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Estrogen receptor-α expression in nociceptive-responsive neurons in the medullary dorsal horn of the female rat
Division of Cell Biology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University. (Neurofysiologi)
2010 (English)In: European Journal of Pain, ISSN 1090-3801, E-ISSN 1532-2149, Vol. 14, no 3, 245-248 p.Article in journal (Refereed) Published
Abstract [en]

Estrogens exert a substantial influence on the transmission of nociceptive stimuli and the susceptibility to pain disorders as made evident by studies in both animals and human subjects. The estrogen receptor (ER) seems to be of crucial importance to the cellular mechanisms underlying such an influence. However, it has not been clarified whether nociceptive neurons activated by pain express ERs. In this study, a noxious injection of formalin was given into the lower lip of female rats, thereby activating nociceptive neurons in the trigeminal subnucleus caudalis as demonstrated by immunohistochemical labeling of Fos. Using a dual-label immunohistochemistry protocol ERalpha-containing cells were visualized in the same sections. In the superficial layers of the medullary dorsal horn, 12% of ERalpha-labeled cells, mainly located in lamina II, also expressed noxious-induced Fos. These findings show that nociceptive-responsive neurons in the medullary dorsal horn express ERalpha, thus providing a possible morphological basis for the hypothesis that estrogens directly regulate pain transmission at this level.

Place, publisher, year, edition, pages
Elsevier , 2010. Vol. 14, no 3, 245-248 p.
Keyword [en]
Estrogen receptor, Spinal trigeminal nucleus, Gonadal hormone, Pain, Fos
National Category
Research subject
Clinical Neurophysiology
URN: urn:nbn:se:uu:diva-120674DOI: 10.1016/j.ejpain.2009.05.008PubMedID: 19525133OAI: oai:DiVA.org:uu-120674DiVA: diva2:303809
Available from: 2010-03-15 Created: 2010-03-15 Last updated: 2014-05-20Bibliographically approved
In thesis
1. Estrogen receptor expression in relation to pain modulation and transmission: experimental studies in rats
Open this publication in new window or tab >>Estrogen receptor expression in relation to pain modulation and transmission: experimental studies in rats
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [sv]

Estrogens have a remarkably wide range of actions in the mammalian brain. They not only play a pivotal role in reproductive behavior and sexual differentiation, but also contribute to e.g. thermoregulation, feeding, memory, neuronal survival and the perception of somatosensory stimuli. A multitude of studies on both animals and human subjects has demonstrated potential effects of gonadal hormones, such as estrogens, on pain transmission. These effects most likely involve multiple neuroanatomical circuits as well as diverse neurochemical systems and therefore need to be evaluated specifically in relation to the localization and intrinsic characteristics of the neurons engaged. The overall aim of this thesis is to gain specific knowledge of the possible cellular mechanisms by which estrogens may influence the transmission of nociceptive stimuli at the level of the spinal cord.

The estrogen receptors, by which estrogens regulate non-genomic as well as genomic mechanisms, are crucial to estrogen signaling in general and essential to the estrogen-induced effects in the brain. In Paper I, we use immunohistochemistry to label neurons containing estrogen receptor-! (ERα) in the medullary and spinal dorsal horn of female rats. Large numbers of ER!-expressing neurons were found in lamina I and lamina II, i.e. in the areas involved in the processing of primary afferent nociceptive information. This distribution in part overlaps that of enkephalin, a potent pain-inhibiting endogenous opioid. The effects of gonadal hormones on pain modulation may, to a great extent, be blocked by the opioid antagonist naloxone, suggesting an involvement of the endogenous opioid system in the prosecution of hormonal pain regulation. By combining immunohistochemical labeling of ERα with in situ hybridization of preproenkephalin mRNA (Paper II), we demonstrate that the majority of enkephalinergic neurons in the superficial laminae of the spinal and medullary dorsal horn express ER!. This co-localization and the fact that the preproenkephalin gene contains a sequence that binds ERs, suggest that estrogens may potentially regulate enkephalin expression in these cells. This is further supported by the findings in Paper III in which we show that a single subcutaneous injection of estradiol induces a significant increase (on average 68%) in preproenkephalin mRNA content in the spinal cord after 4 hours. The expression of the enkephalin gene in the spinal cord is thus sensitive to fluctuating estradiol levels. In Paper IV, a noxious injection of formalin is used to induce activation of a neuronal population involved in nociceptive transmission from the face. By using a dual-labeling immunohistochemistry protocol, we were able to identify ER!-expressing cells within this neuronal population suggesting that nociceptive-responsive neurons in the medullary dorsal horn express ER!. In all, our findings provide morphological as well as biochemical evidence in support for an estrogen-dependent modulation of nociceptive processing at the level of the dorsal horn.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2009. 90 p.
, Linköping University medical dissertation, ISSN 0345-0082 ; 1122
National Category
Cell and Molecular Biology
Research subject
Medical Cell Biology
urn:nbn:se:uu:diva-125111 (URN)978-91-7393-644-6 (ISBN)
Public defence
2009-05-26, Berzeliussalen, Campus US, Linköpings Universitet, Linköping, 13:00 (English)
Available from: 2011-03-04 Created: 2010-05-07 Last updated: 2011-03-04Bibliographically approved

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