Glial-derived neurotrophic factor regulates the expression of TREK2 in rat primary sensory neurons leading to attenuation of axotomy-induced neuropathic pain
Copyright © 2022 Elsevier Inc. All rights reserved..
TREK2 is a member of the 2-pore domain family of K+ channels (K2P) preferentially expressed by unmyelinated, slow-conducting and non-peptidergic isolectin B4-binding (IB4+) primary sensory neurons of the dorsal root ganglia (DRG). IB4+ neurons depend on the glial-derived neurotrophic factor (GDNF) family of ligands (GFL's) to maintain their phenotype. In our previous work, we demonstrated that 7 days after spinal nerve axotomy (SNA) of the L5 DRG, TREK2 moves away from the cell membrane resulting in a more depolarised resting membrane potential (Em). Given that axotomy deprives DRG neurons from peripherally-derived GFL's, we hypothesized that they might control the expression of TREK2. Using a combination of immunohistochemistry, immunocytochemistry, western blotting, in vivo pharmacological manipulation and behavioral tests we examined the ability of the GFL's (GDNF, neurturin and artemin) and their selective receptors (GFRα1, GFRα2 and GFRα3) to regulate the expression and function of TREK2 in the DRG. We found that TREK2 correlated strongly with the three receptors normally and ipsilaterally for all GFR's after SNA. GDNF, but not NGF, neurturin or artemin up-regulated the expression of TREK2 in cultured DRG neurons. In vivo continuous, subcutaneous administration of GDNF restored the subcellular distribution of TREK2 ipsilaterally and reversed mechanical and cold allodynia 7 days after SNA. This is the first demonstration that GDNF controls the expression of a K2P channel in nociceptors. As TREK2 controls the Em of C-nociceptors affecting their excitability, our finding has therapeutic potential in the treatment of chronic pain.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2022 |
|---|---|
| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:357 |
|---|---|
| Enthalten in: |
Experimental neurology - 357(2022) vom: 15. Nov., Seite 114190 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Messina, Diego N [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 09.09.2022 Date Revised 15.10.2022 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1016/j.expneurol.2022.114190 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM344272745 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM344272745 | ||
| 003 | DE-627 | ||
| 005 | 20231226022400.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2022 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.expneurol.2022.114190 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1147.xml |
| 035 | |a (DE-627)NLM344272745 | ||
| 035 | |a (NLM)35907583 | ||
| 035 | |a (PII)S0014-4886(22)00215-1 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Messina, Diego N |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Glial-derived neurotrophic factor regulates the expression of TREK2 in rat primary sensory neurons leading to attenuation of axotomy-induced neuropathic pain |
| 264 | 1 | |c 2022 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 09.09.2022 | ||
| 500 | |a Date Revised 15.10.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2022 Elsevier Inc. All rights reserved. | ||
| 520 | |a TREK2 is a member of the 2-pore domain family of K+ channels (K2P) preferentially expressed by unmyelinated, slow-conducting and non-peptidergic isolectin B4-binding (IB4+) primary sensory neurons of the dorsal root ganglia (DRG). IB4+ neurons depend on the glial-derived neurotrophic factor (GDNF) family of ligands (GFL's) to maintain their phenotype. In our previous work, we demonstrated that 7 days after spinal nerve axotomy (SNA) of the L5 DRG, TREK2 moves away from the cell membrane resulting in a more depolarised resting membrane potential (Em). Given that axotomy deprives DRG neurons from peripherally-derived GFL's, we hypothesized that they might control the expression of TREK2. Using a combination of immunohistochemistry, immunocytochemistry, western blotting, in vivo pharmacological manipulation and behavioral tests we examined the ability of the GFL's (GDNF, neurturin and artemin) and their selective receptors (GFRα1, GFRα2 and GFRα3) to regulate the expression and function of TREK2 in the DRG. We found that TREK2 correlated strongly with the three receptors normally and ipsilaterally for all GFR's after SNA. GDNF, but not NGF, neurturin or artemin up-regulated the expression of TREK2 in cultured DRG neurons. In vivo continuous, subcutaneous administration of GDNF restored the subcellular distribution of TREK2 ipsilaterally and reversed mechanical and cold allodynia 7 days after SNA. This is the first demonstration that GDNF controls the expression of a K2P channel in nociceptors. As TREK2 controls the Em of C-nociceptors affecting their excitability, our finding has therapeutic potential in the treatment of chronic pain | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Axotomy | |
| 650 | 4 | |a K2P | |
| 650 | 4 | |a Neuropathic pain | |
| 650 | 4 | |a Neurotrophins | |
| 650 | 4 | |a Primary sensory neurons | |
| 650 | 4 | |a TREK2 | |
| 650 | 7 | |a Glial Cell Line-Derived Neurotrophic Factor |2 NLM | |
| 650 | 7 | |a Kcnk10 protein, rat |2 NLM | |
| 650 | 7 | |a Neurturin |2 NLM | |
| 650 | 7 | |a Potassium Channels, Tandem Pore Domain |2 NLM | |
| 700 | 1 | |a Peralta, Emanuel D |e verfasserin |4 aut | |
| 700 | 1 | |a Acosta, Cristian G |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Experimental neurology |d 1959 |g 357(2022) vom: 15. Nov., Seite 114190 |w (DE-627)NLM000016624 |x 1090-2430 |7 nnns |
| 773 | 1 | 8 | |g volume:357 |g year:2022 |g day:15 |g month:11 |g pages:114190 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.expneurol.2022.114190 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 357 |j 2022 |b 15 |c 11 |h 114190 | ||