{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T11:11:47Z","timestamp":1790421107690,"version":"4.1.0"},"reference-count":59,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2016,1,8]],"date-time":"2016-01-08T00:00:00Z","timestamp":1452211200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2016,1,8]],"date-time":"2016-01-08T00:00:00Z","timestamp":1452211200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Sex differences play a role in pain sensitivity, efficacy of analgesic drugs and prevalence of neuropathic pain, even if the underlying mechanisms are far from being understood. We demonstrate that male and female mice react differently to structural and functional changes induced by sciatic nerve ligature, used as model of neuropathic pain. Male mice show a gradual decrease of allodynia and a complete recovery while, in females, allodynia and gliosis are still present four months after neuropathy induction. Administration of 17\u03b2-estradiol is able to significantly attenuate this difference, reducing allodynia and inducing a complete recovery also in female mice. Parallel to pain attenuation, 17\u03b2-estradiol treated-mice show a functional improvement of the injured limb, a faster regenerative process of the peripheral nerve and a decreased neuropathy-induced gliosis. These results indicate beneficial effects of 17\u03b2-estradiol on neuropathic pain and neuronal regeneration and focuses on the importance of considering gonadal hormones also in clinical studies.<\/jats:p>","DOI":"10.1038\/srep18980","type":"journal-article","created":{"date-parts":[[2016,1,8]],"date-time":"2016-01-08T11:29:53Z","timestamp":1452252593000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":72,"title":["17beta-estradiol counteracts neuropathic pain: a behavioural, immunohistochemical and proteomic investigation on sex-related differences in mice"],"prefix":"10.1038","volume":"6","author":[{"given":"Valentina","family":"Vacca","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Marinelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luisa","family":"Pieroni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Urbani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siro","family":"Luvisetto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Flaminia","family":"Pavone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,1,8]]},"reference":[{"key":"BFsrep18980_CR1","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1017\/S0140525X97221485","volume":"20","author":"K Berkley","year":"1997","unstructured":"Berkley, K. Sex differences in pain. Behav. Brain Sci. 20, 371\u2013380 (1997).","journal-title":"Behav. Brain Sci."},{"key":"BFsrep18980_CR2","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1016\/j.pain.2011.11.025","volume":"153","author":"M Racine","year":"2012","unstructured":"Racine, M. et al. A systematic literature review of 10 years of research on sex\/gender and experimental pain perception -part 1: are there really differences between women and men? Pain 153, 602\u2013611 (2012a).","journal-title":"Pain"},{"key":"BFsrep18980_CR3","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1016\/j.pain.2011.11.026","volume":"153","author":"M Racine","year":"2012","unstructured":"Racine, M. et al. A systematic literature review of 10 years of research on sex\/gender and pain perception -part 2: do biopsychosocial factors alter pain sensitivity differently in women and men? Pain 153, 619\u2013635 (2012b).","journal-title":"Pain"},{"key":"BFsrep18980_CR4","doi-asserted-by":"crossref","first-page":"S3","DOI":"10.1016\/j.pain.2007.09.028","volume":"132","author":"R Craft","year":"2007","unstructured":"Craft, R. Modulation of pain by estrogens. Pain 132, S3\u2013S12 (2007).","journal-title":"Pain"},{"key":"BFsrep18980_CR5","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/0304-3959(95)00052-T","volume":"62","author":"D Marcus","year":"1995","unstructured":"Marcus, D. Interrelationships of neurochemicals, estrogen and recurring headache. Pain 62, 129\u2013139 (1995).","journal-title":"Pain"},{"key":"BFsrep18980_CR6","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1210\/er.2007-0001","volume":"28","author":"RH Straub","year":"2007","unstructured":"Straub, R. H. The complex role of estrogens in inflammation. Endocr. Rev. 28, 521\u2013574 (2007).","journal-title":"Endocr. Rev."