Activation of p38 and p42/44 MAP kinase in neuropathic pain: Involvement of VPAC2 and NK2 receptors and mediation by spinal glia

Garry, Emer M.; Delaney, Ada; Blackburn-Munro, Gordon; Dickinson, Tracey; Moss, Andrew; Nakalembe, Immaculate; Robertson, Darren; Rosie, Roberta; Robberecht, Patrick; Mitchell, Rory; Fleetwood-Walker, Susan M.

doi:10.1016/j.mcn.2005.08.016

Cited by 38 publications

(38 citation statements)

References 80 publications

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“…For example, following sciatic nerve ligation, sequential activation of ERK in neurons then microglia and astrocytes [52] was reported, while others reported increased activation of p38 and p42/44 MAP kinases where p38 was reduced by TNFα inhibitors and by PPF [19]. Others demonstrate that IL-1β driven wind-up is inhibited by PPF suggesting glial involvement in C-fiber mediated effects on dorsal horn neurons [1].…”

Section: Discussionmentioning

confidence: 99%

Propentofylline attenuates allodynia, glial activation and modulates GABAergic tone after spinal cord injury in the rat

Gwak

Crown

Unabia

et al. 2008

Pain

124

128

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In this study, we evaluated whether propentofylline, a methylxanthine derivative, modulates spinal glial activation and GABAergic inhibitory tone by modulation of glutamic acid decarboxylase (GAD) 65 , the GABA synthase enzyme, in the spinal dorsal horn following spinal cord injury (SCI). Sprague-Dawley rats (225-250 g) were given a unilateral spinal transverse injury, from dorsal to ventral, at the T13 spinal segment. Unilateral spinal injured rats developed robust bilateral hindlimb mechanical allodynia and hyperexcitability of spinal wide dynamic range (WDR) neurons in the lumbar enlargement (L4-L5) compared to sham controls, which was attenuated by intrathecal (i.t.) administration of GABA, dose-dependently (0.01, 0.1, 0.5 μg). Western blotting and immunohistochemical data demonstrated that the expression level of GAD 65 protein significantly decreased on both sides of the lumbar dorsal horn (L4/5) after SCI (p < 0.05). In addition, astrocytes and microglia showed soma hypertrophy as determined by increased soma area and increased GFAP and CD11b on both sides of the lumbar dorsal horn compared to sham controls, respectively (p < 0.05). Intrathecal treatment with propentofylline (PPF 10 mM) significantly attenuated the astrocytic and microglial soma hypertrophy and mechanical allodynia (p < 0.05). Additionally, the Western blotting and immunohistochemistry data demonstrated that i.t. treatment of PPF significantly prevented the decrease of GAD 65 expression in both sides of the lumbar dorsal horn following SCI (p < 0.05). In conclusion, our present data demonstrate that propentofylline modulates glia activation and GABAergic inhibitory tone by modulation of GAD 65 protein expression following spinal cord injury.

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Section: Discussionmentioning

confidence: 99%

Propentofylline attenuates allodynia, glial activation and modulates GABAergic tone after spinal cord injury in the rat

Gwak

Crown

Unabia

et al. 2008

Pain

124

128

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“…Mapk signaling pathways regulate the transcription and mRNA stability of proinflammatory genes such as tumor necrosis factor, interleukin 6, and cyclooxygenase 2 (Chang and Karin, 2001). Intrathecal administration of a p38 inhibitor reduces pain-like behavior after CCI and SNL (Jin et al, 2003;Garry et al, 2005), indicating the importance of the p38 Mapk pathway in neuropathic pain. Intrathecal treatment with MTX, beginning at the time of nerve injury, reduced p38 phosphorylation in the dorsal horn of animals after SNI to almost pre-injury levels and decreased both mechanical and cold allodynia, two major features of clinical neuropathic pain.…”

Section: Discussionmentioning

confidence: 99%

Low-dose methotrexate reduces peripheral nerve injury-evoked spinal microglial activation and neuropathic pain behavior in rats

