Skip to main content

Advertisement

SpringerLink
Log in

Involvement of Estrogen in Rapid Pain Modulation in the Rat Spinal Cord

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

The pivotal role of estrogens in the pain sensitivity has been investigated in many ways. Traditionally, it is ascribed to the slow genomic changes mediated by classical nuclear estrogen receptors (ER), ERα and ERβ, depending on peripheral estrogens. Recently, it has become clear that estrogens can also signal through membrane ERs (mERs), such as G-protein-coupled ER1 (GPER1), mediating the non-genomic effects. However, the spinal specific role played by ERs and the underlying cellular mechanisms remain elusive. The present study investigated the rapid estrogenic regulation of nociception at the spinal level. Spinal administration of 17β-estradiol (E2), the most potent natural estrogen, acutely produced a remarkable mechanical allodynia and thermal hyperalgesia without significant differences among male, female and ovariectomized (Ovx) rats. E2-induced the pro-nociceptive effects were partially abrogated by ICI 182,780 (ERs antagonist), and mimicked by E2-BSA (a mER agonist). Inhibition of local E2 synthesis by 1,4,6-Androstatrien-3,17-dione (ATD, a potent irreversible aromatase inhibitor), or blockade of ERs by ICI 182,780 produced an inhibitory effect on the late phase of formalin nociceptive responses. Notably, lumbar puncture injection of G15 (a selective GPER1 antagonist) resulted in similar but more efficient inhibition of formalin nociceptive responses as compared with ICI 182,780. At the cellular level, the amplitude and decay time of spontaneous inhibitory postsynaptic currents were attenuated by short E2 or E2-BSA treatment in spinal slices. These results indicate that estrogen acutely facilitates nociceptive transmission in the spinal cord via activation of membrane-bound estrogen receptors.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Evrard HC (2006) Estrogen synthesis in the spinal dorsal horn: a new central mechanism for the hormonal regulation of pain. Am J Physiol Regul Integr Comp Physiol 291:R291–R299

    Article  PubMed  CAS  Google Scholar 

  2. Ji Y, Tang B, Traub RJ (2011) Spinal estrogen receptor alpha mediates estradiol-induced pronociception in a visceral pain model in the rat. Pain 152:1182–1191

    Article  PubMed  CAS  Google Scholar 

  3. Sanoja R, Cervero F (2005) Estrogen-dependent abdominal hyperalgesia induced by ovariectomy in adult mice: a model of functional abdominal pain. Pain 118:243–253

    Article  PubMed  CAS  Google Scholar 

  4. 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 85:93–99

    Article  PubMed  CAS  Google Scholar 

  5. Fehrenbacher JC, Loverme J, Clarke W, Hargreaves KM, Piomelli D et al (2009) Rapid pain modulation with nuclear receptor ligands. Brain Res Rev 60:114–124

    Article  PubMed  CAS  Google Scholar 

  6. Mannino CA, South SM, Quinones-Jenab V, Inturrisi CE (2007) Estradiol replacement in ovariectomized rats is antihyperalgesic in the formalin test. J Pain 8:334–342

    Article  PubMed  CAS  Google Scholar 

  7. Cao DY, Ji Y, Tang B, Traub RJ (2012) Estrogen receptor beta activation is antinociceptive in a model of visceral pain in the rat. J Pain 13:685–694

    Article  PubMed  CAS  Google Scholar 

  8. Evrard HC, Balthazart J (2004) Rapid regulation of pain by estrogens synthesized in spinal dorsal horn neurons. J Neurosci 24:7225–7229

    Article  PubMed  CAS  Google Scholar 

  9. Evrard H, Baillien M, Foidart A, Absil P, Harada N, Balthazart J (2000) Localization and controls of aromatase in the quail spinal cord. J Comp Neurol 423:552–564

    Article  PubMed  CAS  Google Scholar 

  10. Liu NJ, Chakrabarti S, Schnell S, Wessendorf M, Gintzler AR (2011) Spinal synthesis of estrogen and concomitant signaling by membrane estrogen receptors regulate spinal κ- and μ-opioid receptor heterodimerization and female-specific spinal morphine antinociception. J Neurosci 31:11836–11845

    Article  PubMed  CAS  Google Scholar 

  11. Papka RE, Storey-Workley M, Shughrue PJ, Merchenthaler I, Collins JJ, Usip S, Saunders PT, Shupnik M (2001) Estrogen receptor-alpha and beta-immunoreactivity and mRNA in neurons of sensory and autonomic ganglia and spinal cord. Cell Tissue Res 304:193–214

