Brain-derived neurotrophic factor-mediated downregulation of brainstem K+-Cl- cotransporter and cell-type-specific GABA impairment for activation of descending pain facilitation.

Abstract

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 μ-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.

• Authors: Zhi Zhang, Xinxing Wang, Wei Wang, Yun-Gang Lu, Zhizhong Z Pan
• Journal: Molecular pharmacology (Mol Pharmacol) Vol. 84 Issue 4 Pg. 511-20 (Oct 2013) ISSN: 1521-0111 [Electronic] United States
• PMID: 23847084 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Brain-Derived Neurotrophic Factor
• Symporters
• potassium-chloride symporters
• gamma-Aminobutyric Acid

Topics

• Animals
• Animals, Newborn
• Brain Stem (cytology, drug effects, metabolism)
• Brain-Derived Neurotrophic Factor (administration & dosage, physiology)
• Down-Regulation (drug effects, physiology)
• Male
• Microinjections
• Organ Culture Techniques
• Pain (metabolism)
• Raphe Nuclei (cytology, drug effects, metabolism)
• Rats
• Rats, Wistar
• Symporters (antagonists & inhibitors, metabolism)
• gamma-Aminobutyric Acid (metabolism)