scholarly journals Activation of p38 Mitogen-activated Protein Kinase in Spinal Microglia Contributes to Incision-induced Mechanical Allodynia

2009 ◽  
Vol 110 (1) ◽  
pp. 155-165 ◽  
Author(s):  
Yeong-Ray Wen ◽  
Marc R. Suter ◽  
Ru-Rong Ji ◽  
Geng-Chang Yeh ◽  
Yen-Sheng Wu ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Dorsal Horn ◽  
Mechanical Allodynia ◽  
Thermal Hyperalgesia ◽  
Early Time ◽  
Radiant Heat ◽  
Mitogen Activated Protein Kinase ◽  
P38 Inhibitor ◽  
Mitogen Activated Protein ◽  
Plantar Incision

Background Recent studies have implicated the activation of stress-activated mitogen-activated protein kinase (MAPK) p38 in spinal microglial cells for development of neuropathic and inflammatory pain. The aim of the present study was to investigate whether phosphorylation of p38 (p-p38) also mediates mechanical allodynia and thermal hyperalgesia induced by plantar incision. Methods After rats received a plantar incision surgery, mechanical allodynia and thermal hyperalgesia were determined by von Frey filaments and radiant heat, respectively, and the number of p-p38 immunoreactive cells in the dorsal horn was quantified to determine p38 activation at different time points after incision. The p38 inhibitor FR167653 was administered intrathecally 30 min before hind paw plantar incision to determine the role of p38 in postoperative pain. Results A significant increase in number of p-p38 immunoreactive cells was observed in the ipsilateral L4-5 spinal dorsal horn from 1 h to 3 days after the incision. p-p38 was found predominantly in microglia. However, microglial activation (assessed by OX-42 upregulation) was not evident until 3 days after plantar incision. Intrathecal pretreatment of FR167653 attenuated incision-induced mechanical allodynia from 1 h to day 2 and significantly reduced activation of p38 in the dorsal horn 1 day after plantar incision. However, FR167653 only inhibited heat hyperalgesia at an early time point. Conclusions Plantar incision-induced mechanical allodynia can be prevented by the p38 inhibitor. Our results suggest that p38 activation in spinal microglia play a role in incision-induced mechanical allodynia in rats. Therefore, p38 inhibition may be useful in treating postsurgical pain.

scholarly journals 5-Aminoimidazole-4-carboxamide riboside (AICAR) enhances GLUT2-dependent jejunal glucose transport: a possible role for AMPK

2005 ◽  
Vol 385 (2) ◽  
pp. 485-491 ◽  
Author(s):  
John WALKER ◽  
Humberto B. JIJON ◽  
Hugo DIAZ ◽  
Payam SALEHI ◽  
Thomas CHURCHILL ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Glucose Uptake ◽  
Glucose Transport ◽  
Western Blotting ◽  
Glucose Transporter ◽  
Mitogen Activated Protein Kinase ◽  
Mrna Levels ◽  
Energy Status ◽  
P38 Inhibitor ◽  
Mitogen Activated Protein

AMPK (AMP-activated protein kinase) is a key sensor of energy status within the cell. Activated by an increase in the AMP/ATP ratio, AMPK acts to limit cellular energy depletion by down-regulating selective ATP-dependent processes. The purpose of the present study was to determine the role of AMPK in regulating intestinal glucose transport. [3H]3-O-methyl glucose fluxes were measured in murine jejunum in the presence and absence of the AMPK activators AICAR (5-aminoimidazole-4-carboxamide riboside) and metformin and the p38 inhibitor, SB203580. To differentiate between a sodium-coupled (SGLT1) and diffusive (GLUT2) route of entry, fluxes were measured in the presence of the SGLT1 and GLUT2 inhibitors phloridzin and phloretin. Glucose transporter mRNA levels were measured by reverse transcriptase–PCR, and localization by Western blotting. Surface-expressed GLUT2 was assessed by luminal biotinylation. Activation of p38 mitogen-activated protein kinase was analysed by Western blotting. We found that treatment of jejunal tissue with AICAR resulted in enhanced net glucose uptake and was associated with phosphorylation of p38 mitogen-activated protein kinase. Inhibition of p38 abrogated the stimulation of AICAR-stimulated glucose uptake. Phloretin abolished the AICAR-mediated increase in glucose flux, whereas phloridzin had no effect, suggesting the involvement of GLUT2. In addition, AICAR decreased total protein levels of SGLT1, concurrently increasing levels of GLUT2 in the brush-border membrane. The anti-diabetic drug metformin, a known activator of AMPK, also induced the localization of GLUT2 to the luminal surface. We conclude that the activation of AMPK results in an up-regulation of non-energy requiring glucose uptake by GLUT2 and a concurrent down-regulation of sodium-dependent glucose transport.

