol. 2008;100(6):3264–74.

    CAS  PubMed  Article  Google Scholar 

  33. 33.

    Louter MA, Bosker JE, van Oosterhout WP, van Zwet EW, Zitman FG, Ferrari MD, Terwindt GM (2013) Cutaneous allodynia as a predictor of migraine chronification. Brain. ;epub ahead of print.

  34. 34.

    Wu J, Renn CL, Faden AI, Dorsey SG. TrkB.T1 contributes to neuropathic pain after spinal cord injury through regulation of cell cycle pathways. J Neurosci. 2013;33(30):12447–63.

    CAS  PubMed  Article  Google Scholar 

  35. 35.

    Matricon J, Gelot A, Etienne M, Lazdunski M, Muller E, Ardid D. Spinal cord plasticity and acid-sensing ion channels involvement in a rodent model of irritable bowel syndrome. Eur J Pain. 2011;15(4):335–43.

    CAS  PubMed  Article  Google Scholar 

  36. 36.

    Desmeules JA, Cedraschi C, Rapitis E, Baumgartner E, Finckh A, Cohn P, et al. Neurophysiologic evidence for a central sensitization in patients with fibromyalgia. Arthritis Rheum. 2003;48(5):1420–9.

    CAS  PubMed  Article  Google Scholar 

  37. 37.

    Friedrich EG. Vulvar vestibulitis syndrome. J Reprod Med. 1987;32:110–4.

    PubMed  Google Scholar 

  38. 38.

    Pukall CF, Binik YM, Khalifé S. A new instrument for pain assessment in vulvar vestibulitis syndrome. J Sex Marital Ther. 2004;30(2):69–78.

    PubMed  Article  Google Scholar 

  39. 39.

    Pukall CF, Binik YM, Khalifé S, Amsel R, Abbott FV. Vestibular pain thresholds in women with vulvar vestibulitis syndrome. Pain. 2002;96(1–2):163–75.

    PubMed  Article  Google Scholar 

  40. 40.

    Bohm-Starke N, Hilliges M, Brodda-Jansen G, Rylander E, Torebjörk E. Psychophysical evidence of nociceptor sensitization in vulvar vestibulitis syndrome. Pain. 2001;94(2):177–83.

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Lowenstein L, Vardi Y, Deutsch M, Friedman M, Granot M, Sprecher E, et al. Vulvar vestibulitis severity – assessment by sensory and pain testing modalities. Pain. 2004;107(1-2):47–53.

    PubMed  Article  Google Scholar 

  42. 42.•

    Farmer MA, Maykut CA, Huberman CA, Huang L, Khalifé S, Binik YM, et al. Psychophysical properties of female genital sensation. Pain. 2013;154:2277–86. This article is the first to systematically investigate vulvar somatic and vaginal visceral sensation in women with and without PVD.

    PubMed  Article  Google Scholar 

  43. 43.

    Giesecke J, Reed BD, Haefner HK, Giesecke T, Clauw DJ, Gracely RH. Quantitative sensory testing in vulvodynia patients and increased peripheral pressure pain sensitivity. Obstet Gynecol. 2004;104(1):126–33.

    PubMed  Article  Google Scholar 

  44. 44.

    Sutton KS, Pukall CF, Chamberlain S. Pain ratings, sensory thresholds, and psychosocial functioning in women with provoked vestibulodynia. J Sex Marital Ther. 2009;35(4):262–81.

    PubMed  Article  Google Scholar 

  45. 45.

    Foster DC, Dworkin RH, Wood RW. Effects of intradermal foot and forearm capsaicin injections in normal and vulvodynia-affected women. Pain. 2005;117(1–2):128–36.

    CAS  PubMed  Article  Google Scholar 

  46. 46.

    Pukall CF, Baron M, Amsel R, Khalifé S, Binik YM. Tender point examination in women with vulvar vestibulitis syndrome. Clin J Pain. 2006;22(7):601–9.

    PubMed  Article  Google Scholar 

  47. 47.

    Danielsson I, Eisemann M, Sjöberg I, Wikman M. Vulvar vestibulitis: a multifactorial condition. BJOG. 2001;108(5):456–61.

    CAS  PubMed  Google Scholar 

  48. 48.

    Granot M, Friedman M, Yarnitsky D, Zimmer EZ. Enhancement of systemic pain in women with vulvar vestibulitis. BJOG. 2002;109(8):863–6.

    PubMed  Article  Google Scholar 

  49. 49.

