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Estrogen Receptor Expression in Relation to Pain Modulation and Transmission: Experimental Studies in Rats
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1122
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-17978ISBN: 978-91-7393-644-6 (print)OAI: oai:DiVA.org:liu-17978DiVA: diva2:213871
Public defence
2009-05-26, Berzeliussalen, Campus US, Linköpings Universitet , Linköping, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2009-04-29 Created: 2009-04-29 Last updated: 2009-04-29Bibliographically approved
List of papers
1. Estrogen receptor-like immunoreactivity in the medullary and spinal dorsal horn of the female rat
Open this publication in new window or tab >>Estrogen receptor-like immunoreactivity in the medullary and spinal dorsal horn of the female rat
1995 (English)In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 196, no 1-2, 25-28 p.Article in journal (Refereed) Published
Abstract [en]

Using an immunohistochemical technique, we demonstrate that large numbers of neurons in the laminar spinal trigeminal nucleus and spinal gray matter of the female rat express estrogen receptors (ER). Densely packed ER-immunoreactive neurons were present in lamina II, but labeled neurons were also present in lamina I, the neck of the dorsal horn, and in lamina X. Labeling was present throughout the length of the spinal cord, with the exception of segments caudal to S1, which were unlabeled. The distribution of ER-containing neurons to areas that are involved in processing of primary afferent nociceptive information suggests that the pain modulatory effects of estrogen may be exerted at the spinal level.

Keyword
Gonadal hormones, Spinal trigeminal nucleus, Spinal cord, Substantia gelatinosa, Pain, Immunohistochemistry
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-17972 (URN)10.1016/0304-3940(95)11828-K (DOI)7501248 (PubMedID)
Available from: 2009-04-29 Created: 2009-04-29 Last updated: 2017-12-13Bibliographically approved
2. Colocalization of oestrogen receptor immunoreactivity and preproenkephalin mRNA expression to neurons in the superficial laminae of the spinal and medullary dorsal horn of rats
Open this publication in new window or tab >>Colocalization of oestrogen receptor immunoreactivity and preproenkephalin mRNA expression to neurons in the superficial laminae of the spinal and medullary dorsal horn of rats
1996 (English)In: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 8, no 11, 2440-2445 p.Article in journal (Refereed) Published
Abstract [en]

A double-labelling procedure combining immunohistochemical staining with in situ hybridization using a radiolabelled cRNA probe was employed to demonstrate oestrogen receptor-like immunoreactivity and preproenkephalin-A mRNA in the medullary and spinal dorsal horn of female rats. Both markers labelled large numbers of neurons in the substantia gelatinosa and its trigeminal homologue. Many of these neurons were double-labelled, displaying both oestrogen receptor-like-immunoreactivity and preproenkephalin-A mRNA; cell counts showed that 40-60% of the of the oestrogen receptor-like-immunoreactive cells in the superficial laminae also were labelled for preproenkephalin-A mRNA, and that 60-70% of the preproenkephalin-A mRNA-labelled neurons in the same laminae displayed oestrogen receptor-like immunoreactivity. Previous studies have shown that oestrogen receptors can bind to the promoter region of the preproenkephalin-A gene, and studies on the hypothalamus have demonstrated that oestrogen regulates enkephalin expression in select neuronal populations. The present results demonstrate that enkephalinergic neurons in the superficial dorsal horn contain oestrogen receptors and suggest that oestrogen may play an important role in the modulation of sensory and nociceptive processing in the lower medulla and spinal cord.

Place, publisher, year, edition, pages
Wiley InterScience, 1996
Keyword
Gonadal hormone enkephalin spinal cord, pain in situ hybridization
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-17973 (URN)10.1111/j.1460-9568.1996.tb01207.x (DOI)8950107 (PubMedID)
Available from: 2009-04-29 Created: 2009-04-29 Last updated: 2017-12-13Bibliographically approved
3. Estrogen-induced alterations of spinal cord enkephalin gene expression
Open this publication in new window or tab >>Estrogen-induced alterations of spinal cord enkephalin gene expression
1999 (English)In: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 83, no 2, 243-248 p.Article in journal (Refereed) Published
Abstract [en]

Enkephalin-synthesizing neurons in the super®cial laminae of the spinal and trigeminal dorsal horn are critical components of the endogenous pain-modulatory system. We have previously demonstrated that these neurons display intracellular estrogen receptors, suggesting that estrogen can potentially influence their enkephalin expression. By using Northern blot, we now show that a bolus injection of estrogen results in a rapid increase in spinal cord enkephalin mRNA levels in ovariectomized female rats. Thus, 4 h after estrogen administration the enkephalin mRNA-expression in the lumbar spinal cord was on average 68% higher (P , 0:05) than in control animals injected with vehicle only. A small increase in the amount of enkephalin mRNA was also seen after 8 h (P , 0:05), whereas no difference between estrogen-injected and control animals was found after 24 h or at time periods shorter than 4 h. Taken together with the previous anatomical data, the present findings imply that estrogen has an acute effect on spinal opioid levels in areas involved in the transmission of nociceptive information.

Place, publisher, year, edition, pages
Elsevier, 1999
Keyword
Preproenkephalin mRNA, Gonadal hormone, Pain, Spinal cord
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-17974 (URN)
Available from: 2009-04-29 Created: 2009-04-29 Last updated: 2017-12-13Bibliographically approved
4. Estrogen receptor-α expression in nociceptive-responsive neurons in the medullary dorsal horn of the female rat
Open this publication in new window or tab >>Estrogen receptor-α expression in nociceptive-responsive neurons in the medullary dorsal horn of the female rat
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 ERα-containing cells were visualized in the same sections. In the superficial layers of the medullary dorsal horn, 12 % of ERα-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 ERα, thus providing a possible morphological basis for the hypothesis that estrogens directly regulate pain transmission at this level.

Keyword
Estrogen receptor, spinal trigeminal nucleus, gonadal hormone, pain, Fos
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-17975 (URN)10.1016/j.ejpain.2009.05.008 (DOI)000275117700003 ()
Note
On the day of the defence date the status of this article was Submitted.Available from: 2009-04-29 Created: 2009-04-29 Last updated: 2017-12-13Bibliographically approved

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