scholarly journals p38-Mitogen-Activated Protein Kinase Stimulated Steroidogenesis in Granulosa Cell-Oocyte Cocultures: Role of Bone Morphogenetic Proteins 2 and 4

Endocrinology ◽  
2008 ◽  
Vol 150 (4) ◽  
pp. 1921-1930 ◽  
Author(s):  
Kenichi Inagaki ◽  
Fumio Otsuka ◽  
Tomoko Miyoshi ◽  
Misuzu Yamashita ◽  
Mina Takahashi ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Bone Morphogenetic Proteins ◽  
Granulosa Cells ◽  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
P38 Inhibitor ◽  
Morphogenetic Protein ◽  
Progesterone Synthesis ◽  
Mitogen Activated Protein ◽  
Estradiol Synthesis

Roles of the p38-MAPK pathway in steroidogenesis were investigated using coculture of rat granulosa cells with oocytes. Activin and FSH readily phosphorylated p38 in granulosa cells. Activin effect on p38 phosphorylation was abolished by a selective activin receptor-like kinase-4, -5, and -7 inhibitor, SB431542. SB431542 decreased FSH-induced estradiol but had no effect on progesterone production with a marginal cAMP reduction, suggesting that endogenous activin is primarily involved in estradiol synthesis. FSH-induced p38 activation was not affected either by SB431542 or follistatin, suggesting that FSH activates p38 not through the endogenous activin. Bone morphogenetic protein (BMP)-2 and BMP-4 also enhanced FSH-induced p38 phosphorylation, which was augmented by oocyte action. A specific p38 inhibitor, SB203580, decreased FSH-induced estradiol production. However, FSH-induced cAMP accumulation was not changed by SB203580, suggesting that p38 activation is linked to estradiol synthesis independently of cAMP. BMP-2 and BMP-4 inhibited FSH- and forskolin (FSK)-induced progesterone and cAMP synthesis regardless of oocyte action. BMP-2, BMP-4, and activin increased FSH-induced estradiol production, which was enhanced in the presence of oocytes. In contrast to activin that enhanced FSK-induced estradiol, BMP-2 and BMP-4 had no effects on FSK-induced estradiol production, suggesting that BMP-2 and BMP-4 directly activate FSH-receptor signaling. Given that activin increased, but BMP-2 and BMP-4 decreased, FSH-induced cAMP, the effects of BMP-2 and BMP-4 on estradiol enhancement appeared to be diverged from the cAMP-protein kinase A pathway. Thus, BMP-2 and BMP-4 differentially regulate steroidogenesis by stimulating FSH-induced p38 and suppressing cAMP. The former is involved in estradiol production and enhanced by oocyte action, whereas the latter leads to reduction of progesterone synthesis.

Carrageenan-induced thermal hyperalgesia in the mouse: role of nerve growth factor and the mitogen-activated protein kinase pathway

2000 ◽  
Vol 876 (1-2) ◽  
pp. 48-54 ◽  
Author(s):  
Melanie J Sammons ◽  
Pravin Raval ◽  
Philip T Davey ◽  
Derek Rogers ◽  
Andrew A Parsons ◽  
...  
Keyword(s):  
Nerve Growth Factor ◽  
Growth Factor ◽  
Protein Kinase ◽  
Thermal Hyperalgesia ◽  
Mitogen Activated Protein Kinase ◽  
Nerve Growth ◽  
Mitogen Activated Protein ◽  
Kinase Pathway

scholarly journals Nerve Conduction Blockade in the Sciatic Nerve Prevents but Does Not Reverse the Activation of p38 Mitogen-activated Protein Kinase in Spinal Microglia in the Rat Spared Nerve Injury Model

