Non-Hebbian plasticity at C-fiber synapses in rat spinal cord lamina I neurons

Naka, Asami; Gruber‐Schoffnegger, Doris; Sandkühler, Jürgen

doi:10.1016/j.pain.2013.04.011

Cited by 35 publications

(24 citation statements)

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“…Such a molecular diversity confers to these channels a variety of specific properties in different cell types and situations. VGCCs play a critical role in neuropathic pain development through the modulation of the release of excitatory neurotransmitters (31), calcium-dependent enzyme activation (32), gene regulation (32)(33)(34) and short-and long-term plasticity changes (35)(36)(37)(38). Abnormal regulation of VGCC subunits, such as α2δs, may contribute to pain signal transduction through several mechanisms including the induction of abnormal synaptogenesis (39,40).…”

Section: Disscussionmentioning

confidence: 99%

Comparative analysis of molecular signatures suggests the use of gabapentin for the management of endometriosis-associated pain

Bellessort

Bachelot

Grouthier

et al. 2018

Preprint

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Capsule: Comparative analysis of gene expression signatures from endometriosis and mouse models shows that CACNAα2δs calcium-channel components involved in nociception are targets for the treatment of endometriosis-associated pain.not peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was . http://dx.doi.org/10.1101/251397 doi: bioRxiv preprint first posted online Jan. 22, 2018; 2 Context: Differential gene expression analyses comparing endometriotic lesions to eutopic endometrium have shown that the transcription factors DLX5 and DLX6 are drastically downregulated in the ectopic implants. These finding suggests that regulatory cascades involving DLX5/6 might be involved in the origin of endometriosis symptoms such as chronic pelvic pain. We have shown that mice in which Dlx5 and Dlx6 are selectively inactivated in the uterus present an endometrial phenotype reminiscent of endometriosis implants.Objective: Identify new targets for the treatment of endometriosis.Design: To better focus the search for endometriosis targets we have compared the profile of genes deregulated in normal and ectopic women endometrium to those deregulated in the uterus of normal and Dlx5/Dlx6-null mice. Settings: Academic research unit and University Hospital research laboratoryAnimals: Mice carrying a uterus-specific deletion of Dlx5/Dlx6. Interventions: Analysis of archive sections from normal endometrium and endometriosis implants.Main Outcome: A novel endometriosis signature suggests that α2δs subunits of voltagegated calcium channel are targets for the management of endometriosis-associated pain. Results:We identify a signature of 30 genes similarly deregulated in human endometriosis implants and in Dlx5/6-null mouse uteri reinforcing the notion that the down-regulation of Dlx5/6 is an early event in the progress of endometriosis. CACNA2D3, a component of the voltage-dependent calcium channel complex is strongly overexpressed both in endometriosis implants and in mutant mouse uteri; other members of the alfa2delta family, CACNA2D1 and CACNA2D2, are also overexpressed in endometriosis.Conclusion: CACNA2D1, CACNA2D2 and CACNA2D3 are directly involved in pain perception. In particular, CACNA2D3 has been associated to pain sensitization and heat nociception in animal models while, in patients, variants of this gene are associated to reduced sensitivity to acute noxious stimuli. As CACNA2Ds are targets of gabapentinoids analgesics, our results suggest to consider the use of these drugs for the treatment of endometriosisassociated pain. Indeed, recent small-scale clinical studies have shown that gabapentin can be effective in the treatment of women chronic pelvic pain. Our findings reinforce the need for a large definitive trial.

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Section: Disscussionmentioning

confidence: 99%

Comparative analysis of molecular signatures suggests the use of gabapentin for the management of endometriosis-associated pain

Bellessort

Bachelot

Grouthier

et al. 2018

Preprint

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“…long-term facilitation of endogenous motoneuronal phrenic or hypoglossal activity following episodic asphyxia (Baker & Mitchell, 2000;Mitchell et al, 2001;Baker-Herman & Mitchell, 2002;Bocchiaro & Feldman, 2004;Dale-Nagle et al, 2010;Baker-Herman & Strey, 2011). Another example of such plasticity would be LTP corresponding to central secondary hyperalgesia in pain pathways (Naka et al, 2013), as it was evoked in the absence of any presynaptic conditioning stimulation and without changes in active or passive properties of the neurons. A common feature of these forms of plasticity and of the effects of local spinal polarization is the tendency for the long-lasting facilitation to develop fairly slowly (Bolzoni & Jankowska, 2015) (Figs 2-7).…”

Section: Activity-independent Long-lasting DC Actionsmentioning

confidence: 99%

“…A common feature of these forms of plasticity and of the effects of local spinal polarization is the tendency for the long-lasting facilitation to develop fairly slowly (Bolzoni & Jankowska, 2015) (Figs 2-7). The same mechanisms might thus contribute to the post-polarization DC effects and to long-term facilitation or LTP, including changes in aamino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor function caused by 5-hydroxytryptamine (serotonin) (Bocchiaro & Feldman, 2004), a rise in the postsynaptic Ca 2+ level resulting from postsynaptic depolarization (Wyllie et al, 1994;Naka et al, 2013), or the effects of DC on vesicular glutamate transporters (Preobraschenski et al, 2014). However, the direct effects evoked during DC application and those following DC polarization differ in several respects, and may be, to some extent, attributable to different mechanisms.…”

