Role of the excitability brake potassium current IKD in cold allodynia induced by chronic peripheral nerve injury

A. González, G. Ugarte, C. Restrepo, G. Herrera, R. Piña, J.A. Gómez-Sánchez, P. Orio, Rodolfo L Madrid Montecinos, María Pertusa Pastor

Research output: Contribution to journalArticle

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Abstract

Cold allodynia is a common symptom of neuropathic and inflammatory pain following peripheral nerve injury. The mechanisms under-lying this disabling sensory alteration are not entirely understood. In primary somatosensory neurons, cold sensitivity is mainly deter-mined by a functional counterbalance between cold-activated TRPM8 channels and Shaker-like Kv1.1-1.2 channels underlying the excitability brake current IKD. Here we studied the role of IKD in damage-triggered painful hypersensitivity to innocuous cold. We found that cold allodynia induced by chronic constriction injury (CCI) of the sciatic nerve in mice, was related to both an increase in the proportion of cold-sensitive neurons (CSNs) in DRGs contributing to the sciatic nerve, and a decrease in their cold temperature threshold. IKD density was reduced in high-threshold CSNs from CCI mice compared with sham animals, with no differences in cold-induced TRPM8-dependent current density. The electrophysiological properties and neurochemical profile of CSNs revealed an increase of nociceptive-like phenotype among neurons from CCI animals compared with sham mice. These results were validated using a mathe-matical model of CSNs, including IKD and TRPM8, showing that a reduction in IKD current density shifts the thermal threshold to higher temperatures and that the reduction of this current induces cold sensitivity in former cold-insensitive neurons expressing low levels of TRPM8-like current. Together, our results suggest that cold allodynia is largely due to a functional downregulation of IKD in both high-threshold CSNs and in a subpopulation of polymodal nociceptors expressing TRPM8, providing a general molecular and neural mechanism for this sensory alteration. © 2017 the authors.
LanguageEnglish
Pages3109-3126
Number of pages18
JournalJournal of Neuroscience
Volume37
Issue number12
DOIs
Publication statusPublished - 2017

Fingerprint

Peripheral Nerve Injuries
Hyperalgesia
Potassium
Neurons
Constriction
Sciatic Nerve
Wounds and Injuries
Nociceptors
Diagnosis-Related Groups
Neuralgia

Keywords

  • 4-AP
  • Kv1 channels
  • PBMC
  • Thermotransduction
  • TRPM8
  • α-DTx
  • calcium
  • Shaker potassium channel
  • transient receptor potential channel M8
  • potassium
  • transient receptor potential channel M
  • TRPM8 protein, mouse
  • adult
  • allodynia
  • animal cell
  • animal experiment
  • animal model
  • Article
  • axonal injury
  • chronic constriction injury
  • cold sensitivity
  • controlled study
  • down regulation
  • electrophysiology
  • gene repression
  • heterologous expression
  • human
  • human cell
  • male
  • mouse
  • nerve excitability
  • nonhuman
  • pain receptor
  • patch clamp technique
  • peripheral nerve injury
  • potassium current
  • priority journal
  • protein expression
  • sciatic nerve
  • sensory analysis
  • sensory nerve cell
  • temperature
  • thermoreceptor
  • young adult
  • adverse effects
  • animal
  • Bagg albino mouse
  • biological model
  • cell culture
  • channel gating
  • chronic disease
  • cold
  • complication
  • computer simulation
  • hyperalgesia
  • metabolism
  • pathophysiology
  • Peripheral Nerve Injuries
  • Animals
  • Cells, Cultured
  • Chronic Disease
  • Cold Temperature
  • Computer Simulation
  • Hyperalgesia
  • Ion Channel Gating
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Models, Neurological
  • Nociceptors
  • Potassium
  • TRPM Cation Channels

Cite this

Role of the excitability brake potassium current IKD in cold allodynia induced by chronic peripheral nerve injury. / González, A.; Ugarte, G.; Restrepo, C.; Herrera, G.; Piña, R.; Gómez-Sánchez, J.A.; Orio, P.; Madrid Montecinos, Rodolfo L; Pertusa Pastor, María.

In: Journal of Neuroscience, Vol. 37, No. 12, 2017, p. 3109-3126.