Scholz

Abele

Marian

et al. 2008

Pain

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Peripheral nerve injuries that provoke neuropathic pain are associated with microglial activation in the spinal cord. We have investigated the characteristics of spinal microglial activation in three distinct models of peripheral neuropathic pain: spared nerve injury (SNI), chronic constriction injury, and spinal nerve ligation. In all models, dense clusters of cells immunoreactive for the microglial marker CD11b formed in the ipsilateral dorsal horn 7 days after injury. Microglial expression of ionized calcium binding adapter molecule 1 (Iba1) increased by up to 40% and phosphorylation of p38 mitogen-activated protein kinase, a marker of microglial activity, by 45%. Expression of the lysosomal ED1-antigen indicated phagocytic activity of the cells. Unlike the peripheral nerve lesions, rhizotomy produced only a weak microglial reaction within the spinal gray matter but a strong activation of microglia and phagocytes in the dorsal funiculus at lumbar and thoracic spinal cord levels. This suggests that although degeneration of central terminals is sufficient to elicit microglial activation, it does not account for the inflammatory response in the dorsal horn after peripheral nerve injury. Early intrathecal treatment with low-dose methotrexate, beginning at the time of injury, decreased microglial activation, reduced p38 phosphorylation, and attenuated pain-like behavior after SNI. In contrast, systemic or intrathecal delivery of the glucocorticoid dexamethasone did not inhibit the activation of microglia or reduce pain-like behavior. We confirm that microglial activation is crucial for the development of pain after nerve injury, and demonstrate that suppression of this cellular immune response is a promising approach for preventing neuropathic pain.

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“…U0126, however, produced no significant change on the PWT to von Frey hairs and PWL to thermal stimulation of the contralateral hind paw (Fig. 3A), suggesting that ERK may play a critical role in CCI-induced neuropathic pain, but it does not interfere with the normal pain sensation (30,31).…”

Section: Inhibition Of Erk Activation Attenuates Cci-induced Behaviormentioning

confidence: 95%

SIP30 Is Regulated by ERK in Peripheral Nerve Injury-induced Neuropathic Pain

Peng

Han

et al. 2009

Journal of Biological Chemistry

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ERK plays an important role in chronic neuropathic pain. However, the underlying mechanism is largely unknown. Here we show that in chronic constriction injury-treated rat spinal cords, up-regulation of SIP30 (SNAP25-interacting protein 30), which is involved in the development and maintenance of chronic constriction injury-induced neuropathic pain, correlates with ERK activation and that the up-regulation of SIP30 is suppressed by intrathecal delivery of the MEK inhibitor U0126. In PC12 cells, up-regulation of SIP30 by nerve growth factor is also dependent on ERK activation. We found that there is an ERK-responsive region in the rat sip30 promoter. Activation of ERK promotes the recruitment of the transcription factor cyclic AMP-response element-binding protein to the sip30 gene promoter. Taken together, our results provide a potential downstream target of ERK activation-mediated neuropathic pain.Neuropathic pain is a chronic painful condition due to nerve injury caused by trauma, disease, or surgical accidents. This kind of chronic pain brings severe distress, which disrupts the quality of life. There is a lack of effective treatment for neuropathic pain, and the underlying mechanism is poorly understood. Recently, attention has been focused on the central sensitization of spinal dorsal horn neurons, which are responsible for the modulation of neuropathic pain transmission. Central sensitization is a consequence of increased neuron excitability (1, 2). It has been shown that MAPKs 4 play a critical role in this sensitization and are responsible for the transduction of nociceptive signals (3). MAPKs are activated in the damaged neurons, and their inhibition can suppress or reverse neuropathic pain (4 -9). In various pain models, ERK, a member of the MAPK family, is specifically activated in the superficial dorsal horn neurons by noxious but not innocuous stimulation. Inhibition of ERK activation alleviates pain hypersensitivity, indicating that ERK may play an important role in neuropathic pain (10 -17). ERK appears to regulate pain hypersensitivity in various aspects. It produces not only short term functional changes by post-translational processes, such as phosphorylation of membrane receptors and channels, but also long term adaptive alterations by changing gene expression (10,12,18,19). Neuropathic pain is a chronic painful situation. It is believed that the long term gene expression regulated by ERK in the spinal cord plays a central role in the development of the disease (14). Thus, understanding of the molecular mechanism by which ERK regulates neuropathic pain is important to understand the pathology of central sensitization.SIP30 (SNAP25-interacting protein 30) was first reported as a SNAP25-interacting protein of 30 kDa that functioned in vesicle trafficking (20). Through a differential screening of a rat brain cDNA library, we found that sip30 was among the genes that were differentially expressed in the spinal cord CCI rats (21). We further showed that sip30 mRNA and protein levels were up-regulate...

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Activation of p38 and p42/44 MAP kinase in neuropathic pain: Involvement of VPAC2 and NK2 receptors and mediation by spinal glia

Cited by 38 publications

References 80 publications

Propentofylline attenuates allodynia, glial activation and modulates GABAergic tone after spinal cord injury in the rat

Propentofylline attenuates allodynia, glial activation and modulates GABAergic tone after spinal cord injury in the rat

Low-dose methotrexate reduces peripheral nerve injury-evoked spinal microglial activation and neuropathic pain behavior in rats

SIP30 Is Regulated by ERK in Peripheral Nerve Injury-induced Neuropathic Pain

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