Estrogen-dependent facilitation on spinal reflex potentiation involves the Cdk5/ERK1/2/NR2B cascade in anesthetized rats

Peng, Hsien Yu; Chen, Gin Den; Tung, Kwong‐Chung; Chien, Ya Wen; Lai, Chih-Sheng; Hsieh, Ming-Che; Chiu, Chien‐Liang; Lee, Shin-Da; Lin, Tzer Bin

doi:10.1152/ajpendo.00129.2009

Cited by 28 publications

(19 citation statements)

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“…Intrathecal catheter Implantation of intrathecal cannula was performed following the method described in a previous study [13]. Under anesthesia with sodium pentobarbital, the L4-L5 spinal processes were exposed and the muscles beside the processes were isolated bluntly.…”

Section: Methodsmentioning

confidence: 99%

Microvesicles shed from microglia activated by the P2X7-p38 pathway are involved in neuropathic pain induced by spinal nerve ligation in rats

Jiang

et al. 2016

Purinergic Signalling

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Microglia are critical in the pathogenesis of neuropathic pain. In this study, we investigated the role of microvesicles (MVs) in neuropathic pain induced by spinal nerve ligation (SNL) in rats. First, we found that MVs shed from microglia were increased in the cerebrospinal fluid and dorsal horn of the spinal cord after SNL. Next, MVs significantly reduced paw withdrawal threshold (PWT) and paw withdrawal latency (PWL). In addition, the P2X7-p38 pathway was related to the bleb of MVs after SNL. Interleukin (IL)-1β was found to be significantly upregulated in the package of MVs, and PWT and PWL increased following inhibition with shRNA-IL-1β. Finally, the amplitude and frequency of spontaneous excitatory postsynaptic currents increased following stimulation with MVs. Our results indicate that the P2X7-p38 pathway is closely correlated with the shedding of MVs from microglia in neuropathic pain, and MVs had a significant effect on neuropathic pain by participating in the interaction between microglia and neurons.

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Section: Methodsmentioning

confidence: 99%

Microvesicles shed from microglia activated by the P2X7-p38 pathway are involved in neuropathic pain induced by spinal nerve ligation in rats

Jiang

et al. 2016

Purinergic Signalling

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“…Mounting evidence indicates that estrogen plays an important role in an extensive spectrum of neural functions, such as nociception (1)(2)(3). The mechanisms by which estrogen modulates pain appear to be highly complex and remain to be elucidated.…”

mentioning

confidence: 99%

“…Estrogen has been reported to rapidly enhance excitatory synaptic transmission, especially via NMDA receptor (NMDAR) 2 -mediated synaptic activity and LTP (8 -13). Estrogen also promotes the formation of new dendritic spines and excitatory synapses in the hippocampus and cortex (13)(14)(15)(16).…”

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confidence: 99%

Estrogen Facilitates Spinal Cord Synaptic Transmission via Membrane-bound Estrogen Receptors

Zhang

Xiao

Zhang

et al. 2012

Journal of Biological Chemistry

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Background: Estrogen is involved in nociception. It is unclear whether estrogen affects spinal synaptic transmission and plasticity. Results: Estrogen facilitates NMDA transmission and spinal LTP via membrane estrogen receptor (mER)-initiated rapid signaling. Conclusion: Estrogen increases spinal nociceptive synaptic transmission via activation of mER and NMDA receptors. Significance: These results reveal a spinal mechanism by which estrogen enhances pain states.

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“…In the last decade, studies have demonstrated that the interactions between EphBRs and their ephrinB ligands modulate neural plasticity induction in the mammalian central nervous system, mainly, but not exclusively, via exhibiting effects on NMDAR (8,12). A recent study also demonstrated that, in association with thermal hyperalgesia, EphBR activation caused by immunoglobulin fusion protein of ephrinB2 (ephrinB2-Fc)-induced, Src kinase-dependent NR2B phosphorylation in the spinal cord (2), suggesting that ephrinB2-EphBR tyrosine kinase interactions could probably modulate pain signaling via spinal Src-dependent NMDAR phosphorylation (2).Although further proof is still needed for the physiological and/or pathophysiological relevance, the induction of pelvicurethra reflex potentiation (15, 16), a form of NR2B phosphorylation-dependent neural plasticity (5,25,31,41), has been linked to the development of visceral pain from pelvic organs (26,27,30,32,33). Studies have shown that the activation of nociceptive afferent fibers expressing transient receptor potential vanilloid/transient receptor potential ankyrin by the instillation of irritants into the uterus (32, 33) and the descending colon (29) facilitated pelvic-urethra reflex activity in a crossorgan manner.…”

