Early Changes of β-Catenins and Menins in Spinal Cord Dorsal Horn after Peripheral Nerve Injury

Zhang, Xiaoqin; Chen, Guoqiang; Xue, Qingsheng; Yu, Bo

doi:10.1007/s10571-010-9517-9

Cited by 20 publications

(20 citation statements)

References 37 publications

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“…It is considered that the transmission of touch sensation by Aβ-fibers is markedly perturbed in the SNI model. In fact, the levels of the β-catenin and menin proteins, which are involved in the formation of new synapses (25), and the number of neurons reacting to the Aβ-fiber stimulation (26) are increased in lamina II of the spinal dorsal horn of SNI rats. In dorsal root ganglia (DRG), macrophages form clusters around the cell bodies of A-fibers, but not small C-fibers, in the SNI model (27).…”

Section: Discussionmentioning

confidence: 99%

Contribution of TRPV1 Receptor^|^ndash;Expressing Fibers to Spinal Ventral Root After-Discharges and Mechanical Hyperalgesia in a Spared Nerve Injury (SNI) Rat Model

2013

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Abstract. Neuropathic pain induces allodynia and hyperalgesia. In the spared nerve injury (SNI) model, marked mechanical hyperalgesia is manifested as prolongation of the duration of paw withdrawal after pin stimulation. We have previously reported that spinal ventral root discharges (after-discharges) after cessation of noxious mechanical stimulation applied to the corresponding hindpaw were prolonged in anesthetized spinalized rats. Since these after-discharges occurred through transient receptor potential (TRP) V1-positive fibers, these fibers could contribute to mechanical hyperalgesia. Therefore, we examined whether selective deletion of TRPV1-positive fibers by resiniferatoxin, an ultrapotent TRPV1 agonist, would affect the behavioral changes and ventral root discharges in SNI rats. Mechanical allodynia in the von Frey test, mechanical hyperalgesia after pin stimulation, and enhancement of ventral root discharges, but not thermal hyperalgesia in the plantar test, appeared in Wistar rats with SNI. Mechanical hyperalgesia was abolished by treatment with resiniferatoxin, whereas mechanical allodynia was not affected. Moreover, resiniferatoxin eliminated after-discharges completely. These results show that TRPV1-positive fibers do not participate in the mechanical allodynia caused by sensitization of Aβ-fibers, but contribute to the enhancement of after-discharges and mechanical hyperalgesia following SNI. It is suggested that the mechanisms responsible for generating mechanical allodynia differ from those for prolongation of mechanical hyperalgesia.

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Section: Discussionmentioning

confidence: 99%

Contribution of TRPV1 Receptor^|^ndash;Expressing Fibers to Spinal Ventral Root After-Discharges and Mechanical Hyperalgesia in a Spared Nerve Injury (SNI) Rat Model

2013

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“…More relevantly, 3 days after L5 spinal nerve ligation, p-AKT expression in the spinal dorsal horn is increased (Xu et al, 2007). In a spared injury-induced neuropathic model, β-catenin has shown to be significantly increased 1 and 3 days following injury in the rat spinal cord (Zhang et al, 2010). Currently, activities of the AKT/GKS3β/β-catenin signaling pathway in the chronic phase of pathologic pain conditions (including neuropathic pain) are unknown.…”

Section: Discussionmentioning

confidence: 99%

Glycogen synthase kinase 3 beta regulates glial glutamate transporter protein expression in the spinal dorsal horn in rats with neuropathic pain

Weng

Gao

Maixner

2014

Experimental Neurology

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Dysfunctional glial glutamate transporters and over production of pro-inflammatory cytokines (including interleukin-1β, IL-1β) are two prominent mechanisms by which glial cells enhance neuronal activities in the spinal dorsal horn in neuropathic pain conditions. Endogenous molecules regulating production of IL-1β and glial glutamate functions remain poorly understood. In this study, we revealed a dynamic alteration of GSK3β activities and its role in regulating glial glutamate transporter 1 (GLT-1) protein expression in the spinal dorsal horn and nociceptive behaviors following the nerve injury. Specifically, GSK3β was expressed in both neurons and astrocytes in the spinal dorsal horn. GSK3β activities were suppressed on day 3 but increased on day 10 following the nerve injury. In parallel, protein expression of GLT-1 in the spinal dorsal horn was enhanced on day 3 but reduced on day 10. In contrast to these time-dependent changes, the activation of astrocytes and over-production of IL-1β were found on both day 3 and day 10. Meanwhile, thermal hyperalgesia was observed from day 2 through day 10 and mechanical allodynia from day 4 through day 10. Pre-emptive pharmacological inhibition of GSK3β activities significantly ameliorated thermal hyperalgesia and mechanical allodynia at the late stage but did not have effects at the early stage. These were accompanied with the suppression of GSK3β activities, prevention of decreased GLT-1 protein expression, inhibition of astrocytic activation, and reduction of IL-1β in the spinal dorsal horn on day 10. These data indicate that the increased GSK3β activity in the spinal dorsal horn is attributable to the downregulation of GLT-1 protein expression in neuropathic rats at the late stage. Further, we also demonstrated that the nerve-injury-induced thermal hyperalgesia on day 10 was transiently suppressed by pharmacological inhibition of GSK3β. Our study suggests that GSK3β may be a potential target for the development of analgesics for chronic neuropathic pain.

