Advertisement

Purinergic Signalling

, Volume 13, Issue 1, pp 105–117 | Cite as

Inhibitory effect of estrogen receptor beta on P2X3 receptors during inflammation in rats

  • Qian Jiang
  • Wen-xin Li
  • Jia-run Sun
  • Tian-tian Zhu
  • Juan Fan
  • Li-hua Yu
  • Geoffrey Burnstock
  • Hua YangEmail author
  • Bei MaEmail author
Original Article

Abstract

Estrogen receptor beta (ERβ) has been shown to play a therapeutic role in inflammatory bowel disease (IBD). However, the mechanism underlying how ERβ exerts therapeutic effects and its relationship with P2X3 receptors (P2X3R) in rats with inflammation is not known. In our study, animal behavior tests, visceromotor reflex recording, and Western blotting were used to determine whether the therapeutic effect of ERβ in rats with inflammation was related with P2X3R. In complete Freund adjuvant (CFA)-induced chronic inflammation in rats, paw withdrawal threshold was significantly decreased which were then reversed by systemic injection of ERβ agonists, DPN or ERB-041. In 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats, weight loss, higher DAI scores, increased visceromotor responses, and inflammatory responses were reversed by application of DPN or ERB-041. The higher expressions of P2X3R in dorsal root ganglia (DRG) of CFA-treated rats and those in rectocolon and DRG of TNBS-treated rats were all decreased by injection of DPN or ERB-041. DPN application also inhibited P2X3R-evoked inward currents in DRG neurons from TNBS rats. Mechanical hyperalgesia and increased P2X3 expression in ovariectomized (OVX) CFA-treated rats were reversed by estrogen replacements. Furthermore, the expressions of extracellular signal-regulated kinase (ERK) in DRG and spinal cord dorsal horn (SCDH) and c-fos in SCDH were significantly decreased after estrogen replacement compared with those of OVX rats. The ERK antagonist U0126 significantly reversed mechanical hyperalgesia in the OVX rats. These results suggest that estrogen may play an important therapeutic role in inflammation through down-regulation of P2X3R in peripheral tissues and the nervous system, probably via ERβ, suggesting a novel therapeutic strategy for clinical treatment of inflammation.

Keywords

Estrogen receptor β P2X3 receptor CFA TNBS Inflammation 

Notes

Acknowledgments

This study is supported by National Natural Science Foundation of China (No, 31471103). We are deeply grateful to Dr. Gillian E. Knight (from the Autonomic Neuroscience Centre, University College Medical School, UK) for her kind assistance in the written English.

