Activation of microglia and p38 mitogen-activated protein kinase in the dorsal column nucleus contributes to tactile allodynia following peripheral nerve injury

Terayama, Ryuji; Omura, Shinji; Fujisawa, Naoko; Yamaai, Tomoichiro; Ichikawa, Hiroyuki; Sugimoto, Tomosada

doi:10.1016/j.neuroscience.2008.03.041

Cited by 81 publications

(61 citation statements)

References 48 publications

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“…As a result, we found that the intrathecal administration of SB203580, a p38 inhibitor by binding to the ATP pocket in the enzyme [25] , may prevent the injury-induced downregulation of GABA(B)R1a expression in the spinal dorsal horn. SB203580 was chosen for that because the p38/MAPK is selectively activated in microglia [5,10,11] .…”

Section: Discussionmentioning

confidence: 90%

“…Unexpectedly, we found that the GABA(B)R1a expression exhibited a transient upregulation on day 1 after SNL, and that the intrathecal administration of SB203580 significantly elevated the GABA(B)R1a expression to a level higher than that of the controls. A study of 21-day observation has shown that a significant increase in the number of p-p38 MAPK-IR cells is detectable on days 3, 14 and 21 after SNL, but not on day 1 [25] . We suppose the GABA(B)R1a expression would be upregulated when there was insufficient p38/MAPK activation, which may occur on the first day after SNL or after SB203580 treatment.…”

Section: Discussionmentioning

confidence: 99%

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p38/MAPK Inhibitor Modulates the Expression of Dorsal Horn GABA(B) Receptors in the Spinal Nerve Ligation Model of Neuropathic Pain

et al. 2011

Neuroimmunomodulation

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Background: Neuropathic pain is one of the most challenging clinical problems due to a lack of understanding the mechanisms. Recent studies have suggested that activated microglia in spinal cord may play a vital role in nerve injury-induced neuropathic pain, but the exact mechanisms have not been fully determined. Methods: First, we investigated the changes of dorsal horn GABA(B) receptor 1 (R1) expression in spinal nerve ligation rats. Second, we explored whether activated microglia contributed to such neuron changes by intrathecal administration of the p38 inhibitor, SB203580. Results: In this study, we found a dynamic change of GABA(B)R1a protein expression after spinal nerve ligation, and the peripheral nerve injury-induced downregulation of GABA(B)R1a expression in the spinal dorsal horn could be prevented by intrathecal administration of a p38/MAPK inhibitor SB203580. Conclusions: Our results provide valuable information for a better understanding of neuropathic pain and may contribute to developing effective treatments in future studies.

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

p38/MAPK Inhibitor Modulates the Expression of Dorsal Horn GABA(B) Receptors in the Spinal Nerve Ligation Model of Neuropathic Pain

et al. 2011

Neuroimmunomodulation

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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: 96%

Microglia in the spinal cord and neuropathic pain

Tsuda

2015

J of Diabetes Invest

208

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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“…These pathways have been recognized as important in the pathogenesis of the tactile allodynia caused by nerve injury (Bian et al, 1998;Sun et al, 2001;Sung et al, 1998;Terayama et al, 2008), and in mechanical, but not thermal, allodynia seen after hemisection injury (Kim et al, 2005). However, a possible role of DC axons in the development of mechanical allodynia after contusion SCI has not been studied.…”

Section: Axonal Sprouting and Sci Painmentioning

confidence: 99%

Vascular Endothelial Growth Factor and Spinal Cord Injury Pain

Nešić

Sundberg

Herrera

et al. 2010

Journal of Neurotrauma

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Vascular endothelial growth factor (VEGF)-A mRNA was previously identified as one of the significantly upregulated transcripts in spinal cord injured tissue from adult rats that developed allodynia. To characterize the role of VEGF-A in the development of pain in spinal cord injury (SCI), we analyzed mechanical allodynia in SCI rats that were treated with either vehicle, VEGF-A isoform 165 (VEGF 165 ), or neutralizing VEGF 165 -specific antibody. We have observed that exogenous administration of VEGF 165 increased both the number of SCI rats that develop persistent mechanical allodynia, and the level of hypersensitivity to mechanical stimuli. Our analysis identified excessive and aberrant growth of myelinated axons in dorsal horns and dorsal columns of chronically injured spinal cords as possible mechanisms for both SCI pain and VEGF 165 -induced amplification of SCI pain, suggesting that elevated endogenous VEGF 165 may have a role in the development of allodynia after SCI. However, the neutralizing VEGF 165 antibody showed no effect on allodynia or axonal sprouting after SCI. It is possible that another endogenous VEGF isoform activates the same signaling pathway as the exogenouslyadministered 165 isoform and contributes to SCI pain. Our transcriptional analysis revealed that endogenous VEGF 188 is likely to be the isoform involved in the development of allodynia after SCI. To the best of our knowledge, this is the first study to suggest a possible link between VEGF, nonspecific sprouting of myelinated axons, and mechanical allodynia following SCI.

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Activation of microglia and p38 mitogen-activated protein kinase in the dorsal column nucleus contributes to tactile allodynia following peripheral nerve injury

Cited by 81 publications

References 48 publications

p38/MAPK Inhibitor Modulates the Expression of Dorsal Horn GABA(B) Receptors in the Spinal Nerve Ligation Model of Neuropathic Pain

p38/MAPK Inhibitor Modulates the Expression of Dorsal Horn GABA(B) Receptors in the Spinal Nerve Ligation Model of Neuropathic Pain

Microglia in the spinal cord and neuropathic pain

Vascular Endothelial Growth Factor and Spinal Cord Injury Pain

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