},{"key":"BFsrep18980_CR7","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/S0304-3959(99)00109-8","volume":"83","author":"A Amandusson","year":"1999","unstructured":"Amandusson, A., Hallbeck, M., Hallbeck, A. L., Hermanson, O. & Blomqvist A. Estrogen induced alterations of spinal cord enkephalin gene expression. Pain 83, 243\u2013248 (1999).","journal-title":"Pain"},{"key":"BFsrep18980_CR8","doi-asserted-by":"crossref","first-page":"7225","DOI":"10.1523\/JNEUROSCI.1638-04.2004","volume":"24","author":"HC Evrard","year":"2004","unstructured":"Evrard, H. C. & Balthazart, J. Rapid regulation of pain by estrogens synthesized in spinal dorsal horn neurons. J. Neurosci. 24, 7225\u20137229 (2004).","journal-title":"J. Neurosci."},{"key":"BFsrep18980_CR9","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1111\/j.1460-9568.2006.04913.x","volume":"24","author":"TB Hucho","year":"2006","unstructured":"Hucho, T. B., Dina, O. A., Kuhn, J. & Levine, J. D. Estrogen controls PKCepsilondependent mechanical hyperalgesia through direct action on nociceptive neurons. Eur. J. Neurosci. 24, 527\u2013534 (2006).","journal-title":"Eur. J. Neurosci."},{"key":"BFsrep18980_CR10","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/S0304-3959(99)00278-X","volume":"85","author":"NJ Liu","year":"2000","unstructured":"Liu, N. J. & Gintzler, A. R. Prolonged ovarian sex steroid treatment of male rats produces antinociception: identification of sex-based divergent analgesic mechanisms. Pain 85, 273\u2013281 (2000).","journal-title":"Pain"},{"key":"BFsrep18980_CR11","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1213\/00000539-200202000-00037","volume":"94","author":"Y Shir","year":"2002","unstructured":"Shir, Y., Campbell, J. N., Raja, S. N. & Seltzer, Z. The correlation between dietary soy phytoestrogens and neuropathic pain behavior in rats after partial denervation. Anesth. Analg. 94, 421\u2013426 (2002).","journal-title":"Anesth. Analg"},{"key":"BFsrep18980_CR12","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1159\/000028314","volume":"59","author":"CM Tsao","year":"1999","unstructured":"Tsao, C. M., Ho, C. M., Tsai, S. K. & Lee, T. Y. Effects of estrogen on autotomy in normal and ovariectomized rats. Pharmacology 59, 142\u2013148 (1999).","journal-title":"Pharmacology"},{"key":"BFsrep18980_CR13","first-page":"369","volume":"17","author":"NJ Olsen","year":"1996","unstructured":"Olsen, N. J. & Kovacs, W. J. Gonadal steroids and immunity. Endocr. Rev. 17, 369\u2013384 (1996).","journal-title":"Endocr. Rev."},{"key":"BFsrep18980_CR14","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1002\/glia.20644","volume":"56","author":"A Sierra","year":"2008","unstructured":"Sierra, A., Gottfried-Blackmore, A. C., Milner, T., McEwen, B. S. & Bulloch, K. Steroid hormone receptor expression and function in microglia. Glia 56, 659\u2013674 (2008).","journal-title":"Glia"},{"key":"BFsrep18980_CR15","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1016\/j.neuint.2010.02.013","volume":"57","author":"AS Ben","year":"2010","unstructured":"Ben, A. S. & Pascual, O. Glia: the many ways to modulate synaptic plasticity. Neurochem. Int. 57, 440\u2013455 (2010).","journal-title":"Neurochem. Int."},{"key":"BFsrep18980_CR16","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1016\/S0149-7634(00)00017-8","volume":"24","author":"R Fillingim","year":"2000","unstructured":"Fillingim, R. & Ness, T. Sex-related hormonal influences on pain and analgesic responses. Neurosci. Biobehav. Rev. 24, 485\u2013501 (2000).","journal-title":"Neurosci. Biobehav. Rev."},{"key":"BFsrep18980_CR17","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1016\/j.yfrne.2012.09.004","volume":"33","author":"AR Gintzler","year":"2012","unstructured":"Gintzler, A. R. & Liu, N. J. Importance of sex to pain and its amelioration; relevance of spinal estrogens and its membrane receptors. Front. Neuroendocrinol. 33, 412\u2013424 (2012).","journal-title":"Front. Neuroendocrinol."