Purinergic Signalling

, Volume 7, Issue 1, pp 73–83 | Cite as

Estrogen modulation of peripheral pain signal transduction: involvement of P2X3 receptors

Original Article

Abstract

There is evidence that gonadal hormones may affect the perception of painful stimulation, although the underlying mechanisms remain unclear. This investigation was undertaken to determine whether the adenosine 5′-triphosphate (ATP) receptor subunit, P2X3, is involved in the modulatory action of estrogen in peripheral pain signal transduction in dorsal root ganglion (DRG). The mechanical pain behavior test, real-time quantitative reverse transcription–polymerase chain reaction analysis, and Western blot methods were used to determine the mean relative concentrations and functions of P2X3 receptors in DRG in sham, ovariectomized (OVX), and estradiol replacement (OVX+E2) female rats and in sham and orchiectomized male rats. The mechanical hyperalgesia appeared after ovariectomy, which was subsequently reversed after estradiol replacement, whereas it was not observed after orchiectomy in male rats. Plantar injection of 2′(3′)-O-(2,4,6-trinitrophenyl) ATP (TNP-ATP), a P2X3 and P2X2/3 receptor antagonist, resulted in an increase of the pain threshold force in OVX rats while had no effect on sham rats. Furthermore, A-317491, a selective P2X3/P2X2/3 receptor antagonist, significantly reversed the hyperalgesia of OVX rats. Injection of ATP into the plantars also caused a significant increase of the paw withdrawal duration in OVX rats compared with that seen in the sham group, which became substantially attenuated by TNP-ATP. P2X3 receptors expressed in DRG were significantly increased in both mRNA and protein levels after ovariectomy and then reversed after estrogen replacement, while a similar increase was not observed after orchiectomy in male rats. Furthermore, P2X3 mRNA was significantly decreased 24 h after the application of 17β-estradiol in a concentration-dependent manner in cultured DRG neurons. ICI 182,780, an estrogen receptor antagonist, blocked the reduction in the protein level. These results suggest that the female gonadal hormone, 17β-estradiol, might participate in the control of peripheral pain signal transduction by modulating P2X3 receptor-mediated events in primary sensory neurons, probably through genomic mechanisms.

