Targeted overexpression of tumor necrosis factor-α increases cyclin-dependent kinase 5 activity and TRPV1-dependent Ca2+ influx in trigeminal neurons

P. Rozas, P. Lazcano, R. Piña, A. Cho, A. Terse, C. Gonzalez-Billault, A.B. Kulkarni, E. Utreras, Rodolfo L Madrid Montecinos, María Pertusa Pastor

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Abstract

We reported earlier that TNF-α, a proinflammatory cytokine implicated in many inflammatory disorders causing orofacial pain, increases the activity of Cdk5, a key kinase involved in brain development and function and recently found to be involved in pain signaling. To investigate a potential mechanism underlying inflammatory pain in trigeminal ganglia (TGs), we engineered a transgenic mouse model (TNF glo) that can conditionally overexpresses TNF-α upon genomic recombination by Cre recombinase. TNF glo mice were bred with Nav1.8-Cre mouse line that expresses the Cre recombinase in sensory neurons to obtain TNF-α:Nav1.8-Cre (TNF-α cTg) mice. Although TNF-α cTg mice appeared normal without any gross phenotype, they displayed a significant increase in TNF-α levels after activation of NFB signaling in the TG. IL-6 and MCP-1 levels were also increased along with intense immunostaining for Iba1 and GFAP in TG, indicating the presence of infiltrating macrophages and the activation of satellite glial cells. TNF-α cTg mice displayed increased trigeminal Cdk5 activity, and this increase was associated with elevated levels of phospho-T407-TRPV1 and capsaicin-evocated Ca 2+ influx in cultured trigeminal neurons. Remarkably, this effect was prevented by roscovitine, an inhibitor of Cdk5, which suggests that TNF-α overexpression induced sensitization of the TRPV1 channel. Furthermore, TNF-α cTg mice displayed more aversive behavior to noxious thermal stimulation (45°C) of the face in an operant pain assessment device as compared with control mice. In summary, TNF-α overexpression in the sensory neurons of TNF-α cTg mice results in inflammatory sensitization and increased Cdk5 activity; therefore, this mouse model would be valuable for investigating the mechanism of TNF-α involved in orofacial pain. © 2016 International Association for the Study of Pain.
LanguageEnglish
Pages1346-1362
Number of pages17
JournalPain
Volume157
Issue number6
DOIs
StatePublished - 2016

Fingerprint

Cyclin-Dependent Kinase 5
Tumor Necrosis Factor-alpha
Neurons
Trigeminal Ganglion
Facial Pain
Sensory Receptor Cells
Pain
Macrophage Activation
Capsaicin
Pain Measurement
Neuroglia
Transgenic Mice
Genetic Recombination

Keywords

  • Cdk5
  • Inflammation
  • Orofacial pain
  • TNF-α
  • TRPV1
  • calcium
  • capsaicin
  • cre recombinase
  • cyclin dependent kinase 5
  • early growth response factor 1
  • glial fibrillary acidic protein
  • Iba1 protein
  • interleukin 6
  • messenger RNA
  • mitogen activated protein kinase 1
  • mitogen activated protein kinase 3
  • monocyte chemotactic protein 1
  • nerve protein
  • protein p35
  • roscovitine
  • tumor necrosis factor alpha
  • unclassified drug
  • vanilloid receptor 1
  • TRPV1 protein, mouse
  • tumor necrosis factor
  • vanilloid receptor
  • animal cell
  • animal experiment
  • animal tissue
  • Article
  • aversive behavior
  • calcium transport
  • cell activation
  • cell infiltration
  • controlled study
  • enzyme activity
  • face pain
  • genetic recombination
  • HEK293 cell line
  • immunohistochemistry
  • inflammatory pain
  • macrophage
  • mouse
  • mouth pain
  • nociceptive stimulation
  • nonhuman
  • pain assessment
  • priority journal
  • protein expression
  • satellite cell
  • sensitization
  • sensory nerve cell
  • signal transduction
  • thermal stimulation
  • trigeminus ganglion
  • animal
  • genetics
  • metabolism
  • transgenic mouse
  • Animals
  • Calcium
  • Chemokine CCL2
  • Cyclin-Dependent Kinase 5
  • Macrophages
  • Mice
  • Mice, Transgenic
  • Sensory Receptor Cells
  • Trigeminal Ganglion
  • TRPV Cation Channels
  • Tumor Necrosis Factor-alpha

Cite this

Targeted overexpression of tumor necrosis factor-α increases cyclin-dependent kinase 5 activity and TRPV1-dependent Ca2+ influx in trigeminal neurons. / Rozas, P.; Lazcano, P.; Piña, R.; Cho, A.; Terse, A.; Gonzalez-Billault, C.; Kulkarni, A.B.; Utreras, E.; Madrid Montecinos, Rodolfo L; Pertusa Pastor, María.

