title: Blocking the GABA transporter GAT-1 ameliorates spinal GABAergic disinhibition and neuropathic pain induced by paclitaxel.
abstract: Paclitaxel is a chemotherapeutic agent widely used for treating carcinomas. Patients receiving paclitaxel often develop neuropathic pain and have a reduced quality of life which hinders the use of this life-saving drug. In this study, we determined the role of GABA transporters in the genesis of paclitaxel-induced neuropathic pain using behavioral tests, electrophysiology, and biochemical techniques. We found that tonic GABA receptor activities in the spinal dorsal horn were reduced in rats with neuropathic pain induced by paclitaxel. In normal controls, tonic GABA receptor activities were mainly controlled by the GABA transporter GAT-1 but not GAT-3. In the spinal dorsal horn, GAT-1 was expressed at presynaptic terminals and astrocytes while GAT-3 was only expressed in astrocytes. In rats with paclitaxel-induced neuropathic pain, the protein expression of GAT-1 was increased while GAT-3 was decreased. This was concurrently associated with an increase in global GABA uptake. The paclitaxel-induced attenuation of GABAergic tonic inhibition was ameliorated by blocking GAT-1 but not GAT-3 transporters. Paclitaxel-induced neuropathic pain was significantly attenuated by the intrathecal injection of a GAT-1 inhibitor. These findings suggest that targeting GAT-1 transporters for reversing disinhibition in the spinal dorsal horn may be a useful approach for treating paclitaxel-induced neuropathic pain. Patients receiving paclitaxel for cancer therapy often develop neuropathic pain and have a reduced quality of life. In this study, we demonstrated that animals treated with paclitaxel develop neuropathic pain, have enhancements of GABA transporter-1 protein expression and global GABA uptake, as well as suppression of GABAergic tonic inhibition in the spinal dorsal horn. Pharmacological inhibition of GABA transporter-1 ameliorates the paclitaxel-induced suppression of GABAergic tonic inhibition and neuropathic pain. Thus, targeting GAT-1 transporters for reversing GABAergic disinhibition in the spinal dorsal horn could be a useful approach for treating paclitaxel-induced neuropathic pain.
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, The University of Georgia College of Pharmacy, Athens, Georgia, USA.
authors.forename: Ruchi
authors.initials: R
authors.lastname: Yadav
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, The University of Georgia College of Pharmacy, Athens, Georgia, USA.|Department of Cardiovascular Medicine, the Third Hospital of Wuhan, Wuhan, Hubei Province, China.
authors.forename: Xisheng
authors.initials: X
authors.lastname: Yan
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, The University of Georgia College of Pharmacy, Athens, Georgia, USA.
authors.forename: Dylan W
authors.initials: DW
authors.lastname: Maixner
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, The University of Georgia College of Pharmacy, Athens, Georgia, USA.
authors.forename: Mei
authors.initials: M
authors.lastname: Gao
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, The University of Georgia College of Pharmacy, Athens, Georgia, USA.
authors.forename: Han-Rong
authors.initials: HR
authors.lastname: Weng
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity*; D015153:Blotting, Western; D004195:Disease Models, Animal; D050485:GABA Plasma Membrane Transport Proteins / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D009437:Neuralgia / Q000139:chemically induced / Q000378:metabolism*; D017239:Paclitaxel / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D066148:Spinal Cord Dorsal Horn / Q000187:drug effects / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D050485:GABA Plasma Membrane Transport Proteins; C493415:Slc6a1 protein, rat; D005680:gamma-Aminobutyric Acid; D017239:Paclitaxel
keywords: IPSCs; neurotoxicity; nociception; patch clamp; taxol; γ-aminobutyric acid
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