Keywords

Estrogen P2X receptors ATP Ovariectomy Pain 

References

  1. 1.
    Fillingim RB (2000) Sex, gender, and pain: women and men really are different. Curr Rev Pain 4(1):24–30PubMedGoogle Scholar
  2. 2.
    Greenspan JD, Craft RM, LeResche L, Arendt-Nielsen L, Berkley KJ, Fillingim RB, Gold MS, Holdcroft A, Lautenbacher S, Mayer EA, Mogil JS, Murphy AZ, Traub RJ (2007) Consensus Working Group of the Sex, Gender, and Pain SIG of the IASP. Pain 132(Suppl 1):S26–S45PubMedCrossRefGoogle Scholar
  3. 3.
    Craft RM (2007) Modulation of pain by estrogens. Pain 132:S3–S12PubMedCrossRefGoogle Scholar
  4. 4.
    Butcher RL, Collins WE, Fugo NW (1974) Plasma concentration of LH, FSH, prolactin, progesterone, and estradiol-17beta throughout the 4-day estrous cycle of the rat. Endocrinology 94:1704–1708PubMedCrossRefGoogle Scholar
  5. 5.
    Frye CA, Bock BC, Kanarek RB (1992) Hormonal milieu affects tailflick latency in female rats and may be attenuated by access to sucrose. Physiol Behav 52:699–706PubMedCrossRefGoogle Scholar
  6. 6.
    Frye CA, Cuevas CA, Kanarek RB (1993) Diet and estrous cycle influence pain sensitivity in rats. Pharmacol Biochem Behav 45:255–260PubMedCrossRefGoogle Scholar
  7. 7.
    Fischer L, Torres-Chávez KE, Clemente-Napimoga JT, Jorge D, Arsati F, de Arruda Veiga MC, Tambeli CH (2008) The influence of sex and ovarian hormones on temporomandibular joint nociception in rats. J Pain 9(7):630–638PubMedCrossRefGoogle Scholar
  8. 8.
    Sanoja R, Cervero F (2005) Estrogen-dependent abdominal hyperalgesia induced by ovariectomy in adult mice: a model of functional abdominal pain. Pain 118(1–2):243–253PubMedCrossRefGoogle Scholar
  9. 9.
    Sanoja R, Cervero F (2008) Estrogen modulation of ovariectomy-induced hyperalgesia in adult mice. Eur J Pain 12:573–581PubMedCrossRefGoogle Scholar
  10. 10.
    Stoffel EC, Ulibarri CM, Craft RM (2003) Gonadal steroid hormone modulation of nociception, morphine antinociception and reproductive indices in male and female rats. Pain 103:285–302PubMedCrossRefGoogle Scholar
  11. 11.
    Formanl LJ, Tingle V, Estilow S, Cater J (1989) The response to analgesia testing is affected by gonadal steroids in the rat. Life Sci 45(5):447–454CrossRefGoogle Scholar
  12. 12.
    Bradshaw HB, Berkley KJ (2002) Estrogen replacement reverses ovariectomy-induced vaginal hyperalgesia in the rat. Maturitas 41:157–165PubMedCrossRefGoogle Scholar
  13. 13.
    Gintzler AR, Bohan MC (1990) Pain thresholds are elevated during pseudopregnancy. Brain Res 507(2):312–316PubMedCrossRefGoogle Scholar
  14. 14.
    Dawson-Basoa ME, Gintzler AR (1998) Gestational and ovarian sex steroid antinociception: synergy between spinal and opioid system. Brain Res 757:37–42CrossRefGoogle Scholar
  15. 15.
    Unruh AM (1996) Gender variations in clinical pain experience. Pain 65:123–167PubMedCrossRefGoogle Scholar
  16. 16.
    Berkley KJ (1997) Sex differences in pain. Behav Brain Sci 20:371–380PubMedGoogle Scholar
  17. 17.
    Robbins A, Berkley KJ, Sato Y (1992) Estrous cycle variation of afferent fibers supplying reproductive organs in the female rat. Brain Res 596(1–2):353–356PubMedCrossRefGoogle Scholar
  18. 18.
    Sapsed-Byrne S, Ma D, Ridout D, Holdcroft A (1996) Estrous cycle phase variations in visceromotor and cardiovascular responses to colonic distension in the anesthetized rat. Brain Res 742(1–2):10–16PubMedCrossRefGoogle Scholar
  19. 19.
    Holdcroft A, Sapsed-Byrne S, Ma D, Hammal D, Forsling ML (2000) Sex and oestrous cycle differences in visceromotor responses and vasopressin release in response to colonic distension in male and female rats anaesthetized with halothane. Br J Anaesth 85(6):907–910PubMedCrossRefGoogle Scholar
  20. 20.
    Aloisi AM, Bonifazi M (2006) Sex hormones, central nervous system and pain. Horm Behav 50:1–7PubMedCrossRefGoogle Scholar
  21. 21.
    Bettini E, Pollio G, Santagati S, Maggi A (1992) Estrogen receptor in rat brain: presence in the hippocampal formation. Neuroendocrinology 56(4):502–508PubMedCrossRefGoogle Scholar
  22. 22.
    Papka RE, Srinivasan B, Miller KE, Hayashi S (1997) Localization of estrogen receptor protein and estrogen receptor messenger RNA in peripheral autonomic and sensory neurons. Neuroscience 79(4):1153–1163PubMedCrossRefGoogle Scholar
  23. 23.