Compliance with ethical standards

Conflict of Interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Berkley KJ (1997) Sex differences in pain. Behav Brain Sci 20(3):371–380PubMedGoogle Scholar
  2. 2.
    Unruh AM (1996) Gender variations in clinical pain experience. Pain 65:123–167CrossRefPubMedGoogle Scholar
  3. 3.
    Chesterton LS, Barlas P, Foster NE, Baxter GD, Wright CC (2003) Gender differences in pressure pain threshold in healthy humans. Pain 101(3):259–266CrossRefPubMedGoogle Scholar
  4. 4.
    Craft RM, Ulibarri C, Leitl MD, Sumner JE (2008) Dose- and time-dependent estradiol modulation of morphine antinociception in adult female rats. Eur J Pain 12:472–479CrossRefPubMedGoogle Scholar
  5. 5.
    Gintzler AR, Bohan MC, Gintzler AR, Bohan M (1990) Pain thresholds are elevated during pseudopregnancy. Brain Res 507(2):312–316CrossRefPubMedGoogle Scholar
  6. 6.
    Dawson-Basoa M, Gintzler AR (1998) Gestational and ovarian sex steroid antinociception: synergy between spinal kappa and delta opioid systems. Brain Res 794(1):61–67CrossRefPubMedGoogle Scholar
  7. 7.
    Craft RM (2007) Modulation of pain by estrogens. Pain Suppl 132(1):S3–S12CrossRefGoogle Scholar
  8. 8.
    Sanoja R, Cervero F (2005) Estrogen-dependent abdominal hyperalegsia induced by ovariectimy in adult mice: a model of functional abdominal pain. Pain 118:243–253CrossRefPubMedGoogle Scholar
  9. 9.
    Aloisi AM, Ceccarelli I (2000) Role of gonadal hormones in formalin-induced pain responses of male rats: modulation by estradiol and naloxone administration. Neuroscience 95:559–566CrossRefPubMedGoogle Scholar
  10. 10.
    Bradshaw H, Miller J, Ling Q, Malsnee K, Ruda MA (2000) Sex differences and phases of the estrous cycle alter the response of spinal cord dynorphin neurons to peripheral inflammation and hyperalgesia. Pain 85:93–99CrossRefPubMedGoogle Scholar
  11. 11.
    De Marinis E, Acaz-Fonseca E, Arevalo MA, Ascenzi P, Fiocchetti M, Marino M, Garcia-Segura LM (2013) 17b-Oestradiol anti-inflammatory effects in primary astrocytes require oestrogen receptor β-mediated neuroglobin up-regulation. J Neuroendocrinol 25:260–270CrossRefPubMedGoogle Scholar
  12. 12.
    De Marinis E, Acaz-Fonseca E, Arevalo MA, Ascenzi P, Fiocchetti M, Marino M, Garcia-Segura LM (2013) Estradiol receptors agonists induced effects in rat intestinal microcirculation during sepsis. Microvasc Res 85:118–127CrossRefGoogle Scholar
  13. 13.
    Li L, Fan X, Warner M, Xu XJ, Gustafsson JA, Wiesenfeld-Hallin Z (2009) Ablation of estrogen receptor a or b eliminates sex differences in mechanical pain threshold in normal and inflamed mice. Pain 143:37–40CrossRefPubMedGoogle Scholar
  14. 14.
    Spooner MF, Robichaud P, Carrier JC, Marchand S (2007) Endogenous pain modulation during the formalin test in estrogen receptor beta knockout mice. Neuroscience 150:675–680CrossRefPubMedGoogle Scholar
  15. 15.
    Edvardsson K, Ström A, Jonsson P, Gustafsson JÅ, Williams C (2011) Estrogen receptor induces antiinflammatory and antitumorigenic networks in colon cancer cells. Mol Endocrinol 25:969–979CrossRefPubMedGoogle Scholar
  16. 16.
    Cao DY, Ji Y, Tang B, Traub RJ (2012) Estrogen receptor β activation is antinociceptive in a model of visceral pain in the rat. J Pain 13:685–694CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Xu S, Cheng Y, Keast JR, Osborne PB (2008) 17β-estradiol activates estrogen receptor βsignalling and inhibits transient receptor potential vanilloid receptor 1 activation by capsaicin in adult rat nociceptor neurons. Endocrinology 149:540–5548Google Scholar
  18. 18.
    Gardell LR, Hyldtoft L, Del Tredici AL, Andersen CB, Fairbairn LC, Lund BW, Gustafsson M, Brann MR, Olsson R, Piu F (2008) Differential modulation of inflammatory pain by a selective estrogen receptor β agonist. Eur J Pharmacol 592:158–159CrossRefPubMedGoogle Scholar
  19. 19.
    Sapsed-Byrnea S, Ma D, Ridoutb D, Holdcrofta A (1996) Estrous cycle phase variations in visceromotor and cardiovascular responses to colonic distension in the anesthetized rat. Brain Res 742(1–2):10–16CrossRefGoogle Scholar
  20. 20.