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“…neuroligin-neurexin 2, 3 ) signaling interactions. Mounting evidence from our group 4–6 and others 7–9 supports the conserved role of menin, the protein product of the MEN1 ( m ultiple e ndocrine n eoplasia type 1 ) tumor suppressor gene 10 , in mediating synapse formation and synaptic plasticity in the CNS. Studies on the role of menin as a tumor suppressor indicate that it is a multifunction scaffold protein that integrates extracellular and cell-cell signaling interactions, intracellular molecular cascades, and nuclear transcription 11 .…”

Section: Introductionmentioning

confidence: 54%

“…The upregulation of menin 7–9 and nAChR α5 subunit 60 expression in the spinal cord dorsal horn have both been reported to be required for the development of neuropathic pain after peripheral nerve injury. The transcriptional upregulation of the modulatory α5 subunit by menin, the contribution of α5 to high-conductance nAChR channels 50, 51 , and the enhanced presynaptic clustering of α7-containing nAChRs via C-menin, would all be consistent with the potentiation of nAChR-induced presynaptic facilitation and synaptic hyperexcitability during neuropathic pain.…”

Section: Discussionmentioning

confidence: 99%

Tumor suppressor menin is required for subunit-specific nAChR α5 transcription and nAChR-dependent presynaptic facilitation in cultured mouse hippocampal neurons

Getz

Visser

et al. 2017

Sci Rep

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In the central nervous system (CNS), cholinergic transmission induces synaptic plasticity that is required for learning and memory. However, our understanding of the development and maintenance of cholinergic circuits is limited, as the factors regulating the expression and clustering of neuronal nicotinic acetylcholine receptors (nAChRs) remain poorly defined. Recent studies from our group have implicated calpain-dependent proteolytic fragments of menin, the product of the MEN1 tumor suppressor gene, in coordinating the transcription and synaptic clustering of nAChRs in invertebrate central neurons. Here, we sought to determine whether an analogous cholinergic mechanism underlies menin’s synaptogenic function in the vertebrate CNS. Our data from mouse primary hippocampal cultures demonstrate that menin and its calpain-dependent C-terminal fragment (C-menin) regulate the subunit-specific transcription and synaptic clustering of neuronal nAChRs, respectively. MEN1 knockdown decreased nAChR α5 subunit expression, the clustering of α7 subunit-containing nAChRs at glutamatergic presynaptic terminals, and nicotine-induced presynaptic facilitation. Moreover, the number and function of glutamatergic synapses was unaffected by MEN1 knockdown, indicating that the synaptogenic actions of menin are specific to cholinergic regulation. Taken together, our results suggest that the influence of menin on synapse formation and synaptic plasticity occur via modulation of nAChR channel subunit composition and functional clustering.

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Early Changes of β-Catenins and Menins in Spinal Cord Dorsal Horn after Peripheral Nerve Injury

Cited by 20 publications

References 37 publications

Contribution of TRPV1 Receptor^|^ndash;Expressing Fibers to Spinal Ventral Root After-Discharges and Mechanical Hyperalgesia in a Spared Nerve Injury (SNI) Rat Model

Contribution of TRPV1 Receptor^|^ndash;Expressing Fibers to Spinal Ventral Root After-Discharges and Mechanical Hyperalgesia in a Spared Nerve Injury (SNI) Rat Model

Glycogen synthase kinase 3 beta regulates glial glutamate transporter protein expression in the spinal dorsal horn in rats with neuropathic pain

Tumor suppressor menin is required for subunit-specific nAChR α5 transcription and nAChR-dependent presynaptic facilitation in cultured mouse hippocampal neurons

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