    Article  PubMed  CAS  Google Scholar 

  12. VanderHorst VG, Gustafsson JA, Ulfhake B (2005) Estrogen receptor-alpha and -beta immunoreactive neurons in the brainstem and spinal cord of male and female mice: relationships to monoaminergic, cholinergic, and spinal projection systems. J Comp Neurol 488:152–179

    Article  PubMed  Google Scholar 

  13. Dun SL, Brailoiu GC, Gao X, Brailoiu E, Arterburn JB, Prossnitz ER, Oprea TI, Dun NJ (2009) Expression of estrogen receptor GPR30 in the rat spinal cord and in autonomic and sensory ganglia. J Neurosci Res 87:1610–1619

    Article  PubMed  CAS  Google Scholar 

  14. Filardo EJ, Quinn JA, Frackelton AR Jr, Bland KI (2002) Estrogen action via the G protein-coupled receptor, GPR30: stimulation of adenylyl cyclase and cAMP-mediated attenuation of the epidermal growth factor receptor-to-MAPK signaling axis. Mol Endocrinol 16:70–84

    Article  PubMed  CAS  Google Scholar 

  15. Feng Y, Gregor P (1997) Cloning of a novel member of the G protein-coupled receptor family related to peptide receptors. Biochem Biophys Res Commun 231:651–654

    Article  PubMed  CAS  Google Scholar 

  16. Maggiolini M, Picard D (2010) The unfolding stories of GPR30, a new membrane-bound estrogen receptor. J Endocrinol 204:105–114

    Article  PubMed  CAS  Google Scholar 

  17. Revankar CM, Cimino DF, Sklar LA, Arterburn JB, Prossnitz ER (2005) A transmembrane intracellular estrogen receptor mediates rapid cell signaling. Science 307:1625–1630

    Article  PubMed  CAS  Google Scholar 

  18. Kuhn J, Dina OA, Goswami C, Suckow V, Levine JD et al (2008) GPR30 estrogen receptor agonists induce mechanical hyperalgesia in the rat. Eur J Neurosci 27:1700–1709

    Article  PubMed  Google Scholar 

  19. Levin ER (2009) Plasma membrane estrogen receptors. Trends Endocrinol Metab 20:477–482

    Article  PubMed  CAS  Google Scholar 

  20. Mermelstein PG (2009) Membrane-localised oestrogen receptor alpha and beta influence neuronal activity through activation of metabotropic glutamate receptors. J Neuroendocrinol 21:257–262

    Article  PubMed  CAS  Google Scholar 

  21. Micevych P, Dominguez R (2009) Membrane estradiol signaling in the brain. Front Neuroendocrinol 30:315–327

    Article  PubMed  CAS  Google Scholar 

  22. Vasudevan N, Pfaff DW (2008) Non-genomic actions of estrogens and their interaction with genomic actions in the brain. Front Neuroendocrinol 29:238–257

    Article  PubMed  CAS  Google Scholar 

  23. Jiang P, Kong Y, Zhang XB, Wang W, Liu CF, Xu TL (2009) Glycine receptor in rat hippocampal and spinal cord neurons as a molecular target for rapid actions of 17-beta-estradiol. Mol Pain 5:2

    Article  PubMed  Google Scholar 

  24. Xu JJ, Walla BC, Diaz MF, Fuller GN, Gutstein HB (2006) Intermittent lumbar puncture in rats: a novel method for the experimental study of opioid tolerance. Anesth Analg 103:714–720

    Article  PubMed  CAS  Google Scholar 

  25. Cheng LZ, Lü N, Zhang YQ, Zhao ZQ (2010) Ryanodine receptors contribute to the induction of nociceptive input-evoked long-term potentiation in the rat spinal cord slice. Mol Pain 6:1

    Article  PubMed  Google Scholar 

  26. Bondar G, Kuo J, Hamid N, Micevych P (2009) Estradiol-induced estrogen receptor-alpha trafficking. J Neurosci 29:15323–15330

    Article  PubMed  CAS  Google Scholar 

  27. Kow LM, Pfaff DW (2004) The membrane actions of estrogens can potentiate their lordosis behavior-facilitating genomic actions. Proc Natl Acad Sci USA 101:12354–12357

    Article  PubMed  CAS  Google Scholar 

  28. Balthazart J, Ball GF (2006) Is brain estradiol a hormone or a neurotransmitter? Trends Neurosci 29:241–249

    Article  PubMed  CAS  Google Scholar 

  29. Hojo Y, Murakami G, Mukai H, Higo S, Hatanaka Y, Ogiue-Ikeda M, Ishii H, Kimoto T, Kawato S (2008) Estrogen synthesis in the brain—role in synaptic plasticity and memory. Mol Cell Endocrinol 290:31–43