Research output: Contribution to journalArticle

González, A. ; Ugarte, G. ; Restrepo, C. ; Herrera, G. ; Piña, R. ; Gómez-Sánchez, J.A. ; Orio, P. ; Madrid Montecinos, Rodolfo L ; Pertusa Pastor, María. / Role of the excitability brake potassium current IKD in cold allodynia induced by chronic peripheral nerve injury. In: Journal of Neuroscience. 2017 ; Vol. 37, No. 12. pp. 3109-3126.
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title = "Role of the excitability brake potassium current IKD in cold allodynia induced by chronic peripheral nerve injury",
abstract = "Cold allodynia is a common symptom of neuropathic and inflammatory pain following peripheral nerve injury. The mechanisms under-lying this disabling sensory alteration are not entirely understood. In primary somatosensory neurons, cold sensitivity is mainly deter-mined by a functional counterbalance between cold-activated TRPM8 channels and Shaker-like Kv1.1-1.2 channels underlying the excitability brake current IKD. Here we studied the role of IKD in damage-triggered painful hypersensitivity to innocuous cold. We found that cold allodynia induced by chronic constriction injury (CCI) of the sciatic nerve in mice, was related to both an increase in the proportion of cold-sensitive neurons (CSNs) in DRGs contributing to the sciatic nerve, and a decrease in their cold temperature threshold. IKD density was reduced in high-threshold CSNs from CCI mice compared with sham animals, with no differences in cold-induced TRPM8-dependent current density. The electrophysiological properties and neurochemical profile of CSNs revealed an increase of nociceptive-like phenotype among neurons from CCI animals compared with sham mice. These results were validated using a mathe-matical model of CSNs, including IKD and TRPM8, showing that a reduction in IKD current density shifts the thermal threshold to higher temperatures and that the reduction of this current induces cold sensitivity in former cold-insensitive neurons expressing low levels of TRPM8-like current. Together, our results suggest that cold allodynia is largely due to a functional downregulation of IKD in both high-threshold CSNs and in a subpopulation of polymodal nociceptors expressing TRPM8, providing a general molecular and neural mechanism for this sensory alteration. {\circledC} 2017 the authors.",
keywords = "4-AP, Kv1 channels, PBMC, Thermotransduction, TRPM8, α-DTx, calcium, Shaker potassium channel, transient receptor potential channel M8, potassium, transient receptor potential channel M, TRPM8 protein, mouse, adult, allodynia, animal cell, animal experiment, animal model, Article, axonal injury, chronic constriction injury, cold sensitivity, controlled study, down regulation, electrophysiology, gene repression, heterologous expression, human, human cell, male, mouse, nerve excitability, nonhuman, pain receptor, patch clamp technique, peripheral nerve injury, potassium current, priority journal, protein expression, sciatic nerve, sensory analysis, sensory nerve cell, temperature, thermoreceptor, young adult, adverse effects, animal, Bagg albino mouse, biological model, cell culture, channel gating, chronic disease, cold, complication, computer simulation, hyperalgesia, metabolism, pathophysiology, Peripheral Nerve Injuries, Animals, Cells, Cultured, Chronic Disease, Cold Temperature, Computer Simulation, Hyperalgesia, Ion Channel Gating, Male, Mice, Mice, Inbred BALB C, Models, Neurological, Nociceptors, Potassium, TRPM Cation Channels",
author = "A. Gonz{\'a}lez and G. Ugarte and C. Restrepo and G. Herrera and R. Pi{\~n}a and J.A. G{\'o}mez-S{\'a}nchez and P. Orio and {Madrid Montecinos}, {Rodolfo L} and {Pertusa Pastor}, Mar{\'i}a",
note = "Cited By :3 Export Date: 11 June 2018 CODEN: JNRSD Correspondence Address: Madrid, R.; Universidad de Santiago de Chile, Alameda L. Bdo. O’Higgins 3363, Chile; email: rodolfo.madrid@usach.cl Chemicals/CAS: calcium, 7440-70-2, 14092-94-5; potassium, 7440-09-7; Potassium; TRPM Cation Channels; TRPM8 protein, mouse Funding details: METI, Ministry of Economy, Trade and Industry Funding details: WI177114, Pfizer Funding details: ACT-1113 Funding details: FB0008 Funding details: 1161733 Funding details: 11130144 Funding details: 1131064 Funding details: 1130862 Funding details: 3150431 Funding text: This work was supported by FONDECYT Grants 1161733 and 1131064 to R.M., 1130862 to P.O., 11130144 to M.P., and 3150431 to A.G., CONICYT Anillo Grant ACT-1113 to R.M., P.O., M.P., and G.U., and the Advanced Center for Electrical and Electronic Engineering CONICYT FB0008 to P.O. R.M. thanks Pfizer Inc. (WI177114) and VRIDEIUSACH. G.H. holds a CONICYT PhD fellowship. The Centro Interdisciplinario de Neurociencia de Valpara?so is a Millennium Science Institute funded by the Ministry of Economy, Chile. The funders had no role in study conception, design, data collection, and interpretation or in the decision to submit the manuscript for publication. We thank Drs. F. Viana and C. Belmonte for comments on the manuscript; and J. Salas, M. Campos, and R. Pino for excellent technical assistance. 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year = "2017",
doi = "10.1523/JNEUROSCI.3553-16.2017",
language = "English",
volume = "37",
pages = "3109--3126",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "12",