    Harris HA, Albert LM, Leathurby Y, Malamas MS, Mewshaw RE, Miller CP, Kharode YP, Marzolf J, Komm BS, Winneker RC, Frail DE, Henderson RA, Zhu Y, Keith JC Jr (2003) Evaluation of an estrogen receptor-beta agonist in animal models of human disease. Endocrinology 144(10):4241–4249CrossRefPubMedGoogle Scholar
  21. 21.
    Cattaneo M (2015) The platelet P2 receptors in inflammation. Hamostaseologie 35(3):262–266CrossRefPubMedGoogle Scholar
  22. 22.
    Burnstock G (2007) Physiology and pathophysiology of purinergic neurotransmission. Physiol Rev 87:659–797CrossRefPubMedGoogle Scholar
  23. 23.
    Wynn G, Ma B, Ruan HZ, Burnstock G (2004) Purinergic component of mechanosensory transduction is increased in a rat model of colitis. Am J Physiol Gastrointest Liver Physiol 287:G647–G657CrossRefPubMedGoogle Scholar
  24. 24.
    Shinoda M, Feng B, Gebhart GF (2009) Peripheral and central P2X3 receptor contributions to colon mechanosensitivity and hypersensitivity in the mouse. Gastroenterology 137:2096–2104CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Xiang Z, Xiong Y, Yan N, Li X, Mao Y, Ni X, He C, LaMotte RH, Burnstock G, Sun J (2008) Functional up-regulation of P2X3 receptors in the chronically compressed dorsal root ganglion. Pain 140:23–34CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Oliveira MC, Pelegrini-da-Silva A, Tambeli CH, Parada CA (2009) Peripheral mechanisms underlying the essential role of P2X3, 2/3 receptors in the development of inflammatory hyperalgesia. Pain 141(1–2):127–134CrossRefPubMedGoogle Scholar
  27. 27.
    Hsieh YL, Chiang H, Lue JH, Hsieh ST (2012) P2X3-mediated peripheral sensitization of neuropathic pain in resiniferatoxin-induced neuropathy. Exp Neurol 235:316–325CrossRefPubMedGoogle Scholar
  28. 28.
    Fan J, Yu LH, Zhang YM, Ni X, Ma B, Burnstock G (2009) Estrogen altered visceromotor reflex and P2X3 mRNA expression in a rat model of colitis. Steroids 74:956–962CrossRefPubMedGoogle Scholar
  29. 29.
    Lu Y, Jiang Q, Yu L, Lu ZY, Meng SP, Su D, Burnstock G, Ma B (2013) 17β-estradiol rapidly attenuates P2X3 receptor-mediated peripheral pain signal transduction via ERα and GPR30. Endocrinology 154(7):2421–2433CrossRefPubMedGoogle Scholar
  30. 30.
    Ma B, Yu LH, Fan J, Cong BH, He P, Ni X, Burnstock G (2011) Estrogen modulation of peripheral pain signal transduction: involvement of P2X3 receptors. Purinergic Signal 7:73–83CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Lu Y, Li Z, Li HJ, Du D, Wang LP, Yu LH, Geoffrey B, Chen AM, Ma B (2012) A comparative study of 17β-estradiol and estriol on peripheral pain behavior in rats. Steroids 77:241–249CrossRefPubMedGoogle Scholar
  32. 32.
    Rovenský J, Stančíkova M, Svík K, Bauerová K, Jurčovičová J (2011) The effects of β-glucan isolated from Pleurotusostreatus on methotrexate treatment in rats with adjuvant arthritis. Rheumatol Int 31(4):507–511CrossRefPubMedGoogle Scholar
  33. 33.
    Tsubota M, Kawabata A (2014) Role of hydrogen sulfide, a gasotransmitter, in colonic pain and inflammation. Yakugaku Zasshi 134(12):1245–1252CrossRefPubMedGoogle Scholar
  34. 34.
    Liu CY, Lu ZY, Li N, Yu LH, Zhao YF, Ma B (2015) The role of large-conductance, calcium-activated potassium channels in a rat model of trigeminal neuropathic pain. Cephalalgia 35(1):16–35CrossRefPubMedGoogle Scholar
  35. 35.
    Ji RR, Befort K, Brenner GJ (2002) ERK MAP kinase activation in superficial spinal cord neurons induces prodynorphin and NK-1 upregulation and contributes to persistent inflammatory pain hypersensitivity. J Neurosci 22:478–485PubMedGoogle Scholar
  36. 36.
    Mannino CA, South SM, Quinones-Jenab V, Inturrisi CE (2007) Estradiol replacement in ovariectomized rats is antihyperalgesic in the formalin test. J Pain 8(4):334–342CrossRefPubMedGoogle Scholar
  37. 37.
    Mannino CA, South SM, Inturrisi CE, Quinones-Jenab V (2005) Pharmacokinetics and effects of 17β-estradiol and progesterone implants in ovariectomized rats. J Pain 6:809–816CrossRefPubMedGoogle Scholar
  38. 38.
    Taleghany N, Sarajari S, DonCarlos LL, Gollapudi L, Oblinger MM (1999) Differential expression of estrogen receptor α and β in rat dorsal root ganglion neurons. J Neurosci Res 57:603–615CrossRefPubMedGoogle Scholar
  39. 39.