mentioning

confidence: 99%

“…Although further proof is still needed for the physiological and/or pathophysiological relevance, the induction of pelvicurethra reflex potentiation (15, 16), a form of NR2B phosphorylation-dependent neural plasticity (5,25,31,41), has been linked to the development of visceral pain from pelvic organs (26,27,30,32,33). Studies have shown that the activation of nociceptive afferent fibers expressing transient receptor potential vanilloid/transient receptor potential ankyrin by the instillation of irritants into the uterus (32, 33) and the descending colon (29) facilitated pelvic-urethra reflex activity in a crossorgan manner.…”

mentioning

confidence: 99%

EphrinB2 induces pelvic-urethra reflex potentiation via Src kinase-dependent tyrosine phosphorylation of NR2B

Chang

Peng

et al. 2011

American Journal of Physiology-Renal Physiology

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Recently, the role of EphB receptor (EphBR) tyrosine kinase and their ephrinB ligands in painrelated neural plasticity at the spinal cord level have been identified. To test whether Src-family tyrosine kinase-dependent glutamatergic N-methyl-D-aspartate receptor NR2B subunit phosphorylation underlies lumbosacral spinal EphBR activation to mediate pelvic-urethra reflex potentiation, we recorded external urethra sphincter electromyogram reflex activity and analyzed protein expression in the lumbosacral (L6-S2) dorsal horn in response to intrathecal ephrinB2 injections. When compared with vehicle solution, exogenous ephrinB2 (5 g/rat it)-induced reflex potentiation, in associated with phosphorylation of EphB1/2, Src-family kinase, NR2B Y1336 and Y1472 tyrosine residues. Both intrathecal EphB1 and EphB2 immunoglobulin fusion protein (both 10 g/rat it) prevented ephrinB2-dependent reflex potentiation, as well as protein phosphorylation. Pretreatment with PP2 (50 M, 10 l it), an Src-family kinase antagonist, reversed the reflex potentiation, as well as Src kinase and NR2B phosphorylation. Together, these results suggest the ephrinB2-dependent EphBR activation, which subsequently provokes Src kinase-mediated N-methyl-D-aspartate receptor NR2B phosphorylation in the lumbosacral dorsal horn, is crucial for the induction of spinal reflex potentiation contributing to the development of visceral pain and/or hyperalgesia in the pelvic area. pelvic pain; urethra; Src-family kinase; N-methyl-D-aspartate IN THE LUMBOSACRAL DORSAL horn, neurotransmission mediated by glutamatergic N-methyl-D-aspartate receptors (NMDARs) has been implicated in processing nociceptive afferent inputs coming from the lower urinary tract (4, 10). Spinal administration of NMDAR agonists has dose-dependently facilitated the visceromotor reflex, together with pressor responses to pelvic noxious stimulation (14). Conversely, blockage of NMDAR using pharmacological antagonists has inhibited pain behavior caused by irritation of the pelvic viscera (24, 43). Among subunits of NMDAR, the role of the NR2B subunit in pain development has been intensively investigated, as electrophysiological studies have demonstrated that phosphorylation of specific NR2B tyrosine residues is an important determinant for NMDAR-mediated currents (22), which defines the role of NMDARs in pain-related neural plasticity (3,17,18,20). The signaling of Src kinases, a family of protooncogenic tyrosine kinases, has been shown to modulate NMDAR-mediated synaptic transmission and plasticity (1). In inflammatory animal models, the intrathecal administration of Src-family kinase inhibitors prevented spinal NR2B phosphorylation and behavior hyperalgesia, implying that Src-dependent phosphorylation of NMDAR NR2B subunits plays a crucial role in the development of postinflammatory pain and/or hyperalgesia (35).EphB receptors (EphBRs), transmembrane molecules, were initially identified as guidance cues during neural development (40). In the last decade, studies have demonstrated that the intera...

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Estrogen-dependent facilitation on spinal reflex potentiation involves the Cdk5/ERK1/2/NR2B cascade in anesthetized rats

Cited by 28 publications

References 93 publications

Microvesicles shed from microglia activated by the P2X7-p38 pathway are involved in neuropathic pain induced by spinal nerve ligation in rats

Microvesicles shed from microglia activated by the P2X7-p38 pathway are involved in neuropathic pain induced by spinal nerve ligation in rats

Estrogen Facilitates Spinal Cord Synaptic Transmission via Membrane-bound Estrogen Receptors

EphrinB2 induces pelvic-urethra reflex potentiation via Src kinase-dependent tyrosine phosphorylation of NR2B

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