},{"key":"BFsrep18980_CR18","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.mce.2006.12.010","volume":"266","author":"ER Prossnitz","year":"2007","unstructured":"Prossnitz, E. R., Arterburn, J. B. & Sklar, L. A. GPR30: a G protein-coupled receptor for estrogen. Mol. Cell Endocrinol. 266, 138\u2013142 (2007).","journal-title":"Mol. Cell Endocrinol."},{"key":"BFsrep18980_CR19","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/j.molmed.2012.12.007","volume":"19","author":"J Cui","year":"2013","unstructured":"Cui, J., Shen, Y. & Li, R. Estrogen synthesis and signaling pathways during ageing: from periphery to brain. Trends Mol. Med. 19, 197\u2013209 (2013).","journal-title":"Trends Mol. Med"},{"key":"BFsrep18980_CR20","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1016\/S0306-4522(97)00076-6","volume":"79","author":"RE Papka","year":"1997","unstructured":"Papka, R. E., Srinivasan, B., Miller, K. E. & Hayashi, S. Localization of estrogen receptor protein and estrogen receptor messenger RNA in peripheral autonomic and sensory neurons. Neuroscience 79, 1153\u20131163 (1997).","journal-title":"Neuroscience"},{"key":"BFsrep18980_CR21","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1002\/(SICI)1097-4547(19990901)57:5<603::AID-JNR3>3.0.CO;2-R","volume":"57","author":"N Taleghany","year":"1999","unstructured":"Taleghany, N., Sarajari, S., DonCarlos, L. L., Gollapudi, L. & Oblinger, M. M. Differential expression of estrogen receptor alpha and beta in rat dorsal root ganglion neurons. J. Neurosci. Res. 57, 603\u2013615 (1999).","journal-title":"J. Neurosci. Res."},{"key":"BFsrep18980_CR22","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1016\/j.pain.2013.10.027","volume":"155","author":"V Vacca","year":"2014","unstructured":"Vacca, V. et al. Higher pain perception and lack of recovery from neuropathic pain in females: a behavioural, immunohistochemical and proteomic investigation on sex-related differences in mice. Pain 155, 388\u2013402 (2014).","journal-title":"Pain"},{"key":"BFsrep18980_CR23","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/S0301-0082(00)00025-3","volume":"63","author":"LM Garcia-Segura","year":"2001","unstructured":"Garcia-Segura, L. M., Azcoitia, I. & DonCarlos, L. L. Neuroprotection by estradiol. Prog. Neurobiol. 63, 29\u201360 (2001).","journal-title":"Prog. Neurobiol"},{"key":"BFsrep18980_CR24","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.mce.2008.04.008","volume":"290","author":"M Morissette","year":"2008","unstructured":"Morissette, M., Sweidi, S., Callier, S. & Di Paolo, T. Estrogen and SERM neuroprotection in animal models of Parkinson\u2019s disease. Mol. Cell Endocrinol. 290, 60\u201369 (2008).","journal-title":"Mol. Cell Endocrinol."},{"key":"BFsrep18980_CR25","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1016\/j.yfrne.2008.04.001","volume":"29","author":"E Vegeto","year":"2008","unstructured":"Vegeto, E., Benedusi, V. & Maggi, A. Estrogen anti-inflammatory activity in brain: a therapeutic opportunity for menopause and neurodegenerative disease. Front. Neuroendocrinol. 29, 507\u2013519 (2008).","journal-title":"Front. Neuroendocrinol."},{"key":"BFsrep18980_CR26","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1146\/annurev.ne.13.030190.000355","volume":"13","author":"JW Fawcett","year":"1990","unstructured":"Fawcett, J. W. & Keynes, R. J. Peripheral nerve regeneration. Annu. Rev. Neurosci. 13, 43\u201360 (1990).","journal-title":"Annu. Rev. Neurosci."},{"key":"BFsrep18980_CR27","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1227\/01.NEU.0000358537.30354.63","volume":"65","author":"OA Sulaiman","year":"2009","unstructured":"Sulaiman, O. A. & Gordon, T. Role of chronic Schwann cell denervation in poor functional recovery after nerve injuries and experimental strategies to combat it. Neurosurgery 65, 105\u2013114 (2009).","journal-title":"Neurosurgery"},{"key":"BFsrep18980_CR28","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1139\/o80-125","volume":"58","author":"A Isaque","year":"1980","unstructured":"Isaque, A., Roomi, M. W., Szymanska, I., Kowalski, S. & Eylar, E. H. The P0 glycoprotein of peripheral nerve myelin. Can. J. Biochem. 