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Hormonal and neurochemical determinants of sex differences in chronic radicular pain.

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Call No.	QP367 .L33 2006
Author	LaCroix-Fralish, Michael Lee.
Title	Hormonal and neurochemical determinants of sex differences in chronic radicular pain.
Date	2006
Abstract	Chronic low back pain is a debilitating and devastating disease affecting millions of people worldwide. Considerable evidence indicates that there are sex-related differences in clinical and experimental pain sensitivity in men and women. Women typically have a lower threshold to a variety of painful stimuli and report a higher incidence of various painful diseases when compared to men. In this thesis, we investigated the role of gonadal steroids and gonadal steroid-regulated signaling molecules as potential mediators of sex differences in pain. We observed that female rats display higher levels of evoked pain behaviors as compared to males following L5 nerve root injury, a model of low back pain associated with radiculopathy. Ovariectomy of female rats prior to nerve root injury abolished the female pain hypersensitivity phenotype. Conversely, using a hormone-replacement paradigm in ovariectomized female rats we demonstrated that progesterone is the gonadal steroid mediator that results in sensitization of female rats. Using a microarray gene expression screen, we identified the female-specific upregulation of neuregulin 1 and the neuregulin 1 receptor, ErbB4, following L5 nerve root injury. We observed that progesterone was required for upregulation of spinal cord neuregulin 1 expression in female rats. Furthermore, intrathecal administration of recombinant neuregulin 1 protein into the lumbar spinal cord produced a significant decrease in the tactile threshold, demonstrating that neuregulin 1 is a pronociceptive sensitizing molecule. Finally, progesterone treatment of cultured primary astrocytes caused an increase in the expression of neuregulin 1 mRNA and protein. This effect of progesterone was not observed in cultured neurons suggesting that progesterone regulation of neuregulin 1 occurs primarily in astrocytes. In conclusion, this thesis research demonstrated that gonadal steroids, progesterone in particular, are absolutely essential for mediating the female pain hypersensitivity phenotype. Increases in spinal neuregulin 1 expression following L5 nerve root injury was dependent on the presence of progesterone and was only observed in female rats. These data demonstrate that progesterone-dependent regulation of spinal neuregulin 1 expression is a novel, sex-specific mechanism involved in mediating sex differences in pain sensitivity.
Description	xviii, 270 leaves : ill. (some col.) 28 cm.
Format	application/pdf
Advisor	Joyce A. DeLeo
Subject	Radiculitis -- Endocrine aspects. Radiculitis -- Sex factors. Radiculitis -- Pathophysiology. Pain -- Sex factors. Progesterone -- Physiological effect. Cellular signal transduction. Neuregulin-1 -- physiology.
College	Dartmouth Medical School -- Department of Pharmacology and Toxicology.
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D.)--Dartmouth College.
Copyright	All rights reserved. No part of this book may be reproduced in any form by any electronic or mechanical means without permission in writing from the author.
DOI	http://dx.doi.org/10.1349/ddlp.134

Title	Page 1
Format	application/pdf
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D.)--Dartmouth College.
Full Text	Hormonal and Neurochemical Determinants of Sex Differences in Chronic Radicular Pain A Thesis Submitted to the Faculty in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Pharmacology and Toxicology by Michael Lee LaCroix-Fralish DARTMOUTH COLLEGE Hanover, New Hampshire October 24th, 2006 ______________________________ Charles K. Barlowe, Ph.D. Dean of Graduate Studies Examining Committee: _______________________________ (chair) Joyce A. DeLeo, Ph.D. _______________________________ Brent T. Harris, M.D., Ph.D. _______________________________ Leslie P. Henderson, Ph.D. _______________________________ Lionel D. Lewis, M.B., B.Ch., M.D. _______________________________ Kathleen A. Martin, Ph.D. _______________________________ James N. Weinstein, D.O., M.S.

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