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Estradiol attenuates spinal cord injury-related central pain by decreasing glutamate levels in thalamic VPL nucleus in male rats

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Abstract

Central neuropathic pain (CNP) is a complicated medical problem that involves both the spinal and supraspinal regions of the central nervous system. Estrogen, a neuroprotective agent, has been considered a possible candidate for CNP treatment. In this study, we examined the effects of a single dose of 17β-estradiol on glutamate levels in the ventral posterolateral (VPL) nucleus of the rat thalamus. Furthermore, we determined whether there was a correlation between glutamate levels and neuropathic pain induced by unilateral electrolytic spinothalamic tract (STT) lesion. STT lesioning was performed in male Wistar rats at the T8-T9 vertebrae; rats were then administered 17β-estradiol (4 mg/kg, i.p.) 30 min after injury. Glutamate samples were collected using a microdialysis probe and quantified by high performance liquid chromatography. Mechanical allodynia (MA) and thermal hyperalgesia (TH) thresholds were measured pre-injury and 7, 14, and 28 days post-injury. We found that STT lesion significantly increased glutamate levels in the ipsilateral VPL nucleus 14 and 28 days post-injury; this was accompanied by allodynia and hyperalgesia in the hind paws of the rats. Administering 17β-estradiol to the rats decreased glutamate levels in the ipsilateral VPL nucleus and significantly increased MA and TH thresholds. These results suggest that glutamate in the VPL nucleus of the thalamus is involved in the pathology of neuropathic pain after STT injury; furthermore, 17β-estradiol may attenuate this neuropathic pain by decreasing glutamate levels.

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References

  • Abarca C, Silva E, Sepúlveda MJ, Oliva P, Contreras E (2000) Neurochemical changes after morphine, dizocilpine or riluzole in the ventral posterolateral thalamic nuclei of rats with hyperalgesia. Eur J Pharmacol 403(1):67–74

    Article  CAS  PubMed  Google Scholar 

  • Becker D, Sadowsky CL, McDonald JW (2003) Restoring function after spinal cord injury. Neurologist 9(1):1–15

    Article  PubMed  Google Scholar 

  • Bordi F, Quartaroli M (2000) Modulation of nociceptive transmission by NMDA/glycine site receptor in the ventroposterolateral nucleus of the thalamus. Pain 84(2):213–224

    Article  CAS  PubMed  Google Scholar 

  • Chaplan S, Bach F, Pogrel J, Chung J, Yaksh T (1994) Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 53(1):55–63

    Article  CAS  PubMed  Google Scholar 

  • Cimarosti H, O’Shea RD, Jones NM, Horn AP, Simão F, Zamin LL, Nassif M, Frozza R, Netto CA, Beart PM (2006) The effects of estradiol on estrogen receptor and glutamate transporter expression in organotypic hippocampal cultures exposed to oxygen–glucose deprivation. Neurochem Res 31(4):483–490

    Article  CAS  PubMed  Google Scholar 

  • Crown ED, Gwak YS, Ye Z, Johnson KM, Hulsebosch CE (2008) Activation of p38 MAP kinase is involved in central neuropathic pain following spinal cord injury. Exp Neurol 213(2):257–267

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Day NL, Floyd CL, D'Alessandro TL, Hubbard WJ, Chaudry IH (2013) 17β-estradiol confers protection following traumatic brain injury in the rat and involves activation of G Protein-coupled estrogen receptor 1 (GPER). J Neurotrauma (ja)

  • Elham S, Fatemeh A, Kobra N, Samar G, Mina A, Ali H, Farzaneh R, Masoumeh J (2013) Estradiol attenuates spinal cord injury-induced pain by suppressing microglial activation in thalamic VPL nuclei of rats. Neurosci Res 5(4):316–323

  • Finnerup NB, Baastrup C, Jensen TS (2009) Neuropathic pain following spinal cord injury pain: mechanisms and treatment. Scand J Pain 1:S3–S11

    Article  Google Scholar 

  • Ghanbari A, Asgari A, Kaka G, Falahatpishe H, Naderi A, Jorjani M (2014) In vivo microdialysis of glutamate in ventroposterolateral nucleus of thalamus following electrolytic lesion of spinothalamic tract in rats. Exp Brain Res 232(2):415–421

    Article  CAS  PubMed  Google Scholar 

  • Green PS, Simpkins JW (2000) Neuroprotective effects of estrogens: potential mechanisms of action. Int J Dev Neurosci 18(4):347–358

    Article  CAS  PubMed  Google Scholar 

  • Gupta DS, Hubscher CH (2012) Estradiol treatment prevents injury induced enhancement in spinal cord dynorphin expression. Front Physiol 3:28