58, 913\u2013921 (1980).","journal-title":"Can. J. Biochem."},{"key":"BFsrep18980_CR29","first-page":"483","volume":"186","author":"GJ Snipes","year":"1995","unstructured":"Snipes, G. J. & Suter, U. Molecular anatomy and genetics of myelin proteins in the peripheral nervous system. J. Anat. 186, 483\u2013494 (1995).","journal-title":"J. Anat."},{"key":"BFsrep18980_CR30","doi-asserted-by":"crossref","first-page":"190","DOI":"10.2337\/diab.44.2.190","volume":"44","author":"JH Thurston","year":"1995","unstructured":"Thurston, J. H., McDougal, D. B. Jr., Hauhart, R. E. & Schulz, D. W. Effects of acute, subacute and chronic diabetes on carbohydrate and energy metabolism in rat sciatic nerve. Relation to mechanisms of peripheral neuropathy. Diabetes 44, 190\u2013195 (1995).","journal-title":"Diabetes"},{"key":"BFsrep18980_CR31","doi-asserted-by":"crossref","first-page":"4632","DOI":"10.1016\/j.jprot.2012.05.029","volume":"75","author":"V Marzano","year":"2012","unstructured":"Marzano, V. et al. Proteomic profiling of ATM kinase proficient and deficient cell lines upon blockage of proteasome activity. J. Proteomics 75, 4632\u20134646 (2012).","journal-title":"J. Proteomics"},{"key":"BFsrep18980_CR32","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1039\/C0MB00135J","volume":"7","author":"L Pieroni","year":"2011","unstructured":"Pieroni, L. et al. Proteomics investigation of human platelets in healthy donors and cystic fibrosis patients by shotgun nUPLC-MSE and 2DE: a comparative study. Mol. Biosyst. 7, 630\u2013639 (2011).","journal-title":"Mol. Biosyst."},{"key":"BFsrep18980_CR33","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/0304-3940(95)11828-K","volume":"196","author":"A Amandusson","year":"1995","unstructured":"Amandusson, A., Hermanson, O. & Blomqvist A. Estrogen receptor-like immunoreactivity in the medullary and spinal dorsal horn of the female rat. Neurosci. Lett. 196, 25\u201328 (1995).","journal-title":"Neurosci. Lett."},{"key":"BFsrep18980_CR34","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1056\/NEJMra000471","volume":"346","author":"CJ Gruber","year":"2002","unstructured":"Gruber, C. J., Tschugguel, W., Schneeberger, C. & Huber, J. C. Production and Actions of Estrogens. N. Engl. J. Med. 346, 340\u2013352 (2002).","journal-title":"N. Engl. J. Med."},{"key":"BFsrep18980_CR35","doi-asserted-by":"crossref","first-page":"7722","DOI":"10.1523\/JNEUROSCI.20-20-07722.2000","volume":"20","author":"HB Bradshaw","year":"2000","unstructured":"Bradshaw, H. B. & Berkley, K. J. Estrous changes in responses of rat gracile nucleus neurons to stimulation of skin and pelvic viscera. J. Neurosci. 20, 7722\u20137727 (2000).","journal-title":"J. Neurosci."},{"key":"BFsrep18980_CR36","doi-asserted-by":"crossref","first-page":"8710","DOI":"10.1523\/JNEUROSCI.6323-09.2010","volume":"30","author":"YW Wu","year":"2010","unstructured":"Wu, Y. W. et al. 17-Beta-estradiol enhanced allodynia of inflammatory temporomandibular joint through upregulation of hippocampal TRPV1 in ovariectomized rats. J. Neurosci. 30, 8710\u20138719 (2010).","journal-title":"J. Neurosci."},{"key":"BFsrep18980_CR37","doi-asserted-by":"crossref","first-page":"1389","DOI":"10.1002\/j.1532-2149.2012.00139.x","volume":"16","author":"G Draisci","year":"2012","unstructured":"Draisci, G. et al. Pregnancy-induced analgesia: a combined psychophysical and neurophysiological study. Eur. J. Pain 16, 1389\u20131397 (2012).","journal-title":"Eur. J. Pain"},{"key":"BFsrep18980_CR38","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1016\/j.ejpain.2007.09.003","volume":"12","author":"R Sanoja","year":"2008","unstructured":"Sanoja, R. & Cervero, F. Estrogen modulation of ovariectomy-induced hyperalgesia in adult mice. Eur. J. Pain 12, 573\u2013581 (2008).","journal-title":"Eur. J. Pain"},{"key":"BFsrep18980_CR39","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.neulet.2004.11.006","volume":"375","author":"X Zhao","year":"2005","unstructured":"Zhao, X. et al. Ovariotomy and persistent pain affect long term Fos expression in spinal cord. Neurosci. Lett. 375, 165\u2013169 (2005).","journal-title":"Neurosci. Lett."