Section: Activity-independent Long-lasting DC Actionsmentioning

confidence: 99%

Evidence that some long‐lasting effects of direct current in the rat spinal cord are activity‐independent

Jankowska

Kaczmarek

Bolzoni

et al. 2016

Eur J of Neuroscience

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The effects of trans-spinal direct current (DC) stimulation (tsDCS) on specific neuronal populations are difficult to elucidate, as it affects a variety of neuronal networks. However, facilitatory and depressive effects on neurons processing information from the skin and from muscles can be evaluated separately when weak (0.2-0.3 μA) DC is applied within restricted areas of the rat spinal cord. The effects of such local DC application were recently demonstrated to persist for at least 1 h, and to include changes in the excitability of afferent fibres and their synaptic actions. However, whether these effects require activation of afferent fibres in spinal neuronal pathways during DC application, i.e. whether they are activity-dependent or activity-independent, remained an open question. The aim of the present study was to address this question by analysing the effects of local DC application on monosynaptic actions of muscle and skin afferents (extracellular field potentials) and afferent fibre excitability. The results revealed that long-lasting post-polarization changes evoked without concomitant activation of afferent fibres replicate changes evoked by stimuli applied during, before and after polarization. The study leads to the conclusion that the reported effects are activity-independent. As this conclusion applies to the local effects of DC application in at least two spinal pathways and to the effects of both cathodal and anodal polarization, it indicates that some of the more widespread effects of trans-spinal and trans-cranial stimulation (both tsDCS and transcranial DC stimulation) may be activity-independent. The results may therefore contribute to the design of more specific DC applications in clinical practice.

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“…It has also been reported that a rise in intracellular Ca 2+ levels of spinal lamina I neurons is enough to induce synaptic long‐term potentiation in the absence of any presynaptic stimulation (Naka et al . ).…”

Section: Discussionmentioning

confidence: 97%

Acute spatial spread of NO‐mediated potentiation during hindpaw ischaemia in mice

Onishi

Watanabe

Sasaki

et al. 2019

The Journal of Physiology

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Key points Neuropathic pain spreads spatially beyond the injured sites, and the mechanism underlying the spread has been attributed to inflammation occurring in the spinal cord.However, the spatial spread of spinal/cortical potentiation induced by conduction block of the peripheral nerves can be observed prior to inflammation.In the present study, we found that spreading potentiation and hypersensitivity acutely induced by unilateral hindpaw ischaemia are nitric oxide (NO)‐dependent and that NO is produced by ischaemia and quickly diffuses within the spinal cord.We also found that NO production induced by ischaemia is not observed in the presence of an antagonist for group II metabotropic glutamate receptors (mGluRs) and that neuronal NO synthase‐positive dorsal horn neurons express group II mGluRs.These results suggest strongly that NO‐mediated spreading potentiation in the spinal cord is one of the trigger mechanisms for neuropathic pain. AbstractCortical/spinal responses to hindpaw stimulation are bilaterally potentiated by unilateral hindpaw ischaemia in mice. We tested the hypothesis that hindpaw ischaemia produces nitric oxide (NO), which diffuses in the spinal cord to induce spatially spreading potentiation. Using flavoprotein fluorescence imaging, we confirmed that the spreading potentiation in hindpaw responses was induced during ischaemia in the non‐stimulated hindpaw. This spreading potentiation was blocked by spinal application of l‐NAME, an inhibitor of NO synthase (NOS). Furthermore, no spreading potentiation was observed in neural NOS (nNOS) knockout mice. Spinal application of an NO donor was enough to induce cortical potentiation and mechanical hypersensitivity. The spatial distribution of NO during unilateral hindpaw ischaemia was visualized using 4‐amino‐5‐methylamino‐2′,7′‐difluorofluorescein (DAF‐FM). An increase in fluorescence derived from the complex of DAF‐FM with NO was observed on the ischaemic side of the spinal cord. A similar but smaller increase was also observed on the contralateral side. Somatosensory potentiation after hindpaw ischaemia is known to be inhibited by spinal application of LY354740, an agonist of group II metabotropic glutamate receptors (mGluRs). We confirmed that the spinal DAF‐FM fluorescence increases during hindpaw ischaemia were not observed in the presence of LY354740. We also confirmed that approximately half of the nNOS‐positive neurons in the superficial laminae of the dorsal horn expressed mGluR2 mRNA. These results suggest that disinhibition of mGluR2 produces NO which in turn induces a spreading potentiation in a wide area of the spinal cord. Such spreading, along with the consequent non‐specific potentiation in the spinal cord, may trigger neuropathic pain.

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Non-Hebbian plasticity at C-fiber synapses in rat spinal cord lamina I neurons

Abstract: SummaryThis study identified and characterized non-Hebbian type LTP in nociceptive pathways, a potential synaptic mechanism of secondary hyperalgesia.

Cited by 35 publications

References 63 publications

Comparative analysis of molecular signatures suggests the use of gabapentin for the management of endometriosis-associated pain

Comparative analysis of molecular signatures suggests the use of gabapentin for the management of endometriosis-associated pain

Evidence that some long‐lasting effects of direct current in the rat spinal cord are activity‐independent

Acute spatial spread of NO‐mediated potentiation during hindpaw ischaemia in mice

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