In: Pain, Vol. 157, No. 6, 2016, p. 1346-1362.

Research output: Contribution to journalArticle

Rozas, P. ; Lazcano, P. ; Piña, R. ; Cho, A. ; Terse, A. ; Gonzalez-Billault, C. ; Kulkarni, A.B. ; Utreras, E. ; Madrid Montecinos, Rodolfo L ; Pertusa Pastor, María. / Targeted overexpression of tumor necrosis factor-α increases cyclin-dependent kinase 5 activity and TRPV1-dependent Ca2+ influx in trigeminal neurons. In: Pain. 2016 ; Vol. 157, No. 6. pp. 1346-1362
@article{3a5bfb524e3c4a9291e57b4f2b616ca9,
title = "Targeted overexpression of tumor necrosis factor-α increases cyclin-dependent kinase 5 activity and TRPV1-dependent Ca2+ influx in trigeminal neurons",
abstract = "We reported earlier that TNF-α, a proinflammatory cytokine implicated in many inflammatory disorders causing orofacial pain, increases the activity of Cdk5, a key kinase involved in brain development and function and recently found to be involved in pain signaling. To investigate a potential mechanism underlying inflammatory pain in trigeminal ganglia (TGs), we engineered a transgenic mouse model (TNF glo) that can conditionally overexpresses TNF-α upon genomic recombination by Cre recombinase. TNF glo mice were bred with Nav1.8-Cre mouse line that expresses the Cre recombinase in sensory neurons to obtain TNF-α:Nav1.8-Cre (TNF-α cTg) mice. Although TNF-α cTg mice appeared normal without any gross phenotype, they displayed a significant increase in TNF-α levels after activation of NFB signaling in the TG. IL-6 and MCP-1 levels were also increased along with intense immunostaining for Iba1 and GFAP in TG, indicating the presence of infiltrating macrophages and the activation of satellite glial cells. TNF-α cTg mice displayed increased trigeminal Cdk5 activity, and this increase was associated with elevated levels of phospho-T407-TRPV1 and capsaicin-evocated Ca 2+ influx in cultured trigeminal neurons. Remarkably, this effect was prevented by roscovitine, an inhibitor of Cdk5, which suggests that TNF-α overexpression induced sensitization of the TRPV1 channel. Furthermore, TNF-α cTg mice displayed more aversive behavior to noxious thermal stimulation (45°C) of the face in an operant pain assessment device as compared with control mice. In summary, TNF-α overexpression in the sensory neurons of TNF-α cTg mice results in inflammatory sensitization and increased Cdk5 activity; therefore, this mouse model would be valuable for investigating the mechanism of TNF-α involved in orofacial pain. {\circledC} 2016 International Association for the Study of Pain.",
keywords = "Cdk5, Inflammation, Orofacial pain, TNF-α, TRPV1, calcium, capsaicin, cre recombinase, cyclin dependent kinase 5, early growth response factor 1, glial fibrillary acidic protein, Iba1 protein, interleukin 6, messenger RNA, mitogen activated protein kinase 1, mitogen activated protein kinase 3, monocyte chemotactic protein 1, nerve protein, protein p35, roscovitine, tumor necrosis factor alpha, unclassified drug, vanilloid receptor 1, TRPV1 protein, mouse, tumor necrosis factor, vanilloid receptor, animal cell, animal experiment, animal tissue, Article, aversive behavior, calcium transport, cell activation, cell infiltration, controlled study, enzyme activity, face pain, genetic recombination, HEK293 cell line, immunohistochemistry, inflammatory pain, macrophage, mouse, mouth pain, nociceptive stimulation, nonhuman, pain assessment, priority journal, protein expression, satellite cell, sensitization, sensory nerve cell, signal transduction, thermal stimulation, trigeminus ganglion, animal, genetics, metabolism, transgenic mouse, Animals, Calcium, Chemokine CCL2, Cyclin-Dependent Kinase 5, Macrophages, Mice, Mice, Transgenic, Sensory Receptor Cells, Trigeminal Ganglion, TRPV Cation Channels, Tumor Necrosis Factor-alpha",
author = "P. Rozas and P. Lazcano and R. Pi{\~n}a and A. Cho and A. Terse and C. Gonzalez-Billault and A.B. Kulkarni and E. Utreras and {Madrid Montecinos}, {Rodolfo L} and {Pertusa Pastor}, Mar{\'i}a",
note = "Cited By :10 Export Date: 11 June 2018 CODEN: PAIND Correspondence Address: Utreras, E.; Department of Biology, Faculty of Sciences, Universidad de Chile, Las Palmeras 3425, Chile; email: elias.utreras@uchile.cl Chemicals/CAS: calcium, 7440-70-2, 14092-94-5; capsaicin, 404-86-4; mitogen activated protein kinase 1, 137632-08-7; mitogen activated protein kinase 3, 137632-07-6; roscovitine, 186692-46-6; vanilloid receptor 1, 363242-41-5; Calcium; Chemokine CCL2; Cyclin-Dependent Kinase 5; TRPV Cation Channels; TRPV1 protein, mouse; Tumor Necrosis Factor-alpha Funding details: FONDECYT 1131064 Funding details: FONDECYT 11130144 Funding details: ACT-1113 Funding details: ACT-1114 Funding details: NIH, National Institutes of Health Funding details: 11110136 Funding details: FONDECYT 1140325 Funding details: PAI-79100009 Funding details: 1151043 Funding details: NIDCR, National Institute of Dental and Craniofacial Research Funding text: This work was supported by FONDECYT 11110136 and 1151043, and PAI-79100009 (to E.U.), and FONDECYT 1140325 and ACT-1114 (to C.G.-B.); FONDECYT 1131064 (to R.M.) and ACT-1113 (to R.M. and M.P.); FONDECYT 11130144 (to M.P.); and the Division of Intramural Research, National Institute of Dental and Craniofacial Research, National Institutes of Health. 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year = "2016",
doi = "10.1097/j.pain.0000000000000527",
language = "English",
volume = "157",
pages = "1346--1362",
journal = "Pain",
issn = "0304-3959",
publisher = "Lippincott Williams and Wilkins",
number = "6",

