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The role of glia in neuropathic pain: a journey into the tetrapartite synapse.

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Call No.	QP363.2 .T39 2006
Author	Tawfik, Vivianne Lily.
Title	The role of glia in neuropathic pain: a journey into the tetrapartite synapse.
Date	2006
Abstract	Neuropathic pain is a debilitating condition that affects millions of individuals worldwide. Unfortunately, opioids are only partially effective in treating neuropathic pain while entraining tolerance and a myriad of side effects from the high doses required. The ultimate generation of pain results from aberrant neuronal firing. However, the role of glia in the central nervous system (CNS) is intimately integrated with the functions of the other players in the tetrapartite synapse composed of pre- and post-synaptic neurons, the astrocyte and the microglial cell. Each of these cells is crucial to synaptic homeostasis and therefore neuroimmune activation (glial activation and cytokine expression), which can occur following an insult to the peripheral or central nervous systems, can contribute to CNS dysfunction. In Part I of this thesis, we explored the hypothesis that chronic opioid treatment in the presence or absence of neuropathic pain induces central glial activation and selective cytokine expression that leads to analgesic tolerance. We determined that opioid analgesics each demonstrate a unique pattern of neuroimmune activation that may provide a basis for the variation in analgesic tolerance seen clinically and experimentally. In Parts II and III we use in vitro and in vivo methods, respectively, in order to investigate the hypothesis that nerve injury induces activation and dedifferentiation of astrocytes, rendering them incapable of maintaining glutamate homeostasis in the CNS. This would lead to excessive excitatory signaling at neuronal glutamate receptors and eventually to the expression of pain behaviours. In this section, we demonstrate that the glial modulating agent, propentofylline, induces functional GLT-1 expression in cultured astrocytes and enhances GLT-1 in mouse and rat models of neuropathic pain, suggesting a potential mechanism for its anti-allodynic action. In addition, we observed that late-phase activation of microglia plays a key role in the long-term maintenance of neuropathic pain after peripheral nerve injury and that propentofylline is capable of modulating this activation to reverse existing, long-term allodynia. In summary, we demonstrate that glial cells act as orchestrators in the tetrapartite synapse and control of their activation state is crucial to the integrity of CNS function.
Description	xxii, 293 leaves : ill. (some col.) 28 cm.
Format	application/pdf
Advisor	Joyce A. DeLeo
Subject	Neuroglia -- Effect of drugs on. Astrocytes. Opioids -- Physiological effect. Central nervous system -- Pathophysiology. Nerves
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.113

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	The Role of Glia in Neuropathic Pain: A Journey into the Tetrapartite Synapse A Thesis Submitted to the Faculty in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Pharmacology and Toxicology by Vivianne Lily Tawfik DARTMOUTH COLLEGE Hanover, New Hampshire August 14th, 2006. Examining Committee: Joyce A. DeLeo, PhD (Chair) Ethan Dmitrovsky, MD Alan I. Green, MD Brent T. Harris, MD, PhD John Hwa, MBBS, PhD Charles K. Barlowe, Ph.D. Dean of Graduate Studies

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