Neuropathic Pain Research Paper

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
by: K.VENKATESAN Stage: Proof Chapter No.: 8 Title Name: Toth-&-Moulin
Date:4/6/13 Time:19:27:38 Page Number: 91

Chapter 8: Pathophysiology of neuropathic pain: signaling pathways and their magnification

are able to recognize a myriad of endogenous and exogenous molecules including microbial cell walls or pathogen-specific nucleic acids.
Integral to the initial agonist-induced TLR signaling cascades is receptor dimerization which enables cells to achieve specificity for agonists. Most TLRs, with the exception of TLR1, TLR2, and TLR6, form homodimers. [8,9]. Downstream of the homodimerization step between TLRs and TIR domains are TLR signaling pathway adaptor proteins. This group includes myeloid differentiation factor 88 (MyD88);
TIR-domain-containing adaptor protein (TIRAP; also known as MyD88 adaptor-like [MAL]), Toll/ interleukin-1 receptor (TIR) domain-containing adaptor-inducing interferon-beta (TRIF) and the TLR4TRIF-related adapter molecule (TRAM) [10]. TIRAP is utilized by TLR2 and TLR4 to bridge MyD88 to its receptors and is integral to activating the transcription factor, nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB), and leads to induction of inflammatory cytokines [11,12]. The activation
This group also determined that following seizure onset (due to kainic acid activation of glutamate receptors or inhibition of GABA receptors), HMGB1 was profoundly increased in both astrocytes and microglial cells [55]. As a proof of concept, the authors then explored the functional relevance of
HMGB1 and TLR4 in seizure activity by injecting
HMGB1 into the hippocampus of TLR4-sufficient and TLR4-deficient C3H/HeJ mice. They found that
HMGB1 increases the frequency and duration of experimentally induced seizures in a dose-dependent manner in the TLR4-sufficient mice while similar injections were not pro-convulsant in the TLR4deficient C3H/HeJ mice. Importantly, this study demonstrated that direct activation of TLR4 on adult CNS neurons by endogenous release of HMGB1 within the nervous system promotes abnormal or excessive neuronal activity.

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TLR4 signal pathway and neuropathic pain
The involvement of TLR4 function in the generation of neuropathic pain is highlighted by observations of both diminished spinal cord inflammation and pain behavior in TLR4 knockout mice [56,57]. Similar observations have been made in rats that were