Dual contribution of ASIC1a channels in the spinal processing of pain information by deep projection neurons revealed by computational modeling.
Dorsal horn of the spinal cord is an important crossroad of pain neuraxis, especially for the neuronal plasticity mechanisms that can lead to chronic pain states. Windup is a well-known spinal pain facilitation process initially described several decades ago, but its exact mechanism is still not ful...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2023-04-01
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| Series: | PLoS Computational Biology |
| Online Access: | https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1010993&type=printable |
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| author | Magda Chafaï Ariane Delrocq Perrine Inquimbert Ludivine Pidoux Kevin Delanoe Maurizio Toft Frederic Brau Eric Lingueglia Romain Veltz Emmanuel Deval |
| author_facet | Magda Chafaï Ariane Delrocq Perrine Inquimbert Ludivine Pidoux Kevin Delanoe Maurizio Toft Frederic Brau Eric Lingueglia Romain Veltz Emmanuel Deval |
| author_sort | Magda Chafaï |
| collection | DOAJ |
| description | Dorsal horn of the spinal cord is an important crossroad of pain neuraxis, especially for the neuronal plasticity mechanisms that can lead to chronic pain states. Windup is a well-known spinal pain facilitation process initially described several decades ago, but its exact mechanism is still not fully understood. Here, we combine both ex vivo and in vivo electrophysiological recordings of rat spinal neurons with computational modeling to demonstrate a role for ASIC1a-containing channels in the windup process. Spinal application of the ASIC1a inhibitory venom peptides mambalgin-1 and psalmotoxin-1 (PcTx1) significantly reduces the ability of deep wide dynamic range (WDR) neurons to develop windup in vivo. All deep WDR-like neurons recorded from spinal slices exhibit an ASIC current with biophysical and pharmacological characteristics consistent with functional expression of ASIC1a homomeric channels. A computational model of WDR neuron supplemented with different ASIC1a channel parameters accurately reproduces the experimental data, further supporting a positive contribution of these channels to windup. It also predicts a calcium-dependent windup decrease for elevated ASIC conductances, a phenomenon that was experimentally validated using the Texas coral snake ASIC-activating toxin (MitTx) and calcium-activated potassium channel inhibitory peptides (apamin and iberiotoxin). This study supports a dual contribution to windup of calcium permeable ASIC1a channels in deep laminae projecting neurons, promoting it upon moderate channel activity, but ultimately leading to calcium-dependent windup inhibition associated to potassium channels when activity increases. |
| format | Article |
| id | doaj-art-8145c22d0aba4767bbe0cc391ea7fa9b |
| institution | DOAJ |
| issn | 1553-734X 1553-7358 |
| language | English |
| publishDate | 2023-04-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Computational Biology |
| spelling | doaj-art-8145c22d0aba4767bbe0cc391ea7fa9b2025-08-20T03:02:03ZengPublic Library of Science (PLoS)PLoS Computational Biology1553-734X1553-73582023-04-01194e101099310.1371/journal.pcbi.1010993Dual contribution of ASIC1a channels in the spinal processing of pain information by deep projection neurons revealed by computational modeling.Magda ChafaïAriane DelrocqPerrine InquimbertLudivine PidouxKevin DelanoeMaurizio ToftFrederic BrauEric LinguegliaRomain VeltzEmmanuel DevalDorsal horn of the spinal cord is an important crossroad of pain neuraxis, especially for the neuronal plasticity mechanisms that can lead to chronic pain states. Windup is a well-known spinal pain facilitation process initially described several decades ago, but its exact mechanism is still not fully understood. Here, we combine both ex vivo and in vivo electrophysiological recordings of rat spinal neurons with computational modeling to demonstrate a role for ASIC1a-containing channels in the windup process. Spinal application of the ASIC1a inhibitory venom peptides mambalgin-1 and psalmotoxin-1 (PcTx1) significantly reduces the ability of deep wide dynamic range (WDR) neurons to develop windup in vivo. All deep WDR-like neurons recorded from spinal slices exhibit an ASIC current with biophysical and pharmacological characteristics consistent with functional expression of ASIC1a homomeric channels. A computational model of WDR neuron supplemented with different ASIC1a channel parameters accurately reproduces the experimental data, further supporting a positive contribution of these channels to windup. It also predicts a calcium-dependent windup decrease for elevated ASIC conductances, a phenomenon that was experimentally validated using the Texas coral snake ASIC-activating toxin (MitTx) and calcium-activated potassium channel inhibitory peptides (apamin and iberiotoxin). This study supports a dual contribution to windup of calcium permeable ASIC1a channels in deep laminae projecting neurons, promoting it upon moderate channel activity, but ultimately leading to calcium-dependent windup inhibition associated to potassium channels when activity increases.https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1010993&type=printable |
| spellingShingle | Magda Chafaï Ariane Delrocq Perrine Inquimbert Ludivine Pidoux Kevin Delanoe Maurizio Toft Frederic Brau Eric Lingueglia Romain Veltz Emmanuel Deval Dual contribution of ASIC1a channels in the spinal processing of pain information by deep projection neurons revealed by computational modeling. PLoS Computational Biology |
| title | Dual contribution of ASIC1a channels in the spinal processing of pain information by deep projection neurons revealed by computational modeling. |
| title_full | Dual contribution of ASIC1a channels in the spinal processing of pain information by deep projection neurons revealed by computational modeling. |
| title_fullStr | Dual contribution of ASIC1a channels in the spinal processing of pain information by deep projection neurons revealed by computational modeling. |
| title_full_unstemmed | Dual contribution of ASIC1a channels in the spinal processing of pain information by deep projection neurons revealed by computational modeling. |
| title_short | Dual contribution of ASIC1a channels in the spinal processing of pain information by deep projection neurons revealed by computational modeling. |
| title_sort | dual contribution of asic1a channels in the spinal processing of pain information by deep projection neurons revealed by computational modeling |
| url | https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1010993&type=printable |
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