Role of the CX3CR1/p38 MAPK pathway in spinal microglia for the development of neuropathic pain following nerve injury-induced cleavage of fractalkine

Zhuang, Zhi-Ye; Kawasaki, Yuki; Tan, Ping-Heng; Wen, Yeong-Ray; Huang, Jing; Ji, Ru-Rong

doi:10.1016/j.bbi.2006.11.003

Cited by 319 publications

(329 citation statements)

References 50 publications

(80 reference statements)

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“…Fortunately, in last several years, we have seen several potential markers, such as the ATP receptor P2X4 (Tsuda et al, 2003), the chemokine receptors CCR2 (Abbadie et al, 2003) and CX3CR1 Zhuang et al, 2007), as well as Toll-like recepotor-4 (TLR4) (Tanga et al, 2005).…”

Section: Microglia Activation and Proliferation In The Spinal Cord Inmentioning

confidence: 99%

“…Nerve injury induces a rapid cleavage of fractalkine from the membrane , which involves a cysteine protease cathepsin S that is expressed in microglia (Clark et al, 2007b). Notably, the fractalkine receptor CX3CR1 is only expressed in spinal microglia and upregulated after nerve injury Zhuang et al, 2007). Intrathecal injection of a CX3CR1 neutralizing antibody has been shown to inhibit neuropathic pain and inflammatory pain (Sun et al, 2007).…”

Section: The Role Of Microglia In Pain Controlmentioning

confidence: 99%

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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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Section: Microglia Activation and Proliferation In The Spinal Cord Inmentioning

confidence: 99%

Section: The Role Of Microglia In Pain Controlmentioning

confidence: 99%

Do glial cells control pain?

Wen²,

et al. 2007

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“…Fractalkine is another factor released by neurons of the pain pathway, which has been documented to mediate pathological pain (Clark et al, 2007, Lindia et al, 2005, Milligan et al, 2005c, Zhuang et al, 2007. Fractalkine, first discovered as neurotactin (Pan et al, 1997) is a chemokine, a term which refers to a family of over 50 proteins classically known as chemotactic cytokines (Asensio and Campbell, 1999) that induces leukocyte migration and facilitates inflammation (Thomson and Lotze, 2003).…”

Section: Neuron-to-glia Signals: Fractalkinementioning

confidence: 99%

Glia in pathological pain: A role for fractalkine

Milligan

Sloane

Watkins

2008

Journal of Neuroimmunology

104

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Microglia and/or astrocytes play a significant role in the creation and maintenance of exaggerated pain states with inflammatory and/or neuropathic etiologies. The chemokine, fractalkine, has several functions, including the newly recognized role of mediating neuropathic pain conditions. Although constitutively expressed and released during inflammation, increased release of fractalkine binds to and activates microglia glia leading to pathological pain. We review the critical role of fractalkine in neuron-to-glial communication after peripheral nerve injury and inflammation and explore anti-inflammatory cytokines like interleukin-10 as a novel and effective approach for clinical pain control. KeywordsNeuropathic pain; spinal cord; microglia; astrocytes; interleukin-10; gene therapy Previously Understood Views of PainTraditionally, our understanding about neuronal signaling for pain transmission from the body to the central nervous system (CNS) occurs as a series of relay signals that are eventually processed in the brain. These relay signals are thought to serve protective and adaptive roles, with the first synaptic relay, between the first order (sensory) neuron and the second order neuron in the dorsal horn of the spinal cord. Neurons that receive and respond to pain information are primarily located in anatomically discrete regions of the spinal cord, that is, laminae I, II and V of the spinal cord dorsal horns. From the spinal cord dorsal horn, pain projection neurons relay their information to higher pain centers, such as to the brainstem and various relevant pain areas in the brain. Interestingly, the dorsal horn of the spinal cord can strongly modulate pain signaling (Millan, 1999). Although the neuronal functioning of these pain pathways has been examined for decades, the induction and maintenance of non-adaptive, pathological pain is poorly understood. However, since the early 1990's, there has been mounting evidence that glial cells (both astrocytes and microglia), in addition to neurons, also play a critical role in pain modulation (DeLeo et al., 2007).

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“…Specifically, nerve injury upregulates several receptors, such as the chemokine receptor CX3CR1 and ATP receptor P2X4 in spinal microglia. Either blocking or deleting these receptors results in decreased neuropathic pain (Tsuda et al, 2003;Verge et al, 2004;Zhuang et al, 2006b). Intrathecal injection of ATP-activated microglia induces mechanical allodynia (a nociceptive response to normally innocuous mechanical stimulation) that requires microglial production of BDNF (Tsuda et al, 2003;Coull et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

“…Notably, studies from different laboratories have demonstrated that p38 mitogen-activated protein kinase (MAPK) is activated in spinal microglia under different chronic pain conditions, and that blocking this kinase attenuates pain hypersensitivity (Table 1 ( Jin et al, 2003;Schafers et al, 2003;Tsuda et al, 2004;Boyle et al, 2006;Hains and Waxman, 2006). A recent study shows that nerve injury-induced cleavage of the chemokine fractalkine results in activation of p38 in spinal microglia via CX3CR1 receptors (Zhuang et al, 2006b).…”

Section: Introductionmentioning

confidence: 99%

Possible role of spinal astrocytes in maintaining chronic pain sensitization: review of current evidence with focus on bFGF/JNK pathway

et al. 2006

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Although pain is regarded traditionally as neuronally mediated, recent progress shows an important role of spinal glial cells in persistent pain sensitization. Mounting evidence has implicated spinal microglia in the development of chronic pain (e.g. neuropathic pain after peripheral nerve injury). Less is known about the role of astrocytes in pain regulation. However, astrocytes have very close contact with synapses and maintain homeostasis in the extracellular environment. In this review, we provide evidence to support a role of spinal astrocytes in maintaining chronic pain. In particular, cJun N-terminal kinase (JNK) is activated persistently in spinal astrocytes in a neuropathic pain condition produced by spinal nerve ligation. This activation is required for the maintenance of neuropathic pain because spinal infusion of JNK inhibitors can reverse mechanical allodynia, a major symptom of neuropathic pain. Further study reveals that JNK is activated strongly in astrocytes by basic fibroblast growth factor (bFGF), an astroglial activator. Intrathecal infusion of bFGF also produces persistent mechanical allodynia. After peripheral nerve injury, bFGF might be produced by primary sensory neurons and spinal astrocytes because nerve injury produces robust bFGF upregulation in both cell types. Therefore, the bFGF/JNK pathway is an important signalling pathway in spinal astrocytes for chronic pain sensitization. Investigation of signaling mechanisms in spinal astrocytes will identify new molecular targets for the management of chronic pain.

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Role of the CX3CR1/p38 MAPK pathway in spinal microglia for the development of neuropathic pain following nerve injury-induced cleavage of fractalkine

Cited by 319 publications

References 50 publications

Do glial cells control pain?

Do glial cells control pain?

Glia in pathological pain: A role for fractalkine

Possible role of spinal astrocytes in maintaining chronic pain sensitization: review of current evidence with focus on bFGF/JNK pathway

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