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Molecular Pharmacology

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Research ArticleArticle

Brain-Derived Neurotrophic Factor–Mediated Downregulation of Brainstem K+–Cl– Cotransporter and Cell-Type–Specific GABA Impairment for Activation of Descending Pain Facilitation

Zhi Zhang, Xinxing Wang, Wei Wang, Yun-Gang Lu and Zhizhong Z. Pan
Molecular Pharmacology October 2013, 84 (4) 511-520; DOI: https://doi.org/10.1124/mol.113.086496
Zhi Zhang
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.)
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Xinxing Wang
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.)
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Wei Wang
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.)
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Yun-Gang Lu
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.)
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Zhizhong Z. Pan
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.)
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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.

Footnotes

    • Received March 1, 2013.
    • Accepted July 11, 2013.
  • This work was supported by the National Institutes of Health National Institute on Drug Abuse [Grants DA023069 and DA027541] (to Z.Z.P.); and the National Natural Science Foundation of China [Grant 31100802] (to Z.Z.).

  • dx.doi.org/10.1124/mol.113.086496.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 84 (4)
Molecular Pharmacology
Vol. 84, Issue 4
1 Oct 2013
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Research ArticleArticle

Brainstem BDNF and KCC2 in Descending Pain Facilitation

Zhi Zhang, Xinxing Wang, Wei Wang, Yun-Gang Lu and Zhizhong Z. Pan
Molecular Pharmacology October 1, 2013, 84 (4) 511-520; DOI: https://doi.org/10.1124/mol.113.086496

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Research ArticleArticle

Brainstem BDNF and KCC2 in Descending Pain Facilitation

Zhi Zhang, Xinxing Wang, Wei Wang, Yun-Gang Lu and Zhizhong Z. Pan
Molecular Pharmacology October 1, 2013, 84 (4) 511-520; DOI: https://doi.org/10.1124/mol.113.086496
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