    Article  PubMed Central  PubMed  Google Scholar 

  • Gwak YS, Hulsebosch CE (2011) GABA and central neuropathic pain following spinal cord injury. Neuropharmacology 60(5):799–808

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Gwak YS, Kim HK, Kim HY, Leem JW (2010) Bilateral hyperexcitability of thalamic VPL neurons following unilateral spinal injury in rats. J Physiol Sci 60(1):59–66

    Article  PubMed  Google Scholar 

  • Hains BC, Saab CY, Waxman SG (2005) Changes in electrophysiological properties and sodium channel Nav1. 3 expression in thalamic neurons after spinal cord injury. Brain 128(10):2359–2371

    Article  PubMed  Google Scholar 

  • Hoffman GE, Merchenthaler I, Zup SL (2006) Neuroprotection by ovarian hormones in animal models of neurological disease. Endocrine 29(2):217–231

    Article  CAS  PubMed  Google Scholar 

  • Horn TF, Engelmann M (2001) In Vivo microdialysis for nonapeptides in Rat Brain—a practical guide. Methods 23(1):41–53

    Article  CAS  PubMed  Google Scholar 

  • Hubscher CH, Fell JD, Gupta DS (2010) Sex and hormonal variations in the development of at-level allodynia in a rat chronic spinal cord injury model. Neurosci Lett 477(3):153–156

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Hubscher CH, Johnson RD (2006) Chronic spinal cord injury induced changes in the responses of thalamic neurons. Exp Neurol 197(1):177–188

    Article  PubMed  Google Scholar 

  • Hulsebosch CE, Hains BC, Crown ED, Carlton SM (2009) Mechanisms of chronic central neuropathic pain after spinal cord injury. Brain Res Rev 60(1):202–213

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kuba T, Wu H-BK, Nazarian A, Festa ED, Barr GA, Jenab S, Inturrisi CE, Quinones-Jenab V (2006) Estradiol and progesterone differentially regulate formalin-induced nociception in ovariectomized female rats. Horm Behav 49(4):441–449

    Article  CAS  PubMed  Google Scholar 

  • Leventhal L, Brandt MR, Cummons TA, Piesla MJ, Rogers KE, Harris HA (2006) An estrogen receptor-β agonist is active in models of inflammatory and chemical-induced pain. Eur J Pharmacol 553(1):146–148

    Article  CAS  PubMed  Google Scholar 

  • Likavčanová K, Urdzíková L, Hájek M, Syková E (2008) Metabolic changes in the thalamus after spinal cord injury followed by proton MR spectroscopy. Magn Reson Med 59(3):499–506

    Article  PubMed  Google Scholar 

  • Ma B, L-h Y, Fan J, Cong B, He P, Ni X, Burnstock G (2011) Estrogen modulation of peripheral pain signal transduction: involvement of P2X3 receptors. Purinergic Signal 7(1):73–83

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Maeda S, Kawamoto A, Yatani Y, Shirakawa H, Nakagawa T, Kaneko S (2008) Gene transfer of GLT-1, a glial glutamate transporter, into the spinal cord by recombinant adenovirus attenuates inflammatory and neuropathic pain in rats. Mol Pain 4(65):4

    Google Scholar 

  • Marcus DA (1995) Interrelationships of neurochemicals, estrogen, and recurring headache. Pain 62(2):129–139

    Article  CAS  PubMed  Google Scholar 

  • Naseri K, Saghaei E, Abbaszadeh F, Afhami M, Haeri A, Rahimi F, Jorjani M (2013) Role of microglia and astrocyte in central pain syndrome following electrolytic lesion at the spinothalamic tract in rats. J Mol Neurosci 49(3):470–479

    Article  CAS  PubMed  Google Scholar 

  • Nie H, Weng H-R (2010) Impaired glial glutamate uptake induces extrasynaptic glutamate spillover in the spinal sensory synapses of neuropathic rats. J Neurophysiol 103(5):2570–2580

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ogata T, Nakamura Y, Tsuji K, Shibata T, Kataoka K (1993) Steroid hormones protect spinal cord neurons from glutamate toxicity. Neuroscience 55(2):445–449

    Article  CAS  PubMed  Google Scholar 

  • Olsen ML, Campbell SC, McFerrin MB, Floyd CL, Sontheimer H (2010) Spinal cord injury causes a wide-spread, persistent loss of Kir4. 1 and glutamate transporter 1: benefit of 17β-oestradiol treatment. Brain 133(4):1013–1025

