Phosphatidylinositol 3-Kinase Is a Key Mediator of Central Sensitization in Painful Inflammatory Conditions

Pezet, Sophie; Marchand, Fabien; D’Mello, Richard; Grist, John; Clark, Anna K.; Malcangio, Marzia; Dickenson, Anthony H.; Williams, Robert J.; McMahon, Stephen B.

doi:10.1523/jneurosci.5392-07.2008

Cited by 129 publications

(139 citation statements)

References 46 publications

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“…Interestingly, inhibiting ERK activation by PD98059 (25 M) also abolished this enhancement (Fig. 2C), agreeing with the previous reports that PI3K and ERK signaling pathways are associated in the DRG and spinal cord (Pezet et al, 2008) during peripheral inflammation.…”

Section: Pi3k/akt Pathway Upregulates the Activity Of Asic1a Channelsupporting

confidence: 92%

PI3-kinase/Akt Pathway-Regulated Membrane Insertion of Acid-Sensing Ion Channel 1a Underlies BDNF-Induced Pain Hypersensitivity

et al. 2012

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Central neural plasticity plays a key role in pain hypersensitivity. This process is modulated by brain-derived neurotrophic factor (BDNF) and also involves the type 1a acid-sensing ion channel (ASIC1a). However, the interactions between the BDNF receptor, tropomyosinrelated kinase B (TrkB), and ASIC1a are unclear. Here, we show that deletion of ASIC1 gene suppressed the sustained mechanical hyperalgesia induced by intrathecal BDNF application in mice. In both rat spinal dorsal horn neurons and heterologous cell cultures, the BDNF/TrkB pathway enhanced ASIC1a currents via phosphoinositide 3-kinase (PI3K)-protein kinase B (PKB/Akt) cascade and phosphorylation of cytoplasmic residue Ser-25 of ASIC1a, resulting in enhanced forward trafficking and increased surface expression. Moreover, in both rats and mice, this enhanced ASIC1a activity was required for BDNF-mediated hypersensitivity of spinal dorsal horn nociceptive neurons and central mechanical hyperalgesia, a process that was abolished by intrathecal application of a peptide representing the N-terminal region of ASIC1a encompassing Ser-25. Thus, our results reveal a novel mechanism underlying central sensitization and pain hypersensitivity, and reinforce the critical role of ASIC1a channels in these processes.

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Section: Pi3k/akt Pathway Upregulates the Activity Of Asic1a Channelsupporting

confidence: 92%

PI3-kinase/Akt Pathway-Regulated Membrane Insertion of Acid-Sensing Ion Channel 1a Underlies BDNF-Induced Pain Hypersensitivity

et al. 2012

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“…It adjusts neuron apoptosis, promotes the restoration of the myelin sheath of nerve fibers, and is important in the process of synaptic maturation and plasticity. Furthermore, BDNF effects in injury, inflammatory pain and NP as pain-causing factors in Cornu dorsal medullae spinalis have been confirmed generally (40)(41)(42).…”

Section: B Amentioning

confidence: 86%

Brain-derived neurotrophic factor expression in dorsal root ganglia of a lumbar spinal stenosis model in rats

Liu

Chu

et al. 2013

Molecular Medicine Reports

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Abstract. This study aimed to investigate the expression of brain-derived neurotrophic factor (BDNF) in dorsal root ganglia (DRG) of a rat model of lumbar spinal stenosis (LSS). Adult male rats were divided into the operation and sham operation groups. The operation group was comprised of the rat models of LSS. Walking distance and BDNF expression levels in DRG were measured in the two groups at different time points. The total BDNF protein levels and positive cell mean optical density (MOD) values in the operation group were significantly higher at each time point compared with that of the sham operation and preoperative control groups (P<0.05). The total BDNF protein levels and MOD values following sport in the operation group were significantly higher compared with those prior to sport (P<0.05). In the sham operation group, BDNF protein levels and MOD values before and after sport at each time point showed no significant differences than those of the operation group (P>0.05). Moreover, BDNF protein levels and MOD values in the operation group indicated a negative correlation with walking distance. The present study demonstrated that the expression of BDNF in rat models of LSS increased with time and was associated with a decrease in walking distance. BDNF was therefore important for the process of intermittent claudication caused by LSS.