},{"key":"BFsrep18980_CR40","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.brainres.2006.05.089","volume":"1106","author":"I Ceccarelli","year":"2006","unstructured":"Ceccarelli, I., Fiorenzani, P., Massafra, C. & Aloisi, A. M. Repeated nociceptive stimulation induces different behavioral and neuronal responses in intact and gonadectomized female rats. Brain Res. 1106, 142\u2013149 (2006).","journal-title":"Brain Res."},{"key":"BFsrep18980_CR41","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1016\/j.bbagen.2009.10.002","volume":"1800","author":"MA Arevalo","year":"2010","unstructured":"Arevalo, M. A., Santos-Galindo, M., Bellini, M. J., Azcoitia, I. & Garcia-Segura, L. M. Actions of estrogens on glial cells: Implications for neuroprotection. Biochimica et Biophysica Acta 1800, 1106\u20131112 (2010).","journal-title":"Biochimica et Biophysica Acta"},{"key":"BFsrep18980_CR42","doi-asserted-by":"crossref","first-page":"1440","DOI":"10.1016\/j.jprot.2011.11.014","volume":"75","author":"A D\u2019Alessandro","year":"2012","unstructured":"D\u2019Alessandro, A. et al. Protein repertoire impact of Ubiquitin-Proteasome System impairment: Insight into the protective role of beta \u2013 estradiol. Journal of Proteomics 75, 1440\u20131453 (2012).","journal-title":"Journal of Proteomics"},{"key":"BFsrep18980_CR43","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.pain.2013.09.013","volume":"155","author":"S Marinelli","year":"2014","unstructured":"Marinelli, S. et al. Schwann cell autophagy counteracts the onset and chronification of neuropathic pain. Pain 155, 93\u2013107 (2014).","journal-title":"Pain"},{"key":"BFsrep18980_CR44","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1111\/j.1756-185X.2011.01598.x","volume":"14","author":"X Chang","year":"2011","unstructured":"Chang, X. & Wei, C. Glycolysis and rheumatoid arthritis. International Journal of Rheumatic Diseases 14, 217\u2013222 (2011).","journal-title":"International Journal of Rheumatic Diseases"},{"key":"BFsrep18980_CR45","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/0304-3940(94)11154-B","volume":"184","author":"AL Clatworthy","year":"1995","unstructured":"Clatworthy, A. L., Illich, P. A., Castro, G. A. & Walters, E. T. Role of peri-axonal inflammation in the development of thermal hyperalgesia and guarding behavior in a rat model of neuropathic pain. Neurosci. Lett. 184, 5\u20138 (1995).","journal-title":"Neurosci. Lett."},{"key":"BFsrep18980_CR46","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/0304-3959(93)90100-4","volume":"54","author":"TJ Maves","year":"1993","unstructured":"Maves, T. J., Pechman, P. S., Gebhart, G. F. & Meller, S. T. Possible chemical contribution from chromic gut sutures produces disorders of pain sensation like those seen in man. Pain 54, 57\u201369 (1993).","journal-title":"Pain"},{"key":"BFsrep18980_CR47","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1016\/j.neuroscience.2005.10.019","volume":"138","author":"AJ Mhyre","year":"2006","unstructured":"Mhyre, A. J. & Dorsa, D. M. Estrogen activates rapid signaling in the brain: role of estrogen receptor alpha and estrogen receptor beta in neurons and glia. Neuroscience 138, 851\u2013858 (2006).","journal-title":"Neuroscience"},{"key":"BFsrep18980_CR48","doi-asserted-by":"crossref","first-page":"S21","DOI":"10.1016\/j.metabol.2010.07.011","volume":"59","author":"JP O\u2019Callaghan","year":"2010","unstructured":"O\u2019Callaghan, J. P. & Miller, D. B. Spinal glia and chronic pain. Metabolism 59, S21\u2013S26 (2010).","journal-title":"Metabolism"},{"key":"BFsrep18980_CR49","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/0165-0173(92)90007-9","volume":"17","author":"WE Thomas","year":"1992","unstructured":"Thomas, W. E. Brain macrophages: evaluation of microglia and their functions. Brain Res. Rev. 17, 61\u201374 (1992).","journal-title":"Brain Res. Rev."