}

TY - JOUR

T1 - Targeted overexpression of tumor necrosis factor-α increases cyclin-dependent kinase 5 activity and TRPV1-dependent Ca2+ influx in trigeminal neurons

AU - Rozas,P.

AU - Lazcano,P.

AU - Piña,R.

AU - Cho,A.

AU - Terse,A.

AU - Gonzalez-Billault,C.

AU - Kulkarni,A.B.

AU - Utreras,E.

AU - Madrid Montecinos,Rodolfo L

AU - Pertusa Pastor,María

N1 - Cited By :10 Export Date: 11 June 2018 CODEN: PAIND Correspondence Address: Utreras, E.; Department of Biology, Faculty of Sciences, Universidad de Chile, Las Palmeras 3425, Chile; email: elias.utreras@uchile.cl Chemicals/CAS: calcium, 7440-70-2, 14092-94-5; capsaicin, 404-86-4; mitogen activated protein kinase 1, 137632-08-7; mitogen activated protein kinase 3, 137632-07-6; roscovitine, 186692-46-6; vanilloid receptor 1, 363242-41-5; Calcium; Chemokine CCL2; Cyclin-Dependent Kinase 5; TRPV Cation Channels; TRPV1 protein, mouse; Tumor Necrosis Factor-alpha Funding details: FONDECYT 1131064 Funding details: FONDECYT 11130144 Funding details: ACT-1113 Funding details: ACT-1114 Funding details: NIH, National Institutes of Health Funding details: 11110136 Funding details: FONDECYT 1140325 Funding details: PAI-79100009 Funding details: 1151043 Funding details: NIDCR, National Institute of Dental and Craniofacial Research Funding text: This work was supported by FONDECYT 11110136 and 1151043, and PAI-79100009 (to E.U.), and FONDECYT 1140325 and ACT-1114 (to C.G.-B.); FONDECYT 1131064 (to R.M.) and ACT-1113 (to R.M. and M.P.); FONDECYT 11130144 (to M.P.); and the Division of Intramural Research, National Institute of Dental and Craniofacial Research, National Institutes of Health. 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PY - 2016

Y1 - 2016

N2 - We reported earlier that TNF-α, a proinflammatory cytokine implicated in many inflammatory disorders causing orofacial pain, increases the activity of Cdk5, a key kinase involved in brain development and function and recently found to be involved in pain signaling. To investigate a potential mechanism underlying inflammatory pain in trigeminal ganglia (TGs), we engineered a transgenic mouse model (TNF glo) that can conditionally overexpresses TNF-α upon genomic recombination by Cre recombinase. TNF glo mice were bred with Nav1.8-Cre mouse line that expresses the Cre recombinase in sensory neurons to obtain TNF-α:Nav1.8-Cre (TNF-α cTg) mice. Although TNF-α cTg mice appeared normal without any gross phenotype, they displayed a significant increase in TNF-α levels after activation of NFB signaling in the TG. IL-6 and MCP-1 levels were also increased along with intense immunostaining for Iba1 and GFAP in TG, indicating the presence of infiltrating macrophages and the activation of satellite glial cells. TNF-α cTg mice displayed increased trigeminal Cdk5 activity, and this increase was associated with elevated levels of phospho-T407-TRPV1 and capsaicin-evocated Ca 2+ influx in cultured trigeminal neurons. Remarkably, this effect was prevented by roscovitine, an inhibitor of Cdk5, which suggests that TNF-α overexpression induced sensitization of the TRPV1 channel. Furthermore, TNF-α cTg mice displayed more aversive behavior to noxious thermal stimulation (45°C) of the face in an operant pain assessment device as compared with control mice. In summary, TNF-α overexpression in the sensory neurons of TNF-α cTg mice results in inflammatory sensitization and increased Cdk5 activity; therefore, this mouse model would be valuable for investigating the mechanism of TNF-α involved in orofacial pain. © 2016 International Association for the Study of Pain.

