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: Ruchi Yadav, Xisheng Yan, Dylan W Maixner, Mei Gao, Han-Rong Weng
• Journal: Journal of neurochemistry (J Neurochem) Vol. 133 Issue 6 Pg. 857-69 (Jun 2015) ISSN: 1471-4159 [Electronic] England
• PMID: 25827582 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2015 International Society for Neurochemistry.

Chemical References

• Antineoplastic Agents, Phytogenic
• GABA Plasma Membrane Transport Proteins
• Slc6a1 protein, rat
• gamma-Aminobutyric Acid
• Paclitaxel

Topics

• Animals
• Antineoplastic Agents, Phytogenic (toxicity)
• Blotting, Western
• Disease Models, Animal
• GABA Plasma Membrane Transport Proteins (metabolism)
• Immunohistochemistry
• Male
• Neuralgia (chemically induced, metabolism)
• Paclitaxel (toxicity)
• Rats
• Rats, Sprague-Dawley
• Spinal Cord Dorsal Horn (drug effects, metabolism)
• gamma-Aminobutyric Acid (metabolism)