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“…This indicates that glutamate receptors may play an important role in MAPK activation; therefore, we examined the effect of the NMDAR channel blocker, dizocilpine, on the CFA-induced pain model. Recent studies have suggested that spinal NMDAR NR2B subunit phosphorylation is closely related to the development of inflammatory hyperalgesia, and that suppression of this particular subunit suggests compensation for the enhanced nociceptive activity (3,23). The results of the present study revealed that treatment with EA or dizocilpine alone did not induce significant changes in NR2B phosphorylation on serine residues, but that co-treatment with dizocilpine and EA led to a marked decrease in NR2B activation compared to CFA-injected rats that was correlated with behavioral changes.…”

Section: Discussionmentioning

confidence: 99%

“…Among the NMDAR subunits, NR2B is the most commonly expressed NR2 subunit in the spinal cord and phosphorylation of this subunit contributes to pain conditions including the initiation and development of inflammatory hyperalgesia (2). Inhibition of the phosphorylation of the NR2B subunit suggests that there is potent compensation for enhanced nociceptive activity (3).…”

Section: Introductionmentioning

confidence: 99%

Synergistic antinociceptive effects of N-methyl-D-aspartate receptor antagonist and electroacupuncture in the complete Freund's adjuvant-induced pain model

Choi¹

2011

Int J Mol Med

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Abstract. This study examined the synergistic antinociceptive effects associated with signaling pathway proteins of the spinal cord in a complete Freund's adjuvant (CFA)-induced pain model when electroacupuncture (EA) and a N-methyl-D-aspartate receptor (NMDAR) antagonist were administered in combination. EA stimulation (2 Hz, 1 mA) was needledelivered for 20 min once daily at acupoints corresponding to Zusanli and Sanyinjiao with intrathecal injection of the NMDAR antagonist dizocilpine (MK801). Thermal sensitivity of the hindpaw induced by CFA was strongly inhibited by dizocilpine injection and EA stimulation. Co-treatment with EA and dizocilpine showed a synergistic antinociceptive effect against inflammatory pain. On day two of the experiment, we examined the phosphorylation of the NMDAR NR2B subunit, of the extracellular signal-regulated kinase (ERK), p38 and of the cAMP response element-binding protein (CREB) in the ipsilateral dorsal horn of L4-5 segments by Western blot analysis. Phosphorylation of the NMDAR NR2B subunit induced by CFA was markedly inhibited by co-treatment with dizocilpine and EA, but not by dizocilpine or EA treatment alone. CFA-induced phosphorylation of the ERK was inhibited by both dizocilpine and EA, but that of p38 was inhibited by EA only. CFA-induced phosphorylation of CREB was inhibited by dizocilpine, but did not show marked changes. Immunohistochemical analyses confirmed that there was a significant difference in the NMDAR NR2B subunit and ERK phosphorylation. It is possible that the combined treatment with EA and the NMDAR antagonist dizocilpine resulted in synergistic antinociceptive effects in an inflammatory pain model via the inactivation of both the NMDAR NR2B subunit and ERK of the spinal cord.

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Phosphatidylinositol 3-Kinase Is a Key Mediator of Central Sensitization in Painful Inflammatory Conditions

Cited by 129 publications

References 46 publications

PI3-kinase/Akt Pathway-Regulated Membrane Insertion of Acid-Sensing Ion Channel 1a Underlies BDNF-Induced Pain Hypersensitivity

PI3-kinase/Akt Pathway-Regulated Membrane Insertion of Acid-Sensing Ion Channel 1a Underlies BDNF-Induced Pain Hypersensitivity

Brain-derived neurotrophic factor expression in dorsal root ganglia of a lumbar spinal stenosis model in rats

Synergistic antinociceptive effects of N-methyl-D-aspartate receptor antagonist and electroacupuncture in the complete Freund's adjuvant-induced pain model

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