2007 ◽  
Vol 107 (2) ◽  
pp. 312-321 ◽  
Author(s):  
Yeong-Ray Wen ◽  
Marc R. Suter ◽  
Yasuhiko Kawasaki ◽  
Jin Huang ◽  
Marie Pertin ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Protein Kinase ◽  
Sciatic Nerve ◽  
Nerve Injury ◽  
Mitogen Activated Protein Kinase ◽  
Current Evidence ◽  
Spared Nerve Injury ◽  
P38 Inhibitor ◽  
Mitogen Activated Protein ◽  
Intrathecal Infusion

Background Current evidence indicates that p38 mitogen-activated protein kinase activation in spinal microglia contributes to the development of neuropathic pain. However, how nerve injury activates p38 in spinal microglia is incompletely unknown. Nerve injury-induced ectopic spontaneous activity is essential for the generation of neuropathic pain. The authors examined whether peripheral neural activity is necessary for p38 activation in spinal microglia. Methods To examine whether spinal microglia activation depends on peripheral activity in the rat spared nerve injury (SNI) model, the authors blocked conduction in the sciatic nerve before or 2 days after SNI. The block was produced by applying bupivacaine-loaded microspheres above the nerve injury site. The p38 activation was examined by p38 phosphorylation using a phosphorylated p38 antibody, and neuropathic pain-related behavior was evaluated before and after intrathecal infusion of a p38 inhibitor. Results Three days after SNI, there was a marked p38 activation in the medial two thirds of the dorsal horn, where the injured tibial and peroneal nerves terminated and where isolectin B4 staining was lost. Phosphorylated p38 was only colocalized with the microglial surface marker OX-42, indicating a microglial localization of phosphorylated p38 in the SNI model. Bupivacaine microspheres produced persistent block (loss of sensory and motor function) of the sciatic nerve for the whole period of the study (3 days). This blockade prevented but did not reverse p38 activation in spinal microglia. Intrathecal infusion of the p38 inhibitor FR167653 prevented and reversed mechanical allodynia on post-SNI day 3. Conclusions After nerve injury, activity in the peripheral nerve is required for the induction but not the maintenance of p38 activation in spinal microglia.

scholarly journals Gi-Coupled Receptor Activation Potentiates Piezo2 Currents via Gβγ

2019 ◽  
Author(s):  
John Smith Del Rosario ◽  
Yevgen Yudin ◽  
Songxue Su ◽  
Cassandra Hartle ◽  
Tooraj Mirshahi ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Dorsal Root Ganglion ◽  
Dorsal Root ◽  
Mechanical Allodynia ◽  
Receptor Activation ◽  
Mitogen Activated Protein Kinase ◽  
Drg Neurons ◽  
Cellular Mechanisms ◽  
Mitogen Activated Protein ◽  
Phosphoinositide 3 Kinase

SUMMARYDysregulation of mechanosensitive Piezo2 channels is a hallmark of mechanical allodynia, yet the cellular mechanisms that sensitize mechanoreceptors are still poorly understood. Activation of Gi-coupled receptors sensitizes Piezo2 currents, but whether Gi-coupled receptors regulate the activity of Piezo2 channels is not known. Here, we found that activation of Gi-coupled receptors potentiates Piezo2 currents in dorsal root ganglion (DRG) neurons and in heterologous systems, but inhibits Piezo1 currents in heterologous systems. The potentiation, or inhibition of Piezo currents is abolished when blocking Gβγ with the c-terminal domain of the beta-adrenergic kinase (βARKct). Pharmacological inhibition of kinases downstream of Gβγ, phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK), also abolished the potentiation of Piezo2 currents. Hence, our studies illustrate an indirect mechanism of action of Gβγ to sensitize Piezo2 currents after activation of Gi-coupled receptors.

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