    Article  PubMed Central  PubMed  Google Scholar 

  • Pawlak J, Brito V, Küppers E, Beyer C (2005) Regulation of glutamate transporter GLAST and GLT-1 expression in astrocytes by estrogen. Mol Brain Res 138(1):1–7

    Article  CAS  PubMed  Google Scholar 

  • Paxinos G, Watson C (2006) The rat brain in stereotaxic coordinates: hard cover edition. Access Online via Elsevier

  • Petkova-Kirova P, Rakovska A, Della Corte L, Zaekova G, Radomirov R, Mayer A (2008) Neurotensin modulation of acetylcholine, GABA, and aspartate release from rat prefrontal cortex studied in vivo with microdialysis. Brain Res Bull 77(2):129–135

    Article  CAS  PubMed  Google Scholar 

  • Piu F, Cheevers C, Hyldtoft L, Gardell LR, Del Tredici AL, Andersen CB, Fairbairn LC, Lund BW, Gustafsson M, Schiffer HH (2008) Broad modulation of neuropathic pain states by a selective estrogen receptor beta agonist. Eur J Pharmacol 590(1):423–429

    Article  CAS  PubMed  Google Scholar 

  • Platania P, Seminara G, Aronica E, Troost D, Vincenza Catania M, Angela Sortino M (2005) 17β-estradiol rescues spinal motoneurons from AMPA-induced toxicity: a role for glial cells. Neurobiol Dis 20(2):461–470

    Article  CAS  PubMed  Google Scholar 

  • Ren K (1999) An improved method for assessing mechanical allodynia in the rat. Physiol Behav 67(5):711–716

    Article  CAS  PubMed  Google Scholar 

  • Ritz M-F, Hausmann ON (2008) Effect of 17β-estradiol on functional outcome, release of cytokines, astrocyte reactivity and inflammatory spreading after spinal cord injury in male rats. Brain Res 1203:177–188

    CAS  PubMed  Google Scholar 

  • Ro L, Chang K (2005) Neuropathic pain: mechanisms and treatments. Chang Gung Med J 28(9):597

    PubMed  Google Scholar 

  • Rowan MP, Berg KA, Milam SB, Jeske NA, Roberts JL, Hargreaves KM, Clarke WP (2010) 17β-Estradiol rapidly enhances bradykinin signaling in primary sensory neurons in vitro and in vivo. J Pharmacol Exp Ther 335(1):190–196

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Saghaei E, Abbaszadeh F, Naseri K, Ghorbanpoor S, Afhami M, Haeri A, Rahimi F, Jorjani M (2013) Estradiol attenuates spinal cord injury-induced pain by suppressing microglial activation in thalamic VPL nuclei of rats. Neurosci Res 75(4):316–323

    Article  CAS  PubMed  Google Scholar 

  • Samantaray S, Smith JA, Das A, Matzelle DD, Varma AK, Ray SK, Banik NL (2011) Low dose estrogen prevents neuronal degeneration and microglial reactivity in an acute model of spinal cord injury: effect of dosing, route of administration, and therapy delay. Neurochem Res 36(10):1809–1816

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Sarajari S, Oblinger MM (2010) Estrogen effects on pain sensitivity and neuropeptide expression in rat sensory neurons. Exp Neurol 224(1):163–169

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Schmidt AP, Tort AB, Silveira PP, Böhmer AE, Hansel G, Knorr L, Schallenberger C, Dalmaz C, Elisabetsky E, Crestana RH (2009) The NMDA antagonist MK-801 induces hyperalgesia and increases CSF excitatory amino acids in rats: reversal by guanosine. Pharmacol Biochem Behav 91(4):549–553

    Article  CAS  PubMed  Google Scholar 

  • Siddall P (2008) Management of neuropathic pain following spinal cord injury: now and in the future. Spinal Cord 47(5):352–359

    Article  PubMed  Google Scholar 

  • Silva E, Quiñones B, Freund N, Gonzalez LE, Hernandez L (2001) Extracellular glutamate, aspartate and arginine increase in the ventral posterolateral thalamic nucleus during nociceptive stimulation. Brain Res 923(1):45–49

    CAS  PubMed  Google Scholar 

  • Smith YR, Stohler CS, Nichols TE, Bueller JA, Koeppe RA, Zubieta J-K (2006) Pronociceptive and antinociceptive effects of estradiol through endogenous opioid neurotransmission in women. J Neurosci 26(21):5777–5785

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Sribnick EA, Wingrave JM, Matzelle DD, Ray SK, Banik NL (2003) Estrogen as a neuroprotective agent in the treatment of spinal cord injury. Ann N Y Acad Sci 993(1):125–133