    Granot M, Lavee Y. Psychological factors associated with perception of experimental pain in vulvar vestibulitis syndrome. J Sex Marital Ther. 2005;31(4):285–302.

    PubMed  Article  Google Scholar 

  50. 50.

    Kosek E, Ekholm J, Hansson P. Sensory dysregulation in fibromyalgia patients with implications for pathogenic mechanisms. Pain. 1996;68(2–3):375–83.

    CAS  PubMed  Article  Google Scholar 

  51. 51.

    Verne GN, Robinson ME, Price DD. Hypersensitivity to visceral and cutaneous pain in the irritable bowel syndrome. Pain. 2001;93(1):7–14.

    CAS  PubMed  Article  Google Scholar 

  52. 52.

    Le Bars D. the whole body receptive field of dorsal horn multireceptive neurones. Brain Res Rev. 2002;40:29–44.

    PubMed  Article  Google Scholar 

  53. 53.

    Lautenbacher S, Rollman GB. Possible deficiencies of pain modulation in fibromyalgia. Clin J Pain. 1997;13:189–96.

    CAS  PubMed  Article  Google Scholar 

  54. 54.

    Edwards RR, Ness TJ, Weigent DA, et al. Individual differences in diffuse noxious inhibitory controls (DNIC): Association with clinical variables. Pain. 2003;106:427–37.

    PubMed  Article  Google Scholar 

  55. 55.

    Le Bars D, Dickenson AH, Besson JM. Diffuse noxious inhibitory controls (DNIC). I. Effects on dorsal horn convergent neurones in the rat. Pain. 1979;6:283–304.

    PubMed  Article  Google Scholar 

  56. 56.

    Bouharissa D, Villaneuva L, Bing Z, Le Bars D. Involvement of the subnucleus reticularis dorsalis in diffuse noxious inhibitory controls in the rat. Brain Res. 1992;595:353–7.

    Article  Google Scholar 

  57. 57.

    Hu JW. Response properties of nociceptive and non-nociceptive neurons in the rat’s trigeminal subnucleus caudalis (medullary dorsal horn) related to cutaneous and deep craniofacial afferent stimulation and modulation by diffuse noxious inhibitory controls. Pain. 2009;41:331–45.

    Article  Google Scholar 

  58. 58.

    Sutton KS, Pukall CF, Chamberlain S. Diffuse noxious inhibitory control function in women with provoked vestibulodynia. Clin J Pain. 2012;28(8):667–74.

    PubMed  Article  Google Scholar 

  59. 59.

    Johannesson U, de Boussard CN, Brodda Jansen G, Bohm-Starke N. Evidence of diffuse noxious inhibitory controls (DNIC) elicited by cold noxious stimulation in patients with provoked vestibulodynia. Pain. 2007;130(1–2):31–9.

    PubMed  Article  Google Scholar 

  60. 60.

    Zhang Z, Zolnoun DA, Francisco EM, Holden JK, Dennis RG, Tommerdahl M. Altered central sensitization in subgroups of women with vulvodynia. Clin J Pain. 2011;27(9):755–63.

    PubMed Central  PubMed  Article  Google Scholar 

  61. 61.

    Coghill RC, Sang CN, Maisog JM, Iadorola MJ. Pain intensity processing within the human brain: A bilateral, distributed mechanism. J Neurophysiol. 1999;82:1934–43.

    CAS  PubMed  Google Scholar 

  62. 62.

    Hofbauer RK, Rainville P, Duncan GH, Bushnell MC. Cortical representation of the sensory dimension of pain. J Neurophysiol. 2001;86:402–11.

    CAS  PubMed  Google Scholar 

  63. 63.

    Kuchinad A, Schweinhardt P, Seminowicz DA, Wood PB, Chizh BA, Bushnell MC (2007) Accelerated brain gray matter loss in fibromyalgia patients: Premature aging of the brain? J Neurosci. ;4004-4007.

  64. 64.

    Pukall CF, Strigo IA, Binik YM, Amsel R, Khalifé S, Bushnell MC. Neural correlates of painful genital touch in women with vulvar vestibulitis syndrome. Pain. 2005;115(1–2):118–27.

    PubMed  Article  Google Scholar 

  65. 65.•

    Hampson JP, Reed BD, Clauw DJ, Bhavsar R, Gracely RH, Haefner HK, et al. Augmented central pain processing in vulvodynia. J Pain. 2013;14(6):579–89. This article is one of the few brain imaging studies of vulvodynia in existence.