AB - We reported earlier that TNF-α, a proinflammatory cytokine implicated in many inflammatory disorders causing orofacial pain, increases the activity of Cdk5, a key kinase involved in brain development and function and recently found to be involved in pain signaling. To investigate a potential mechanism underlying inflammatory pain in trigeminal ganglia (TGs), we engineered a transgenic mouse model (TNF glo) that can conditionally overexpresses TNF-α upon genomic recombination by Cre recombinase. TNF glo mice were bred with Nav1.8-Cre mouse line that expresses the Cre recombinase in sensory neurons to obtain TNF-α:Nav1.8-Cre (TNF-α cTg) mice. Although TNF-α cTg mice appeared normal without any gross phenotype, they displayed a significant increase in TNF-α levels after activation of NFB signaling in the TG. IL-6 and MCP-1 levels were also increased along with intense immunostaining for Iba1 and GFAP in TG, indicating the presence of infiltrating macrophages and the activation of satellite glial cells. TNF-α cTg mice displayed increased trigeminal Cdk5 activity, and this increase was associated with elevated levels of phospho-T407-TRPV1 and capsaicin-evocated Ca 2+ influx in cultured trigeminal neurons. Remarkably, this effect was prevented by roscovitine, an inhibitor of Cdk5, which suggests that TNF-α overexpression induced sensitization of the TRPV1 channel. Furthermore, TNF-α cTg mice displayed more aversive behavior to noxious thermal stimulation (45°C) of the face in an operant pain assessment device as compared with control mice. In summary, TNF-α overexpression in the sensory neurons of TNF-α cTg mice results in inflammatory sensitization and increased Cdk5 activity; therefore, this mouse model would be valuable for investigating the mechanism of TNF-α involved in orofacial pain. © 2016 International Association for the Study of Pain.

KW - Cdk5

KW - Inflammation

KW - Orofacial pain

KW - TNF-α

KW - TRPV1

KW - calcium

KW - capsaicin

KW - cre recombinase

KW - cyclin dependent kinase 5

KW - early growth response factor 1

KW - glial fibrillary acidic protein

KW - Iba1 protein

KW - interleukin 6

KW - messenger RNA

KW - mitogen activated protein kinase 1

KW - mitogen activated protein kinase 3

KW - monocyte chemotactic protein 1

KW - nerve protein

KW - protein p35

KW - roscovitine

KW - tumor necrosis factor alpha

KW - unclassified drug

KW - vanilloid receptor 1

KW - TRPV1 protein, mouse

KW - tumor necrosis factor

KW - vanilloid receptor

KW - animal cell

KW - animal experiment

KW - animal tissue

KW - Article

KW - aversive behavior

KW - calcium transport

KW - cell activation

KW - cell infiltration

KW - controlled study

KW - enzyme activity

KW - face pain

KW - genetic recombination

KW - HEK293 cell line

KW - immunohistochemistry

KW - inflammatory pain

KW - macrophage

KW - mouse

KW - mouth pain

KW - nociceptive stimulation

KW - nonhuman

KW - pain assessment

KW - priority journal

KW - protein expression

KW - satellite cell

KW - sensitization

KW - sensory nerve cell

KW - signal transduction

KW - thermal stimulation

KW - trigeminus ganglion

KW - animal

KW - genetics

KW - metabolism

KW - transgenic mouse

KW - Animals

KW - Calcium

KW - Chemokine CCL2

KW - Cyclin-Dependent Kinase 5

KW - Macrophages

KW - Mice

KW - Mice, Transgenic

KW - Sensory Receptor Cells

KW - Trigeminal Ganglion

KW - TRPV Cation Channels

KW - Tumor Necrosis Factor-alpha

U2 - 10.1097/j.pain.0000000000000527

DO - 10.1097/j.pain.0000000000000527

M3 - Article

VL - 157

SP - 1346

EP - 1362

JO - Pain

T2 - Pain

JF - Pain

SN - 0304-3959

IS - 6

ER -