    Article  CAS  PubMed  Google Scholar 

  • Sribnick EA, Wingrave JM, Matzelle DD, Wilford GG, Ray SK, Banik NL (2005) Estrogen attenuated markers of inflammation and decreased lesion volume in acute spinal cord injury in rats. J Neurosci Res 82(2):283–293

    Article  CAS  PubMed  Google Scholar 

  • Tao Y-X, Gu J, Stephens RL Jr (2005) Role of spinal cord glutamate transporter during normal sensory transmission and pathological pain states. Mol Pain 1:30

    Article  PubMed Central  PubMed  Google Scholar 

  • Teichberg V, Cohen-Kashi-Malina K, Cooper I, Zlotnik A (2009) Homeostasis of glutamate in brain fluids: an accelerated brain-to-blood efflux of excess glutamate is produced by blood glutamate scavenging and offers protection from neuropathologies. Neuroscience 158(1):301–308

    Article  CAS  PubMed  Google Scholar 

  • Wang G, Thompson SM (2008) Maladaptive homeostatic plasticity in a rodent model of central pain syndrome: thalamic hyperexcitability after spinothalamic tract lesions. J Neurosci 28(46):11959–11969

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Weaver CE, Land MB, Purdy RH, Richards KG, Gibbs TT, Farb DH (2000) Geometry and charge determine pharmacological effects of steroids on N-methyl-D-aspartate receptor-induced Ca2+ accumulation and cell death. J Pharmacol Exp Ther 293(3):747–754

    CAS  PubMed  Google Scholar 

  • Weiss HR, Doshi D, Sinha AK, Liu X, Chi OZ (2002) 17Beta-estradiol blocks NMDA-induced increases in regional cerebral O2 consumption. Brain Res 951(2):177–182

    CAS  PubMed  Google Scholar 

  • Werhagen L, Budh C, Hultling C, Molander C (2004) Neuropathic pain after traumatic spinal cord injury–relations to gender, spinal level, completeness, and age at the time of injury. Spinal Cord 42(12):665–673

    Article  CAS  PubMed  Google Scholar 

  • Yezierski RP (2009) Spinal cord injury pain: spinal and supraspinal mechanisms. J Rehabil Res Dev 46(1):95–108

    Article  PubMed  Google Scholar 

  • Zhu Y-S, Cai L-Q, You X, Duan Y, Imperato-McGinley J, Chin WW, Pfaff DW (2001) Molecular analysis of estrogen induction of preproenkephalin gene expression and its modulation by thyroid hormones. Mol Brain Res 91(1):23–33

    Article  CAS  PubMed  Google Scholar 

  • Zlotnik A, Gruenbaum BF, Mohar B, Kuts R, Gruenbaum SE, Ohayon S, Boyko M, Klin Y, Sheiner E, Shaked G (2011) The effects of estrogen and progesterone on blood glutamate levels: evidence from changes of blood glutamate levels during the menstrual cycle in women. Biol Reprod 84(3):581–586

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We are grateful to Dr. Hedayat Sahraei and Dr. Asghar Ghasemi for the critical reading of the manuscript and Hamid Reza Falahatpishe for excellent technical assistance. This project was a part of Ph.D. dissertation supported by the Neuroscience Research Center of Baqiyatallah University of Medical Sciences & Neurobiology Research Center of Shahid Beheshti University of Medical Sciences.

Conflict of interest

The authors declare that there are no conflicts of interest, financial or otherwise in the publication of this manuscript.

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Authors and Affiliations

  1. Department of Physiology & Biophysics, Faculty of Medicine, Baqiyatallah University of Medical Sciences, Tehran, Iran

    Asieh Naderi

  2. Aerospace and Subaquatic Medicine Faculty, AJA Medical Sciences University & Exercise Physiology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran

    Ali Reza Asgari

  3. Department of Emergency Medicine, Imam Khomeini Hospital Complex, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran

    Reza Zahed

  4. Applied Neuroscience Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran

    Ali Ghanbari

  5. Neurobiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Razieh Samandari

  6. Neurobiology Research Center & Department of Pharmacology, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, P.O. Box: 19615-1179, Tehran, Iran

    Masoumeh Jorjani

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  1. Asieh Naderi
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Naderi, A., Asgari, A.R., Zahed, R. et al. Estradiol attenuates spinal cord injury-related central pain by decreasing glutamate levels in thalamic VPL nucleus in male rats. Metab Brain Dis 29, 763–770 (2014). https://doi.org/10.1007/s11011-014-9570-z

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  • DOI: https://doi.org/10.1007/s11011-014-9570-z

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