}

TY - JOUR

T1 - Role of the excitability brake potassium current IKD in cold allodynia induced by chronic peripheral nerve injury

AU - González, A.

AU - Ugarte, G.

AU - Restrepo, C.

AU - Herrera, G.

AU - Piña, R.

AU - Gómez-Sánchez, J.A.

AU - Orio, P.

AU - Madrid Montecinos, Rodolfo L

AU - Pertusa Pastor, María

N1 - Cited By :3 Export Date: 11 June 2018 CODEN: JNRSD Correspondence Address: Madrid, R.; Universidad de Santiago de Chile, Alameda L. Bdo. O’Higgins 3363, Chile; email: rodolfo.madrid@usach.cl Chemicals/CAS: calcium, 7440-70-2, 14092-94-5; potassium, 7440-09-7; Potassium; TRPM Cation Channels; TRPM8 protein, mouse Funding details: METI, Ministry of Economy, Trade and Industry Funding details: WI177114, Pfizer Funding details: ACT-1113 Funding details: FB0008 Funding details: 1161733 Funding details: 11130144 Funding details: 1131064 Funding details: 1130862 Funding details: 3150431 Funding text: This work was supported by FONDECYT Grants 1161733 and 1131064 to R.M., 1130862 to P.O., 11130144 to M.P., and 3150431 to A.G., CONICYT Anillo Grant ACT-1113 to R.M., P.O., M.P., and G.U., and the Advanced Center for Electrical and Electronic Engineering CONICYT FB0008 to P.O. R.M. thanks Pfizer Inc. (WI177114) and VRIDEIUSACH. G.H. holds a CONICYT PhD fellowship. The Centro Interdisciplinario de Neurociencia de Valpara?so is a Millennium Science Institute funded by the Ministry of Economy, Chile. The funders had no role in study conception, design, data collection, and interpretation or in the decision to submit the manuscript for publication. We thank Drs. F. Viana and C. Belmonte for comments on the manuscript; and J. Salas, M. Campos, and R. Pino for excellent technical assistance. 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PY - 2017

Y1 - 2017

N2 - Cold allodynia is a common symptom of neuropathic and inflammatory pain following peripheral nerve injury. The mechanisms under-lying this disabling sensory alteration are not entirely understood. In primary somatosensory neurons, cold sensitivity is mainly deter-mined by a functional counterbalance between cold-activated TRPM8 channels and Shaker-like Kv1.1-1.2 channels underlying the excitability brake current IKD. Here we studied the role of IKD in damage-triggered painful hypersensitivity to innocuous cold. We found that cold allodynia induced by chronic constriction injury (CCI) of the sciatic nerve in mice, was related to both an increase in the proportion of cold-sensitive neurons (CSNs) in DRGs contributing to the sciatic nerve, and a decrease in their cold temperature threshold. IKD density was reduced in high-threshold CSNs from CCI mice compared with sham animals, with no differences in cold-induced TRPM8-dependent current density. The electrophysiological properties and neurochemical profile of CSNs revealed an increase of nociceptive-like phenotype among neurons from CCI animals compared with sham mice. These results were validated using a mathe-matical model of CSNs, including IKD and TRPM8, showing that a reduction in IKD current density shifts the thermal threshold to higher temperatures and that the reduction of this current induces cold sensitivity in former cold-insensitive neurons expressing low levels of TRPM8-like current. Together, our results suggest that cold allodynia is largely due to a functional downregulation of IKD in both high-threshold CSNs and in a subpopulation of polymodal nociceptors expressing TRPM8, providing a general molecular and neural mechanism for this sensory alteration. © 2017 the authors.

