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MAP Kinase and Cell Signaling in DRG Neurons and Spinal Microglia in Neuropathic Pain

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Abstract

Nerve injury is known to produce neuropathic pain by inducing changes not only in neurons such as primary sensory neurons in the dorsal root ganglion (DRG), but also in non-neuronal cells such as microglia in the spinal cord. Increasing evidence suggests that mitogen-activated protein kinases (MAPKs) play important roles in neuropathic pain sensitization by regulating intracellular signaling in both DRG neurons and spinal cord microglia. Intrathecal injection of MAPK inhibitors for the extracellular signal-regulated kinase (ERK), p38, or c-Jun N-terminal kinase (JNK) pathway targets the MAPK pathways at both DRG and spinal cord levels and has been shown to attenuate neuropathic pain in different animal models. In particular, activation of p38 in DRG neurons by nerve growth factor and cytokines contributes to thermal hypersensitivity by increasing the expression and activity of sodium channels (e.g., Nav1.7/Nav1.8) and TRP channels (e.g., TRPV1 and TRPA1). Activation of p38 in spinal microglia by chemokines, cytokines, ATP, and proteases also contributes to neuropathic pain symptoms such as mechanical allodynia. Thus, activation of MAPK pathways in both neurons and glia and in both the peripheral and central nervous system is important for neuropathic pain sensitization, and blocking these pathways at multiple sites may lead to effective therapies for neuropathic pain.

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Abbreviations

AMPA:

α-amino-2,3-dihydro-5-methyl-3-oxo-4-isoxazolepropanic acid

BDNF:

brain-derived neurotrophic factor

CatS:

cysteine protease cathepsin S

DRG:

dorsal root ganglion

GABA:

gamma aminobutyric acid

ERK:

extracelllular signal-regulated kinase

bFGF:

basic fibroblast growth factor

FKN:

fractalkine

IL-1:

Interleukin-1

JNK:

c-Jun-N-terminal kinase

MAPK:

mitogen-activated protein kinases

MCP-1:

monocyte chemoattractant protein-1

NMDA:

N-methyl-d-aspartate

MMP-9:

matrix metalloproteinase-9

NGF:

nerve growth factor

NT-3:

neurotrophin 3

PGE2:

prostaglandin E2

PTN:

pain transmission neurons STZ, streptozotocin

TNF:

tumor necrosis factor

TRP:

transient receptor potential

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Acknowledgments

The work was supported in part by NIH grants NS40698, DE17794, and TW7180.

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  1. Department of Anesthesiology, Pain Research Center, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA

    Ru-Rong Ji

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    Ji, RR. (2009). MAP Kinase and Cell Signaling in DRG Neurons and Spinal Microglia in Neuropathic Pain. In: Malcangio, M. (eds) Synaptic Plasticity in Pain. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-0226-9_20

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