PMID- 37793537
OWN - NLM
STAT- MEDLINE
DCOM- 20240122
LR  - 20240207
IS  - 1528-8447 (Electronic)
IS  - 1526-5900 (Print)
IS  - 1526-5900 (Linking)
VI  - 25
IP  - 2
DP  - 2024 Feb
TI  - Hypernegative GABA(A) Reversal Potential in Pyramidal Cells Contributes to Medial 
      Prefrontal Cortex Deactivation in a Mouse Model of Neuropathic Pain.
PG  - 522-532
LID - S1526-5900(23)00549-7 [pii]
LID - 10.1016/j.jpain.2023.09.021 [doi]
AB  - Deactivation of the medial prefrontal cortex (mPFC) has been broadly reported in 
      both neuropathic pain models and human chronic pain patients. Several cellular 
      mechanisms may contribute to the inhibition of mPFC activity, including enhanced 
      GABAergic inhibition. The functional effect of GABA(A)(gamma-aminobutyric acid type 
      A)-receptor activation depends on the concentration of intracellular chloride in 
      the postsynaptic neuron, which is mainly regulated by the activity of Na-K-2Cl 
      cotransporter isoform 1 (NKCC1) and K-Cl cotransporter isoform 2 (KCC2), 2 
      potassium-chloride cotransporters that import and extrude chloride, respectively. 
      Recent work has shown that the NKCC1-KCC2 ratio is affected in numerous 
      pathological conditions, and we hypothesized that it may contribute to the 
      alteration of mPFC function in neuropathic pain. We used quantitative in situ 
      hybridization to assess the level of expression of NKCC1 and KCC2 in the mPFC of 
      a mouse model of neuropathic pain (spared nerve injury), and we found that KCC2 
      transcript is increased in the mPFC of spared nerve injury mice while NKCC1 is 
      not affected. Perforated patch recordings further showed that this results in the 
      hypernegative reversal potential of the GABA(A) current in pyramidal neurons of 
      the mPFC. Computational simulations suggested that this change in GABA(A) 
      reversal potential is sufficient to significantly reduce the overall activity of 
      the cortical network. Thus, our results identify a novel pathological modulation 
      of GABA(A) function and a new mechanism by which mPFC function is inhibited in 
      neuropathic pain. Our data also help explain previous findings showing that 
      activation of mPFC interneurons has proalgesic effect in neuropathic, but not in 
      control conditions. PERSPECTIVE: Chronic pain is associated with the presence of 
      depolarizing GABA(A) current in the spinal cord, suggesting that pharmacological 
      NKCC1 antagonism has analgesic effects. However, our results show that in 
      neuropathic pain, GABA(A) current is actually hyperinhibitory in the mPFC, where 
      it contributes to the mPFC functional deactivation. This suggests caution in the 
      use of NKCC1 antagonism to treat pain.
CI  - Copyright (c) 2024 United States Association for the Study of Pain, Inc. Published 
      by Elsevier Inc. All rights reserved.
FAU - Kim, Haram R
AU  - Kim HR
AD  - Department of Neuroscience, Feinberg School of Medicine, Northwestern University, 
      Chicago, Illinois.
FAU - Long, Manzhao
AU  - Long M
AD  - Department of Neuroscience, Feinberg School of Medicine, Northwestern University, 
      Chicago, Illinois.
FAU - Sekerkova, Gabriella
AU  - Sekerkova G
AD  - Department of Neuroscience, Feinberg School of Medicine, Northwestern University, 
      Chicago, Illinois.
FAU - Maes, Amadeus
AU  - Maes A
AD  - Department of Neuroscience, Feinberg School of Medicine, Northwestern University, 
      Chicago, Illinois.
FAU - Kennedy, Ann
AU  - Kennedy A
AD  - Department of Neuroscience, Feinberg School of Medicine, Northwestern University, 
      Chicago, Illinois.
FAU - Martina, Marco
AU  - Martina M
AD  - Department of Neuroscience, Feinberg School of Medicine, Northwestern University, 
      Chicago, Illinois.
LA  - eng
GR  - K99 MH117264/MH/NIMH NIH HHS/United States
GR  - P50 DA044121/DA/NIDA NIH HHS/United States
GR  - R00 MH117264/MH/NIMH NIH HHS/United States
GR  - R01 NS112292/NS/NINDS NIH HHS/United States
PT  - Journal Article
DEP - 20231002
PL  - United States
TA  - J Pain
JT  - The journal of pain
JID - 100898657
RN  - 0 (Chlorides)
RN  - 0 (K Cl- Cotransporters)
RN  - 56-12-2 (gamma-Aminobutyric Acid)
RN  - 0 (Protein Isoforms)
RN  - 0 (Solute Carrier Family 12, Member 2)
SB  - IM
MH  - Mice
MH  - Humans
MH  - Animals
MH  - *Chronic Pain
MH  - Chlorides/metabolism/pharmacology
MH  - *Neuralgia/metabolism
MH  - Pyramidal Cells/metabolism
MH  - K Cl- Cotransporters
MH  - gamma-Aminobutyric Acid/metabolism
MH  - Prefrontal Cortex
MH  - Protein Isoforms/metabolism/pharmacology
MH  - Solute Carrier Family 12, Member 2/metabolism
PMC - PMC10841847
MID - NIHMS1944467
OTO - NOTNLM
OT  - Inhibition
OT  - K-Cl cotransporter isoform 2
OT  - Na-K-2Cl cotransporter isoform 1
OT  - neuropathic pain
OT  - perforated patch
EDAT- 2023/10/05 01:00
MHDA- 2024/01/22 06:43
PMCR- 2025/02/01
CRDT- 2023/10/04 19:13
PHST- 2023/05/23 00:00 [received]
PHST- 2023/08/21 00:00 [revised]
PHST- 2023/09/27 00:00 [accepted]
PHST- 2025/02/01 00:00 [pmc-release]
PHST- 2024/01/22 06:43 [medline]
PHST- 2023/10/05 01:00 [pubmed]
PHST- 2023/10/04 19:13 [entrez]
AID - S1526-5900(23)00549-7 [pii]
AID - 10.1016/j.jpain.2023.09.021 [doi]
PST - ppublish
SO  - J Pain. 2024 Feb;25(2):522-532. doi: 10.1016/j.jpain.2023.09.021. Epub 2023 Oct 
      2.