Activation of p38 MAP kinase in the rat dorsal root ganglia and spinal cord following peripheral inflammation and nerve injury

Kim, Sang-Yong; Bae, Jae-Chun; Kim, Jee Young; Lee, Hye-Lim; Lee, Kyung-Min; Kim, Dong–Sun; Cho, Hee-Jung

doi:10.1097/00001756-200212200-00021

Cited by 156 publications

(97 citation statements)

References 15 publications

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“…This is perhaps not surprising given that an isolated sensory neuron could be looked at as a rather severe axotomy model, and previous studies have shown that nerve injury leads to enhanced p38 activity in DRG somata (Kim et al, 2002;Jin et al, 2003). Indeed, our results indicate that there is a low level of active p38 in unstimulated DRG neurons (Fig.…”

Section: Discussionsupporting

confidence: 76%

“…It is now recognized that the p38 MAPK pathway is an important regulator of inflammatory and neuropathic pain (Ji et al, 2002;Kim et al, 2002;Jin et al, 2003;Milligan et al, 2003;Svensson et al, 2003a,b;Inoue et al, 2004;Ji, 2004;Ji and Strichartz, 2004;Obata et al, 2004a,b;Sweitzer et al, 2004a,b;Mizushima et al, 2005;Svensson et al, 2005a,b;Tsuda et al, 2005). Peripheral inflammation results in p38 activation in nociceptive DRG neurons, and p38 participates in the maintenance of inflammatory heat hyperalgesia by increasing TRPV1 expression (Ji et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Acute p38-Mediated Modulation of Tetrodotoxin-Resistant Sodium Channels in Mouse Sensory Neurons by Tumor Necrosis Factor-α

Jin¹,

Gereau²

2006

J. Neurosci.

435

373

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Tumor necrosis factor-␣ (TNF␣) is a proinflammatory cytokine involved in the development and maintenance of inflammatory and neuropathic pain conditions. TNF␣ can have long-lasting effects by regulating the expression of a variety of inflammatory mediators, including other cytokines and TNF␣ itself. However, the speed with which TNF␣ induces tactile and thermal hypersensitivity suggests that transcriptional regulation cannot fully account for its sensitizing effects, and some recent findings suggest that TNF␣ may act directly on primary afferent neurons to induce pain hypersensitivity. In the present study, we show that peripheral administration of TNF␣ induces thermal hypersensitivity in wild-type mice but not in transient receptor potential vanilloid receptor TRPV1 Ϫ/Ϫ mice. In contrast, TNF␣ produced equivalent mechanical hypersensitivity in TRPV1 Ϫ/Ϫ mice and wild-type littermates, suggesting a role for TRPV1 in TNF␣-induced thermal, but not mechanical, hypersensitivity. Because tetrodotoxin (TTX)-resistant Na ϩ channels are a critical site of modulation underlying mechanical hypersensitivity in inflammatory and neuropathic pain conditions, we tested the effects of TNF␣ on these channels in isolated mouse dorsal root ganglion (DRG) neurons. We report that acute application of TNF␣ rapidly enhances TTX-resistant Na ϩ currents in isolated DRG neurons. This potentiation of TTX-resistant currents by TNF␣ is dramatically reduced in DRG neurons from TNF receptor 1 (TNFR1) knock-out mice and is blocked by the p38 mitogen-activated protein kinase inhibitor SB202190 [4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)1H-imidazole]. Mechanical hypersensitivity induced by peripherally applied TNF␣ is also significantly reduced by SB202190. These results suggest that TNF␣ may induce acute peripheral mechanical sensitization by acting directly on TNFR1 in primary afferent neurons, resulting in p38-dependent modulation of TTX-resistant Na ϩ channels.

