The Cathepsin S/Fractalkine Pair: New Players in Spinal Cord Neuropathic Pain Mechanisms

Chapter

Abstract

A recent major conceptual advance has been the recognition of the importance of immune system-neuronal interactions in the modulation of brain function. One example of which is spinal pain processing in neuropathic states. Mounting evidence supports the hypothesis that pro-inflammatory mediators secreted by microglia modulate nociceptive function in the injured CNS and following peripheral nerve damage. Here we examine the evidence that one such mediator, the lysosomal cysteine protease cathepsin S (CatS), is critical for the maintenance of neuropathic pain and spinal microglia activation in neuropathic pain states. CatS exerts its pro-nociceptive effects via cleavage of the transmembrane chemokine fractalkine (FKN). Under conditions of increased nociception, microglial CatS is responsible for the liberation of neuronal FKN which stimulates p38 MAPK phosphorylation in microglia thereby activating neurons via the release of pro-nociceptive mediators, thus establishing a new role for the CatS/FKN pair in the maintenance of neuropathic hypersensitivity and suggest that CatS inhibition constitutes a novel therapeutic approach for the treatment of chronic pain.

Keywords

Attenuation Cysteine Neuropathy NMDA Laminin 

Abbreviations

CatS

cathepsin S

FKN

fractalkine

APCs

antigen presenting cells

DCs

dendritic cells

MHC

major histocompatibility complex

Ii

invariant chain

CLIP

class II-associated Ii peptide

HLA-DM

human leukocyte antigen DM

LHVS

morpholinurea-leucine-homophenylalanine-vinyl sulfone-phenyl

PNL

partial sciatic nerve ligation

CCI

chronic constriction injury

SNL

spinal nerve ligation

ADAM

a disintegrin and metalloprotease domain

TACE

tumour necrosis factor-α converting enzyme

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Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Wolfson Centre for Age Related DiseasesKing’s College LondonSE1 1ULUK

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