},{"key":"BFsrep18980_CR50","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.pain.2006.02.034","volume":"122","author":"JA De Leo","year":"2006","unstructured":"De Leo, J. A., Tawfik, V. L. & LaCroix-Fralish, M. L. The tetrapartite synapse: path to CNS sensitization and chronic pain. Pain 122, 17\u201321 (2006).","journal-title":"Pain"},{"key":"BFsrep18980_CR51","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1046\/j.1471-4159.2000.0750965.x","volume":"75","author":"I Hide","year":"2000","unstructured":"Hide, I. et al. Extracellular ATP triggers tumor necrosis factor alpha release from rat microglia. J. Neurochem. 75, 965\u2013972 (2000).","journal-title":"J. Neurochem."},{"key":"BFsrep18980_CR52","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1093\/oxfordjournals.jbchem.a002969","volume":"130","author":"K Nakajima","year":"2001","unstructured":"Nakajima, K. & Kohsaka, S. Microglia: activation and their significance in the central nervous system. J. Biochem. 130, 169\u2013175 (2001).","journal-title":"J. Biochem"},{"key":"BFsrep18980_CR53","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/S0079-6123(09)17515-5","volume":"175","author":"I Sayeed","year":"2009","unstructured":"Sayeed, I. & Stein, D. G. Progesterone as a neuroprotective factor in traumatic and ischemic brain injury. Prog. Brain Res. 175, 219\u2013237 (2009).","journal-title":"Prog. Brain Res."},{"key":"BFsrep18980_CR54","doi-asserted-by":"crossref","first-page":"2263","DOI":"10.1210\/en.2005-1330","volume":"147","author":"E Vegeto","year":"2006","unstructured":"Vegeto, E. et al. The endogenous estrogen status regulates microglia reactivity in animal models of neuroinflammation. Endocrinology 147, 2263\u20132272 (2006).","journal-title":"Endocrinology"},{"key":"BFsrep18980_CR55","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/0304-3959(83)90201-4","volume":"16","author":"M Zimmermann","year":"1983","unstructured":"Zimmermann, M. Ethical guidelines for investigations of experimental pain in conscious animals. Pain 16, 109\u2013110 (1983).","journal-title":"Pain"},{"key":"BFsrep18980_CR56","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/0304-3959(88)90209-6","volume":"33","author":"GJ Bennett","year":"1988","unstructured":"Bennett, G. J. & Xie, Y. K. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 33, 87\u2013107 (1988).","journal-title":"Pain"},{"key":"BFsrep18980_CR57","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1016\/j.ejpain.2009.10.016","volume":"14","author":"AM Aloisi","year":"2010","unstructured":"Aloisi, A. M. et al. Estradiol and testosterone differently affect visceral pain related behavioural responses in male and female rats. Eur. J. Pain 14, 602\u2013607 (2010).","journal-title":"Eur. J. Pain"},{"key":"BFsrep18980_CR58","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1124\/jpet.111.191403","volume":"342","author":"A Caprioli","year":"2012","unstructured":"Caprioli, A. et al. The novel reversible fatty acid amide hydrolase inhibitor ST4070 increases endocannabinoid brain levels and counteracts neuropathic pain in different animal models. J. Pharmacol. Exp. Ther. 342, 188\u201395 (2012).","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"BFsrep18980_CR59","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/j.jim.2005.05.005","volume":"302","author":"CF Inman","year":"2005","unstructured":"Inman, C. F. et al. Validation of computer-assisted, pixel-based analysis of multiple-colour immunofluorescence histology. J. Immunol. Methods 302, 156\u2013167 (2005).","journal-title":"J. Immunol. Methods"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep18980","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep18980.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep18980.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,4]],"date-time":"2023-01-04T23:33:07Z","timestamp":1672875187000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep18980"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,1,8]]},"references-count":59,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2016,5,10]]}},"alternative-id":["BFsrep18980"],"URL":"https:\/\/doi.org\/10.1038\/srep18980","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,1,8]]},"assertion":[{"value":"8 February 2015","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 September 2015","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 January 2016","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"18980"}}