    PubMed  Article  Google Scholar 

  66. 66.

    Apkarian AV, Sosa Y, Sonty S, Levy RM, Harden RN, Parrish TB, et al. Chronic back pain is associated with decreased prefrontal and thalamic gray matter density. J Neurosci. 2004;24:10410–5.

    CAS  PubMed  Article  Google Scholar 

  67. 67.

    Schmidt-Wilcke T, Leinisch E, Straube A, Kampfe N, Draganski B, Diner HC, et al. Gray matter decreases in patients with chronic tension type headache. Neurology. 2005;65:1483–6.

    CAS  PubMed  Article  Google Scholar 

  68. 68.

    Schmidt-Wilcke T, Leinisch E, Ganssbauer S, Draganski B, Bogdahn U, Altmeppen J, et al. Affective components and intensity of pain correlate with structural differences in gray matter in chronic back pain patients. Pain. 2006;125:89–97.

    CAS  PubMed  Article  Google Scholar 

  69. 69.

    Davis KD, Pope G, Chen J, Kwan CL, Crawley AP, Diamant NE. Cortical thinning in IBS: Implications for homeostatic, attention, and pain processing. Neurology. 2008;70:153–4.

    CAS  PubMed  Article  Google Scholar 

  70. 70.

    Schmidt-Wilcke T, Luerding R, Weigand T, Jurgens T, Schuierer G, Leinisch E, et al. Striatal grey matter increase in patients suffering from fibromyalgia-a voxel-based morphometry study. Pain. 2007;132:S109–16.

    PubMed  Article  Google Scholar 

  71. 71.

    Schweinhardt P, Kuchinad A, Pukall CF, Bushnell MC. Increased gray matter density in young women with chronic vulvar pain. Pain. 2008;140(3):411–9.

    CAS  PubMed  Article  Google Scholar 

  72. 72.••

    Boyer SC, Goldfinger C, Thibault-Gagnon S, Pukall CF. Management of female sexual pain disorders. Adv Psychosom Med. 2011;31:83–104. This chapter provides a recent review of the vulvodynia treatment literature.

    PubMed  Article  Google Scholar 

  73. 73.

    Van Lankveld JJ, Granot M, Weijmar Schultz WC, Binik YM, Wesselmann U, Pukall CF, et al. Women’s sexual pain disorders. J Sex Med. 2010;7(1 Pt 2):615–31.

    PubMed  Article  Google Scholar 

  74. 74.••

    Basson R. The recurrent pain and sexual sequelae of provoked vestibulodynia: A perpetuating cycle. J Sex Med. 2012;9:2077–92. This paper offers for a model of PVD in which peripheral, psychological, and central factors are purported to contribute to the perpetuating cycle of the pain.

    PubMed  Article  Google Scholar 

  75. 75.•

    Farmer MA, Taylor AM, Bailey AL, Tuttle AH, MacIntyre LC, Milagrosa ZE, et al. Repeated vulvovaginal fungal infections cause persistent pain in a mouse model of vulvodynia. Sci Transl Med. 2011;21(101):101ra91. This paper details the first demonstration of an animal model of provoked vulvar pain and attributes the increased sensitivity to heightened innervation.

    Google Scholar 

  76. 76.

    Nguyen RH, Swanson D, Harlow BL. Urogenital infections in relation to the occurrence of vulvodynia. J Reprod Med. 2009;54(6):385–92.

    PubMed  Google Scholar 

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Catherine M. Cahill and Caroline F. Pukall declare that they have no conflict of interest.

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Correspondence to Caroline F. Pukall.

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This article is part of the Topical Collection on Female Sexual Dysfunction and Disorders

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Pukall, C.F., Cahill, C.M. New Developments in the Pathophysiology of Genital Pain: Role of Central Sensitization. Curr Sex Health Rep 6, 11–19 (2014). https://doi.org/10.1007/s11930-013-0007-1

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Keywords

  • Vulvodynia
  • Provoked vestibulodynia
  • Dyspareunia
  • Peripheral sensitization
  • Central factors
  • Central sensitization
  • Pathophysiology
  • Genital pain
  • Sensory innervation
  • Allodynia
  • Hyperalgesia
  • Receptive field expansion
  • GABA
  • Neuronal-glial interactions
  • Nociceptors
  • Pain pathways
  • Quantitative sensory testing
  • Diffuse noxious inhibitory control
  • Functional brain imaging