    Papka RE, Storey-Workley M, Shughrue PJ, Merchentha-ler I, Collins JJ, Usip S, Saunders PT, Shupnik M (2001) Estrogenreceptor-α and β- immunoreactivity and mRNA in neurons of sensory and autonomic ganglia and spinal cord. Cell Tissue Res 304:193–214CrossRefPubMedGoogle Scholar
  40. 40.
    Nilsson S, Gustafsson JÅ (2011) Estrogen receptors: therapies targeted to receptor subtypes. Clin Pharmacol Ther 89:44–55CrossRefPubMedGoogle Scholar
  41. 41.
    Harris HA, Bruner-Tran KL, Zhang X, Osteen KG, Lyttle CR (2005) A selective estrogen receptor-βagonist causes lesion regression in an experimentally induced model of endometriosis. Hum Reprod 20:936–941CrossRefPubMedGoogle Scholar
  42. 42.
    Chen CC, Akopian AN, Sivilotti L, Colquhoun D, Burnstock G, Wood JN (1995) P2X purinoceptor expressed by a subset of sensory neurons. Nature 377:428–431CrossRefPubMedGoogle Scholar
  43. 43.
    Novakovic SD, Kassotakis LC, Oglesby IB, Smith JA, Eglen RM, Ford AP, Hunter JC (1999) Immunocytochemical localization of P2X3 purinoceptors in sensory neurons in naïve rats and following neuropathic injury. Pain 80:273–282CrossRefPubMedGoogle Scholar
  44. 44.
    Xu GY, Huang LY (2002) Peripheral inflammation sensitizes P2X receptor-mediated responses in rat dorsal root ganglion neurons. J Neurosci 22(1):93–102PubMedGoogle Scholar
  45. 45.
    Nakamura T, Katsu Y, Watanabe H, Iguchi T (2008) Estrogen receptor subtypes selectively mediate female mouse reproductive abnormalities induced by neonatal exposure to estrogenic chemicals. Toxicology 253:117–124CrossRefPubMedGoogle Scholar
  46. 46.
    Lee ZH, Kim HH (2003) Signal transduction by receptor activator of nuclear factorkappa B in osteoclasts. Biochem Biophys Res Commun 305:211–214CrossRefPubMedGoogle Scholar
  47. 47.
    Boyle WJ, Simonet WS, Lacey DL (2003) Osteoclast differentiation and activation. Nature 423:337–342CrossRefPubMedGoogle Scholar
  48. 48.
    Khare V, Paul G, Movadat O, Frick A, Jambrich M, Krnjic A, Marian B, Wrba F, Gasche C (2015) IL-10R2 overexpression promotes IL-22/STAT3 signaling in colorectal carcinogenesis. Cancer Immunol Res 3(11):1227–1135CrossRefPubMedGoogle Scholar
  49. 49.
    Cui J, Shen Y, Li R (2013) Estrogen synthesis and signaling pathways during ageing: from periphery to brain. Trends Mol Med 19(3):197–209CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Adachi T, Kar S, Wang M, Carr BI (2002) Transient and sustained ERK phosphorylation and nuclear translocation in growth control. Cell Physiol 192(2):151–159CrossRefGoogle Scholar
  51. 51.
    Chen XQ, Wang B, Wu C, Pan J, Yuan B, Su YY, Jiang XY, Zhang X, Bao L (2012) Endosome-mediated retrograde axonal transport of P2X3 receptor signals in primary sensory neurons. Cell Res 22:677–696CrossRefPubMedGoogle Scholar
  52. 52.
    Shimizu I, Iida T, Guan Y, Zhao C, Raja SN, Jarvis MF, Cockayne DA, Caterina MJ (2005) Enhanced thermal avoidance in mice lacking the ATP receptor P2X3. Pain 116(1–2):96–108CrossRefPubMedGoogle Scholar
  53. 53.
    Herrera DG, Robertson HA (1996) Activation of c-fos in the brain. Prog Neurobiol 50(2–3):83–107CrossRefPubMedGoogle Scholar
  54. 54.
    Harris JA (1998) Using c-fos as a neural marker of pain. Brain Res Bull 45(1):1–8CrossRefPubMedGoogle Scholar
  55. 55.
    Wagstaff SC, Bowler WB, Gallagher JA, Hipskind RA (2000) Extracellular ATP activates multiple signalling pathways and potentiates growth factor-induced c-fos gene expression in MCF-7 breast cancer cells. Carcinogenesis 21(12):2175–2181CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2016

Authors and Affiliations

  • Qian Jiang
    • 1
  • Wen-xin Li
    • 1
  • Jia-run Sun
    • 1
  • Tian-tian Zhu
    • 1
  • Juan Fan
    • 1
  • Li-hua Yu
    • 1
  • Geoffrey Burnstock
    • 2
    • 3
  • Hua Yang
    • 4
    Email author
  • Bei Ma
    • 1
    Email author
  1. 1.Department of PhysiologySecond Military Medical UniversityShanghaiPeople’s Republic of China
  2. 2.Autonomic Neuroscience Centre, Royal Free CampusUniversity College Medical SchoolLondonUK
  3. 3.Department of PharmacologyMelbourne UniversityParkvilleAustralia
  4. 4.Department of Gastroenterology, Changhai HospitalSecond Military Medical UniversityShanghaiPeople’s Republic of China

Personalised recommendations