    Article  PubMed  CAS  Google Scholar 

  30. Collins P, Webb C (1999) Estrogen hits the surface. Nat Med 5:1130–1131

    Article  PubMed  CAS  Google Scholar 

  31. Edwards DP (2005) Regulation of signal transduction pathways by estrogen and progesterone. Annu Rev Physiol 67:335–376

    Article  PubMed  CAS  Google Scholar 

  32. Levin ER (2002) Cellular functions of plasma membrane estrogen receptors. Steroids 67:471–475

    Article  PubMed  CAS  Google Scholar 

  33. Abraham IM, Todman MG, Korach KS, Herbison AE (2004) Critical in vivo roles for classical estrogen receptors in rapid estrogen actions on intracellular signaling in mouse brain. Endocrinology 145:3055–3061

    Article  PubMed  CAS  Google Scholar 

  34. Nadal A, Ropero AB, Fuentes E, Soria B (2001) The plasma membrane estrogen receptor: nuclear or unclear? Trends Pharmacol Sci 22:597–599

    Article  PubMed  CAS  Google Scholar 

  35. Qiu J, Bosch MA, Tobias SC, Grandy DK, Scanlan TS, Ronnekleiv OK, Kelly MJ (2003) Rapid signaling of estrogen in hypothalamic neurons involves a novel G-protein-coupled estrogen receptor that activates protein kinase C. J Neurosci 23:9529–9540

    PubMed  CAS  Google Scholar 

  36. Fillingim RB, King CD, Ribeiro-Dasilva MC, Williams BR, Riley JL III (2009) Sex, gender, and pain: a review of recent clinical and experimental findings. J Pain 10:447–485

    PubMed  Google Scholar 

  37. Berkley KJ (1997) Sex differences in pain. Behav Brain Sci 20:371–380

    PubMed  CAS  Google Scholar 

  38. 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 9:630–638

    Article  PubMed  CAS  Google Scholar 

  39. Unruh AM (1996) Gender variations in clinical pain experience. Pain 65:123–167

    Article  PubMed  CAS  Google Scholar 

  40. Craft RM, Mogil JS, Aloisi AM (2004) Sex differences in pain and analgesia: the role of gonadal hormones. Eur J Pain 8:397–411

    Article  PubMed  CAS  Google Scholar 

  41. Cornil CA, Ball GF, Balthazart J (2006) Functional significance of the rapid regulation of brain estrogen action: where do the estrogens come from? Brain Res 1126:2–26

    Article  PubMed  CAS  Google Scholar 

  42. Kondo D, Yabe R, Kurihara T, Saegusa H, Zong S, Tanabe T (2006) Progesterone receptor antagonist is effective in relieving neuropathic pain. Eur J Pharmacol 541:44–48

    Article  PubMed  CAS  Google Scholar 

  43. Greenspan JD, Craft RM, LeResche L, Arendt-Nielsen L, Berkley KJ, Fillingim RB, Gold MS, Holdcroft A, Lautenbacher S, Mayer EA et al (2007) Studying sex and gender differences in pain and analgesia: a consensus report. Pain 132:S26–S45

    Article  PubMed  Google Scholar 

  44. Ledoux VA, Woolley CS (2005) Evidence that disinhibition is associated with a decrease in number of vesicles available for release at inhibitory synapses. J Neurosci 25:971–976

    Article  PubMed  CAS  Google Scholar 

  45. Li W, Jin X, Covey DF, Steinbach JH (2007) Neuroactive steroids and human recombinantrho1 GABAC receptors. J Pharmacol Exp Ther 323:236–247

    Article  PubMed  CAS  Google Scholar 

  46. Rudick CN, Woolley CS (2001) Estrogen regulates functional inhibition of hippocampal CA1 pyramidal cells in the adult female rat. J Neurosci 21:6532–6543

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by National Basic Research Program of China (Grant 2007CB512502) and National Natural Science Fund of China (NSFC, 31121061, 31070973, 30900444 and 30830044).

Author information

Authors and Affiliations

  1. Institute of Neurobiology, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Shanghai Medical College, Fudan University, 138 Yi Xue Yuan Road, Shanghai, 200032, China

    Yan Zhang, Ning Lü, Zhi-Qi Zhao & Yu-Qiu Zhang

  2. Cell Electrophysiology Laboratory, Wannan Medical College, Wuhu, 241002, China

    Yan Zhang

Authors
  1. Yan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ning Lü
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhi-Qi Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yu-Qiu Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Ning Lü or Yu-Qiu Zhang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhang, Y., Lü, N., Zhao, ZQ. et al. Involvement of Estrogen in Rapid Pain Modulation in the Rat Spinal Cord. Neurochem Res 37, 2697–2705 (2012). https://doi.org/10.1007/s11064-012-0859-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-012-0859-1

Keywords

Search

Navigation