A Critical Role of Toll-like Receptor 2 in Nerve Injury-induced Spinal Cord Glial Cell Activation and Pain Hypersensitivity

In contrast to physiological pain, pathological pain is not dependent on the presence of tissue‐damaging stimuli. One type of pathological pain – neuropathic pain – is often a consequence of nerve injury or of diseases such as diabetes. Neuropathic pain can be agonizing, can persist over long periods and is often resistant to known painkillers. A growing body of evidence shows that many pathological processes within the central nervous system are mediated by complex interactions between neurons and glial cells. In the case of painful peripheral neuropathy, spinal microglia react and undergo a series of changes that directly influence the establishment of neuropathic pain states. After nerve damage, purinergic P2X4 receptors (non‐selective cation channels activated by extracellular adenosine triphosphate) are upregulated in spinal microglia in a manner that depends on the transcription factors interferon regulatory factor 8 and 5, both of which are expressed in microglia after peripheral nerve injury. P2X4 receptor expression on the cell surface of microglia is also regulated at the post‐translational level by signaling from CC chemokine receptor chemotactic cytokine receptor 2. Furthermore, spinal microglia in response to extracellular stimuli results in signal transduction through intracellular signaling cascades, such as mitogen‐activated protein kinases, p38 and extracellular signal‐regulated protein kinase. Importantly, inhibiting the function or expression of these microglial molecules suppresses the aberrant excitability of dorsal horn neurons and neuropathic pain. These findings show that spinal microglia are a central player in mechanisms for neuropathic pain, and might be a potential target for treating the chronic pain state.

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“…Mice lacking either toll‐like receptor 2, 3 or 4 show impaired microglial activation in the dorsal horn after PNI42, 43, 44.…”

Section: Microglia In the Spinal Cord In Pni And Diabetic Animalsmentioning

confidence: 99%

Microglia in the spinal cord and neuropathic pain

Tsuda

2015

J of Diabetes Invest

208

147

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“…It was once thought that pain was mediated solely by neurons, however it is now becoming clear that glial in the spinal cord contributes to the initiation and maintenance of pathological pain from a variety of sources [78,79]. Spinal cord glia are activated by sensory signals from the periphery, and similar to infection, release proinflammatory cytokines that contribute to pain [78,80].…”

Section: Role Of Tlrs In Chronic Painmentioning

confidence: 99%

“…Since TLR3 binds mRNA released from necrotic cells it has been suggested that this may be the mechanism responsible for the TLR3 role in neuropathic pain [79]. This indicates that blockade of TLR3 in spinal cord glial cells may potentially be beneficial in the treatment of neuropathic pain [83].…”

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confidence: 99%

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Evaluating the role of Toll-like receptors in diseases of the central nervous system

Carty

Bowie

2011

Biochemical Pharmacology

134

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A key part of the innate immune system is a network of pattern recognition receptors (PRRs) and their associated intracellular signalling pathways. Toll-like receptors (TLRs) are one such group of PRRs that detect pathogen associated molecular patterns (PAMPs). Activation of the TLRs with their respective agonists results in the activation of intracellular signalling pathways leading to the expression of proinflammatory mediators and anti-microbial effector molecules. Activation of the innate immune system through TLRs also triggers the adaptive immune response, resulting in a comprehensive immune program to eradicate invading pathogens. It is now known that immune surveillance and inflammatory responses occur in the central nervous system (CNS). Furthermore it is becoming increasingly clear that TLRs have a role in such CNS responses andare also implicated in the pathogenesis of a number of conditions in the CNS, such as Alzheimer's, stroke and multiple sclerosis. This is likely due to the generation of endogenous TLR agonists in these conditions which amplifies a detrimental neurotoxic inflammatory response. However TLRs in some situations can be neuroprotective, if triggered in a favourable context. This review aims to examine the recent literature on TLRs in the CNS thus demonstrating their importance in a range of infectious and non-infectious diseases of the brain.

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“…For example, TLR2 and TLR4 are required for nerve injury-induced microglia activation in the spinal cord. Mice lacking TLR2 and TLR4 show attenuated neuropathic pain (Kim et al, 2007;Tanga et al, 2005). However, the cellular localization and injury-induced regulation of TLRs in the spinal cord remain to be investigated.…”

Section: The Role Of Microglia In Pain Controlmentioning

confidence: 99%

Do glial cells control pain?

Wen²,

et al. 2007

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Management of chronic pain is a real challenge, and current treatments focusing on blocking neurotransmission in the pain pathway have only resulted in limited success. Activation of glia cells has been widely implicated in neuroinflammation in the central nervous system, leading to neruodegeneration in many disease conditions such as Alzheimer's and multiple sclerosis. The inflammatory mediators released by activated glial cells, such as tumor necrosis factor-α and interleukin-1β can not only cause neurodegeneration in these disease conditions, but also cause abnormal pain by acting on spinal cord dorsal horn neurons in injury conditions. Pain can also be potentiated by growth factors such as BDNF and bFGF that are produced by glia to protect neurons. Thus, glia cells can powerfully control pain when they are activated to produce various pain mediators. We will review accumulating evidence supporting an important role of microglia cells in the spinal cord for pain control under injury conditions (e.g. nerve injury). We will also discuss possible signaling mechanisms in particular MAP kinase pathways that are critical for glia control of pain. Investigating signaling mechanisms in microglia may lead to more effective management of devastating chronic pain.

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A Critical Role of Toll-like Receptor 2 in Nerve Injury-induced Spinal Cord Glial Cell Activation and Pain Hypersensitivity

Cited by 274 publications

References 59 publications

Microglia in the spinal cord and neuropathic pain

Microglia in the spinal cord and neuropathic pain

Evaluating the role of Toll-like receptors in diseases of the central nervous system

Do glial cells control pain?

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