AB - Cold allodynia is a common symptom of neuropathic and inflammatory pain following peripheral nerve injury. The mechanisms under-lying this disabling sensory alteration are not entirely understood. In primary somatosensory neurons, cold sensitivity is mainly deter-mined by a functional counterbalance between cold-activated TRPM8 channels and Shaker-like Kv1.1-1.2 channels underlying the excitability brake current IKD. Here we studied the role of IKD in damage-triggered painful hypersensitivity to innocuous cold. We found that cold allodynia induced by chronic constriction injury (CCI) of the sciatic nerve in mice, was related to both an increase in the proportion of cold-sensitive neurons (CSNs) in DRGs contributing to the sciatic nerve, and a decrease in their cold temperature threshold. IKD density was reduced in high-threshold CSNs from CCI mice compared with sham animals, with no differences in cold-induced TRPM8-dependent current density. The electrophysiological properties and neurochemical profile of CSNs revealed an increase of nociceptive-like phenotype among neurons from CCI animals compared with sham mice. These results were validated using a mathe-matical model of CSNs, including IKD and TRPM8, showing that a reduction in IKD current density shifts the thermal threshold to higher temperatures and that the reduction of this current induces cold sensitivity in former cold-insensitive neurons expressing low levels of TRPM8-like current. Together, our results suggest that cold allodynia is largely due to a functional downregulation of IKD in both high-threshold CSNs and in a subpopulation of polymodal nociceptors expressing TRPM8, providing a general molecular and neural mechanism for this sensory alteration. © 2017 the authors.

KW - 4-AP

KW - Kv1 channels

KW - PBMC

KW - Thermotransduction

KW - TRPM8

KW - α-DTx

KW - calcium

KW - Shaker potassium channel

KW - transient receptor potential channel M8

KW - potassium

KW - transient receptor potential channel M

KW - TRPM8 protein, mouse

KW - adult

KW - allodynia

KW - animal cell

KW - animal experiment

KW - animal model

KW - Article

KW - axonal injury

KW - chronic constriction injury

KW - cold sensitivity

KW - controlled study

KW - down regulation

KW - electrophysiology

KW - gene repression

KW - heterologous expression

KW - human

KW - human cell

KW - male

KW - mouse

KW - nerve excitability

KW - nonhuman

KW - pain receptor

KW - patch clamp technique

KW - peripheral nerve injury

KW - potassium current

KW - priority journal

KW - protein expression

KW - sciatic nerve

KW - sensory analysis

KW - sensory nerve cell

KW - temperature

KW - thermoreceptor

KW - young adult

KW - adverse effects

KW - animal

KW - Bagg albino mouse

KW - biological model

KW - cell culture

KW - channel gating

KW - chronic disease

KW - cold

KW - complication

KW - computer simulation

KW - hyperalgesia

KW - metabolism

KW - pathophysiology

KW - Peripheral Nerve Injuries

KW - Animals

KW - Cells, Cultured

KW - Chronic Disease

KW - Cold Temperature

KW - Computer Simulation

KW - Hyperalgesia

KW - Ion Channel Gating

KW - Male

KW - Mice

KW - Mice, Inbred BALB C

KW - Models, Neurological

KW - Nociceptors

KW - Potassium

KW - TRPM Cation Channels

U2 - 10.1523/JNEUROSCI.3553-16.2017

DO - 10.1523/JNEUROSCI.3553-16.2017

M3 - Article

VL - 37

SP - 3109

EP - 3126

JO - Journal of Neuroscience

T2 - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 12

ER -