Estradiol attenuates spinal cord injury-related central pain by decreasing glutamate levels in thalamic VPL nucleus in male rats
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.
KeywordsCentral neuropathic pain Estradiol Glutamate Spinal cord injury VPL nucleus
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.
- 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):483–490PubMedCrossRefGoogle 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)Google Scholar
- 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):316–323Google 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):4Google Scholar
- Paxinos G, Watson C (2006) The rat brain in stereotaxic coordinates: hard cover edition. Access Online via ElsevierGoogle 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):1809–1816PubMedCentralPubMedCrossRefGoogle 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):549–553PubMedCrossRefGoogle 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):301–308PubMedCrossRefGoogle 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):581–586PubMedCrossRefGoogle Scholar