    Taleghany N, Sarajari S, DonCarlos LL, Gollapudi L, Oblinger MM (1999) Differential expression of estrogen receptor alpha and beta in rat dorsal root ganglion neurons. J Neurosci Res 57:603–615PubMedCrossRefGoogle Scholar
  24. 24.
    Xiang Z, Bo X, Burnstock G (1998) Localization of ATP-gated P2X receptor immunoreactivity in rat sensory and sympathetic ganglia. Neurosci Lett 256(2):105–108PubMedCrossRefGoogle Scholar
  25. 25.
    Burnstock G (2007) Physiology and pathophysiology of purinergic neurotransmission. Physiol Rev 87(2):659–797PubMedCrossRefGoogle Scholar
  26. 26.
    Cockayne DA, Hamilton SG, Zhu QM, Dunn PM, Zhong Y, Novakovic S, Malmberg AB, Cain G, Berson A, Kassotakis L, Hedley L, Lachnit WG, Burnstock G, McMahon SB, Ford AP (2000) Urinary bladder hyporeflexia and reduced pain-related behaviour in P2X3-deficient mice. Nature 407(6807):1011–1015PubMedCrossRefGoogle Scholar
  27. 27.
    Cockayne DA, Dunn PM, Zhong Y, Rong W, Hamilton SG, Knight GE, Ruan HZ, Ma B, Yip P, Nunn P, McMahon SB, Burnstock G, Ford AP (2005) P2X2 knockout mice and P2X2/P2X3 double knockout mice reveal a role for the P2X2 receptor subunit in mediating multiple sensory effects of ATP. J Physiol 567(Pt 2):621–639PubMedCrossRefGoogle Scholar
  28. 28.
    Chaban VV, Mayer EA, Ennes HS, Micevych PE (2003) Estradiol inhibits ATP-induced intracellular calcium concentration increase in dorsal root ganglia neurons. Neuroscience 118:941–948PubMedCrossRefGoogle Scholar
  29. 29.
    Ma B, Rong W, Dunn PM, Burnstock G (2005) 17β-estradiol attenuates α,β-meATP-induced currents in rat dorsal root ganglion neurons. Life Sci 76(22):2547–2558PubMedCrossRefGoogle Scholar
  30. 30.
    Carley ME, Cliby WA, Spelsberg TC (2002) P2X3 receptor subunit messenger RNA expression in the female mouse bladder after oophorectomy with or without estrogen replacement. Am J Obstet Gynecol 187(1):103–106PubMedCrossRefGoogle Scholar
  31. 31.
    Papka RE, Hafemeister J, Storey-Workley M (2005) P2X receptors in the rat uterine cervix, lumbosacral dorsal root ganglia, and spinal cord during pregnancy. Cell Tissue Res 321(1):35–44PubMedCrossRefGoogle Scholar
  32. 32.
    McGaraughty S, Wismer CT, Zhu CZ, Mikusa J, Honore P, Chu KL, Lee CH, Faltynek CR, Jarvis MF (2003) Effects of A-317491, a novel and selective P2X3/P2X2/3 receptor antagonist, on neuropathic, inflammatory and chemogenic nociception following intrathecal and intraplantar administration. Br J Pharmacol 140(8):1381–1388PubMedCrossRefGoogle Scholar
  33. 33.
    Hamilton SG, Wade A, McMahon SB (1999) The effects of inflammation and inflammatory mediators on nociceptive behaviour induced by ATP analogues in the rat. Br J Pharmacol 126(1):326–332PubMedCrossRefGoogle Scholar
  34. 34.
    Sawynok J, Reid A (1997) Peripheral adenosine 5′-triphosphate enhances nociception in the formalin test via activation of a purinergic p2X receptor. Eur J Pharmacol 330(2–3):115–121PubMedCrossRefGoogle Scholar
  35. 35.
    Gorodeski GI (1998) Estrogen increases the permeability of the cultured human cervical epithelium by modulating cell deformability. Am J Physiol 275:C888–C899PubMedGoogle Scholar
  36. 36.
    Jarvis MF, Wismer CT, Schweitzer E, Yu H, van Biesen T, Lynch KJ, Burgard EC, Kowaluk EA (2001) Modulation of BzATP and formalin induced nociception: attenuation by the P2X receptor antagonist, TNP-ATP and enhancement by the P2X(3) allosteric modulator, cibacron blue. Br J Pharmacol 132(1):259–269PubMedCrossRefGoogle Scholar
  37. 37.
    Tsuda M, Shigemoto-Mogami Y, Koizumi S, Mizokoshi A, Kohsaka S, Salter MW, Inoue K (2003) P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury. Nature 424(6950):778–783PubMedCrossRefGoogle Scholar
  38. 38.
    Wakeling AE, Dukes M, Bowler JA (1991) A potent specific pure antiestrogen with clinical potential. Cancer Res 51:3867–3873PubMedGoogle Scholar
  39. 39.
    Gaumond I, Arsenault P, Marchand S (2002) The role of sex hormones on formalin-induced nociceptive responses. Brain Res 958(1):139–145PubMedCrossRefGoogle Scholar
  40. 40.
    Gaumond I, Arsenault P, Marchand S (2005) Specificity of female and male sex hormones on excitatory and inhibitory phases of formalin-induced nociceptive responses. Brain Res 1052(1):105–111PubMedCrossRefGoogle Scholar
  41. 41.
