Due Allete White TLR Book Chapter Fin

Topics: Immune system, Toll-like receptor, Nervous system Pages: 11 (6552 words) Published: December 4, 2014
Comp. by: K.VENKATESAN Stage: Proof Chapter No.: 8 Title Name: Toth-&-Moulin Date:4/6/13 Time:19:27:38 Page Number: 90

Section 2
Chapter

8

The Condition of Neuropathic Pain

Pathophysiology of neuropathic pain:
Signaling pathways and their magnification –
the role of neuronal Toll-like receptors
Michael R. Due, Yohance M. Allete, and Fletcher A. White

Introduction
Neuropathic pain is a tremendous challenge to the
healthcare system. It is thought that 7–8% of the
population in the USA is affected by chronic pain
and in 5% it may be severe. The personal and economic impacts of chronic pain are significant, as approximately half of sufferers are unable to work
full-time and/or participate fully in the activities of
daily life. Although there are a number of current
treatments available for inflammatory pain, pharmaceuticals for chronic neuropathic pain due to nerve injury are quite often inadequate. Furthermore, many
of these compounds (opioids, non-steroidal antiinflammatory drugs (NSAIDs) and non-NSAIDs such as ziconotide) are not ideal as they suffer from tolerability and/or safety issues. The need for new approaches to this problem is clear. Work described

in this chapter investigates the potential role in neuropathic pain of a class of neuronal receptors formerly thought to only reside on immune and glial cells.
Investigations into neuropathic pain mechanisms
often utilize the rationale that the onset of spontaneous activity in neurons following peripheral nerve injury may trigger abnormal pain behavior in rodents
(perhaps better defined in animals as hyperalgesia)
and neuropathic pain in humans [1]. It may then
follow that the neuropathic pain state is dependent
on chronic alterations in the physiology (spontaneous
and/or ectopic discharge) of both nociceptive and
non-nociceptive sensory neurons [2–4]. Many potential mediators and pathways have been examined as potential contributors to chronic neuropathic pain. In
this chapter, we will study an important mediator and
its associated factors, the Toll-like receptor.

The discovery of receptors responsive to pathogenic endotoxins such as lipopolysaccharide or endogenous agonists of Toll-like receptors (TLRs)
was first described in cells of the immune system
and later in glial cells. The original observation of
functional responses by nociceptive sensory neurons
following administration of lipopolysaccharide (LPS)
by Hou and Wang [5] initiated the first step forward
toward a better understanding of the potential events
associated with TLRs that may influence a significant
number of chronic pain conditions.

Toll-like receptors
The Toll-like receptor family of receptors is typically
utilized by the innate immune system to sense the
invasion of microorganisms by their ability to recognize specific patterns of microbial components. Toll-like receptors family members are structurally
known as being type 1 transmembrane receptors
characterized by an amino-terminal extracellular
domain composed of repeated motifs, high in
leucine and known as leucine-rich repeat (LRR)
followed by a single transmembrane domain. The
intracellular portion of the protein is a globular
cytoplasmic domain called the Toll/interleukin 1
receptor (TIR) due in part to the homology of this
domain to the cytoplasmic region of the interleukin
1 receptor (IL-1R) family and that TIR domains
are found in the cytoplasmic portions of all TLRs,
the IL-1 receptor family, and a group of adaptor
proteins [6,7]. Thirteen TLRs have been identified
in mammals so far. Given their diversity, this family
of receptors is shown to be present on a number of
both immune and non-immune cell types, and they

Neuropathic Pain, ed. Cory Toth and Dwight E. Moulin. Published by Cambridge University Press. © Cambridge University Press 2013.

90

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