PMID- 23847084
OWN - NLM
STAT- MEDLINE
DCOM- 20131125
LR  - 20231213
IS  - 1521-0111 (Electronic)
IS  - 0026-895X (Print)
IS  - 0026-895X (Linking)
VI  - 84
IP  - 4
DP  - 2013 Oct
TI  - Brain-derived neurotrophic factor-mediated downregulation of brainstem K+-Cl- 
      cotransporter and cell-type-specific GABA impairment for activation of descending 
      pain facilitation.
PG  - 511-20
LID - 10.1124/mol.113.086496 [doi]
AB  - Chronic pain is thought to be partly caused by a loss of GABAergic inhibition and 
      resultant neuronal hyperactivation in the central pain-modulating system, but the 
      underlying mechanisms for pain-modulating neurons in the brain are unclear. In 
      this study, we investigated the cellular mechanisms for activation of brainstem 
      descending pain facilitation in rats under persistent pain conditions. In the 
      nucleus raphe magnus (NRM), a critical relay in the brain's descending 
      pain-modulating system, persistent inflammatory pain induced by complete Freund's 
      adjuvant decreased the protein level of K(+)-Cl(-) cotransporter (KCC2) in both 
      total and synaptosomal preparations. Persistent pain also shifted the equilibrium 
      potential of GABAergic inhibitory postsynaptic current (EIPSC) to a more positive 
      level and increased the firing of evoked action potentials selectively in 
      mu-opioid receptor (MOR)-expressing NRM neurons, but not in MOR-lacking NRM 
      neurons. Microinjection of brain-derived neurotrophic factor (BDNF) into the NRM 
      inhibited the KCC2 protein level in the NRM, and both BDNF administration and 
      KCC2 inhibition by furosemide mimicked the pain-induced effects on EIPSC and 
      excitability in MOR-expressing neurons. Furthermore, inhibiting BDNF signaling by 
      NRM infusion of tyrosine receptor kinase B-IgG or blocking KCC2 with furosemide 
      prevented these pain effects in MOR-expressing neurons. These findings 
      demonstrate a cellular mechanism by which the hyperactivity of NRM MOR-expressing 
      neurons, presumably responsible for descending pain facilitation, contributes to 
      pain sensitization through the signaling cascade of BDNF-KCC2-GABA impairment in 
      the development of chronic pain.
FAU - Zhang, Zhi
AU  - Zhang Z
AD  - Department of Anesthesiology and Pain Medicine, University of Texas, MD Anderson 
      Cancer Center, Houston, Texas (Z.Z., W.W., Z.Z.P.); Department of Neurobiology, 
      University of Science and Technology of China, Hefei, People's Republic of China 
      (Z.Z., X.W.); and Department of Integrative Biology and Pharmacology, University 
      of Texas Health Science Center at Houston, Houston, Texas (Y.-G.L.).
FAU - Wang, Xinxing
AU  - Wang X
FAU - Wang, Wei
AU  - Wang W
FAU - Lu, Yun-Gang
AU  - Lu YG
FAU - Pan, Zhizhong Z
AU  - Pan ZZ
LA  - eng
GR  - R01 DA023069/DA/NIDA NIH HHS/United States
GR  - R01 DA027541/DA/NIDA NIH HHS/United States
GR  - DA023069/DA/NIDA NIH HHS/United States
GR  - DA027541/DA/NIDA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20130711
PL  - United States
TA  - Mol Pharmacol
JT  - Molecular pharmacology
JID - 0035623
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Symporters)
RN  - 56-12-2 (gamma-Aminobutyric Acid)
SB  - IM
MH  - Animals
MH  - Animals, Newborn
MH  - Brain Stem/cytology/drug effects/metabolism
MH  - Brain-Derived Neurotrophic Factor/*administration & dosage/physiology
MH  - Down-Regulation/drug effects/*physiology
MH  - Male
MH  - Microinjections
MH  - Organ Culture Techniques
MH  - Pain/*metabolism
MH  - Raphe Nuclei/cytology/drug effects/*metabolism
MH  - Rats
MH  - Rats, Wistar
MH  - Symporters/antagonists & inhibitors/*metabolism
MH  - gamma-Aminobutyric Acid/*metabolism
MH  - K Cl- Cotransporters
PMC - PMC3781381
EDAT- 2013/07/13 06:00
MHDA- 2013/12/16 06:00
PMCR- 2014/10/01
CRDT- 2013/07/13 06:00
PHST- 2013/07/13 06:00 [entrez]
PHST- 2013/07/13 06:00 [pubmed]
PHST- 2013/12/16 06:00 [medline]
PHST- 2014/10/01 00:00 [pmc-release]
AID - mol.113.086496 [pii]
AID - MOL_086496 [pii]
AID - 10.1124/mol.113.086496 [doi]
PST - ppublish
SO  - Mol Pharmacol. 2013 Oct;84(4):511-20. doi: 10.1124/mol.113.086496. Epub 2013 Jul 
      11.