    Mannino CA, South SM, Quinones-Jenab V, Inturrisi CE (2007) Estradiol replacement in ovariectomized rats is antihyperalagesic in the formalin test. J Pain 8(4):334–342PubMedCrossRefGoogle Scholar
  42. 42.
    Cutolo M, Villaggio B, Foppiani L, Briata M, Sulli A, Pizzorni C, Faelli F, Prete C, Felli L, Seriolo B, Giusti M (2000) The hypothalamic–pituitary–adrenocortical and gonadal axis function in rheumatoid arthritis. Z Rheumatol 59(Suppl):S65–S69Google Scholar
  43. 43.
    Navarro MA, Nolla JM, Machuca MI, González A, Mateo L, Bonnin RM, Roig-Escofet D (1998) Salivary testosterone in postmenopausal women with rheumatoid arthritis. J Rheumatol 25:1059–1062PubMedGoogle Scholar
  44. 44.
    Green PG, Dahlqvist SR, Isenberg WM, Strausbaugh HJ, Miao FJ, Levine JD (1999) Sex steroid regulation of the inflammatory response: sympathoadrenal dependence in the female rat. J Neurosci 19:4082–4089PubMedGoogle Scholar
  45. 45.
    Beyenburg S, Stoffel-Wagner B, Bauer J, Watzka M, Blumcke I, Bidlingmaier F, Elger CE (2001) Neuroactive steroids and seizure susceptibility. Epilepsy Res 44:141–153PubMedCrossRefGoogle Scholar
  46. 46.
    Hammer RP Jr, Bridges RS (1987) Preoptric area opiods and opiate receptors increase during pregnancy and decrease during lactation. Brain Res 420(1):48–56PubMedCrossRefGoogle Scholar
  47. 47.
    Dondi D, Limonta P, Maggi R, Piva F (1992) Effects of ovarian hormones on brain opioid binding sites in castrated female rats. Am J Physiol 263(3 Pt 1):E507–E511PubMedGoogle Scholar
  48. 48.
    Quinones-Jenab V, Jenab S, Ogawa S, Inturrisi C, Pfaff DW (1997) Estrogen regulation of mu-opioid receptor mRNA in the forebrain of female rats. Brain Res Mol Brain Res 47(1–2):134–138PubMedCrossRefGoogle Scholar
  49. 49.
    Amandusson A, Hallbeck M, Hallbeck AL, Hermanson O, Blomqvist A (1999) Estrogen-induced alterations of spinal cord enkephalin gene expression. Pain 83(2):243–248PubMedCrossRefGoogle Scholar
  50. 50.
    Burnstock G, Wood JN (1996) Purinergic receptors: their role in nociception and primary afferent neurotransmission. Curr Opin Neurobiol 6(4):526–532PubMedCrossRefGoogle Scholar
  51. 51.
    Chen CC, Akopian AN, Sivilotti L, Colquhoun D, Burnstock G, Wood JN (1995) A P2X purinoreceptors expressed by a subset of sensory neurons. Nature 377:428–431PubMedCrossRefGoogle Scholar
  52. 52.
    Lewis C, Neidhart S, Holy C, North RA, Buell G, Surprenant A (1995) Coexpression of P2X2 and P2X3 receptor subunits can account for ATP-gated currents in sensory neurons. Nature 377:432–435PubMedCrossRefGoogle Scholar
  53. 53.
    North RA (2004) P2X3 receptors and peripheral pain mechanisms. J Physiol 554:301–308PubMedCrossRefGoogle Scholar
  54. 54.
    Kobayashi K, Fukuoka T, Yamanaka H, Dai Y, Obata K, Tokunaga A, Noguchi K (2005) Differential expression patterns of mRNAs for P2X receptor subunits in neurochemically characterized dorsal root ganglion neurons in the rat. J Comp Neurol 481:377–390PubMedCrossRefGoogle Scholar
  55. 55.
    Li L, Fan X, Warner M, Lili Li XuX-J, Gustafsson J-A, Wiesenfeld-Hallin Z (2009) Ablation of estrogen receptor α or β eliminates sex differences in mechanical pain threshold in normal and inflamed mice. Pain 143:37–40PubMedCrossRefGoogle Scholar
  56. 56.
    Fan XT, Kim H-J, Warner M, Gustafsson J (2007) Estrogen receptor β is essential for sprouting of nociceptive primary afferents and for morphogenesis and maintenance of the dorsal horn interneurons. Proc Natl Acad Sci USA 104:13696–13701PubMedCrossRefGoogle Scholar
  57. 57.
    Xu GY, Huang LY (2002) Peripheral inflammation sensitizes P2X receptor mediated responses in rat dorsal root ganglion neurons. J Neurosci 22:93–102PubMedGoogle Scholar
  58. 58.
    Xu GY, Huang LY (2004) Ca2+/calmodulin-dependent protein kinase II potentiates ATP responses by promoting trafficking of P2X receptors. Proc Natl Acad Sci USA 101:11868–11873PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2010

Authors and Affiliations

  1. 1.Department of PhysiologyShanghai Second Military Medical UniversityShanghaiPeople’s Republic of China
  2. 2.Key Laboratory of Molecular Neurobiology, Ministry of EducationSecond Military Medical UniversityShanghaiPeople’s Republic of China
  3. 3.Autonomic Neuroscience CentreUniversity College Medical SchoolLondonUK

Personalised recommendations