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Section: Discussionsupporting

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Acute p38-Mediated Modulation of Tetrodotoxin-Resistant Sodium Channels in Mouse Sensory Neurons by Tumor Necrosis Factor-α

Jin¹,

Gereau²

2006

J. Neurosci.

435

373

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“…In contrast, recent reports demonstrated that peripheral nerve injury induces the activation of p38 in axotomized DRG neurons (Jin et al, 2003;Schafers et al, 2003b). Furthermore, Kim et al (2002) showed p38 activation in small sensory neurons after CCI; however, they did not identify whether these neurons were injured or spared. In the present study, using the L5 SNL model, we demonstrated for the first time that p38, but not ERK and JNK, was activated in the adjacent intact DRG, mainly trkAcontaining small neurons.…”

Section: Discussionmentioning

confidence: 78%

Role of Mitogen-Activated Protein Kinase Activation in Injured and Intact Primary Afferent Neurons for Mechanical and Heat Hypersensitivity after Spinal Nerve Ligation

Obata¹,

Yamanaka²,

Kobayashi³

et al. 2004

J. Neurosci.

290

208

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To investigate whether activation of mitogen-activated protein kinase (MAPK) in damaged and/or undamaged primary afferents participates in neuropathic pain after partial nerve injury, we examined the phosphorylation of extracellular signal-regulated protein kinase (ERK), p38 MAPK, and c-Jun N-terminal kinase (JNK) in the L4 and L5 dorsal root ganglion (DRG) in the L5 spinal nerve ligation (SNL) model. We first confirmed, using activating transcription factor 3 and neuropeptide Y immunoreactivity, that virtually all L4 DRG neurons are spared from axotomy in this model. In the injured L5 DRG, the L5 SNL induced the activation of ERK, p38, and JNK in different populations of DRG neurons. In contrast, in the uninjured L4 DRG, the L5 SNL induced only p38 activation in tyrosine kinase A-expressing small-to medium-diameter neurons. Intrathecal ERK, p38, and JNK inhibitor infusions reversed SNL-induced mechanical allodynia, whereas only p38 inhibitor application attenuated SNL-induced thermal hyperalgesia. Furthermore, the L5 dorsal rhizotomy did not prevent SNL-induced thermal hyperalgesia. We therefore hypothesized that p38 activation in the uninjured L4 DRG might be involved in the development of heat hypersensitivity in the L5 SNL model. In fact, the treatment of the p38 inhibitor and also anti-nerve growth factor reduced SNL-induced upregulation of brain-derived neurotrophic factor and transient receptor potential vanilloid type 1 expression in the L4 DRG. Together, our results demonstrate that the L5 SNL induces differential activation of MAPK in injured and uninjured DRG neurons and, furthermore, that MAPK activation in the primary afferents may participate in generating pain hypersensitivity after partial nerve injury.

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“…Another groups using the same model also shows p38 activation in spinal microglia with slightly delayed time course (Tsuda et al, 2004). Other groups also demonstrate p38 activation in spinal microglia in different pain conditions (Hains & Waxman, 2006;Hua et al, 2005;Kim et al, 2002;Svensson et al, 2003;Svensson et al, 2005b;Xu et al, 2007a;Xu et al, 2007b). In the SNI model of neuropathic pain, the microglia activation of p38 is mostly seen in the medial part of the dorsal horn, where the injured tibial and peroneal nerves terminate .…”

Section: Map Kinase Activation In Microglia and Pain Controlmentioning

confidence: 85%

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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Activation of p38 MAP kinase in the rat dorsal root ganglia and spinal cord following peripheral inflammation and nerve injury

Cited by 156 publications

References 15 publications

Acute p38-Mediated Modulation of Tetrodotoxin-Resistant Sodium Channels in Mouse Sensory Neurons by Tumor Necrosis Factor-α

Acute p38-Mediated Modulation of Tetrodotoxin-Resistant Sodium Channels in Mouse Sensory Neurons by Tumor Necrosis Factor-α

Role of Mitogen-Activated Protein Kinase Activation in Injured and Intact Primary Afferent Neurons for Mechanical and Heat Hypersensitivity after Spinal Nerve Ligation

Do glial cells control pain?

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