p38 Mitogen-Activated Protein Kinase Is Activated after a Spinal Nerve Ligation in Spinal Cord Microglia and Dorsal Root Ganglion Neurons and Contributes to the Generation of Neuropathic Pain

Jin, Shan-Xue; Zhuang, Zhi-Ye; Woolf, Clifford J.; Ji, Ru-Rong

doi:10.1523/jneurosci.23-10-04017.2003

Cited by 786 publications

(717 citation statements)

References 31 publications

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“…After spinal nerve ligation, we have shown that p38 is only activated in OX-42-positive microglia in the spinal cord. This activation is evident as early as 12 hours and peaks after 3 days (Jin et al, 2003). Another groups using the same model also shows p38 activation in spinal microglia with slightly delayed time course (Tsuda et al, 2004).…”

Section: Map Kinase Activation In Microglia and Pain Controlmentioning

confidence: 65%

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: Map Kinase Activation In Microglia and Pain Controlmentioning

confidence: 65%

Do glial cells control pain?

Wen²,

et al. 2007

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“…p38 activation in spinal microglia has been shown in different animal models of neuropathic pain78, 79, 80, 81, including diabetic models23, 26. Furthermore, pharmacological inhibition of p38 activity by repeated injection or by infusion of p38 inhibitors attenuated tactile allodynia caused by PNI76, 77, 82, 83 and by diabetes21, 84. Thus, activation of this kinase is necessary for the pathogenesis of neuropathic pain.…”

Section: Spinal Microglia Are Crucial For Neuropathic Painmentioning

confidence: 97%

Microglia in the spinal cord and neuropathic pain

Tsuda

2015

J of Diabetes Invest

217

147

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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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“…JNK is the least studied member of the MAPK family. Although all three MAPKs are activated in spinal glial cells after nerve injury, they have different patterns: ERK is activated sequentially in microglia and astrocytes, p38 is activated in microglia, whereas JNK is activated persistently in astrocytes (Table 1) (Jin et al, 2003;Zhuang et al, 2005;Zhuang et al, 2006a). Thus, SNL induces a marked increase in pJNK-immunoreactive (IR) cells in the dorsal horn of the injured side (Fig.…”

Section: Activation Of the Jnk Cascade In Spinal Astrocytes And Neuromentioning

confidence: 99%

“…This family includes three major members: extracellular signal-regulated kinase (ERK), p38 and c-Jun-N-terminal kinase (JNK). As mentioned above, p38 is activated in spinal microglia (Jin et al, 2003), and therefore is not the focus of this review. ERK is the most studied member of the MAPK family.…”

Section: Signaling Molecules In Spinal Astrocytes and Their Roles In mentioning

confidence: 99%

“…A non-specific microglial inhibitor minocycline prevents/delays pain development (Raghavendra et al, 2003;Ledeboer et al, 2005;Hua et al, 2005). 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%

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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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p38 Mitogen-Activated Protein Kinase Is Activated after a Spinal Nerve Ligation in Spinal Cord Microglia and Dorsal Root Ganglion Neurons and Contributes to the Generation of Neuropathic Pain

Cited by 786 publications

References 31 publications

Do glial cells control pain?

Do glial cells control pain?

Microglia in the spinal cord and neuropathic pain

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

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