Transplant-mediated enhancement of spinal cord GABAergic inhibition reverses paclitaxel-induced mechanical and heat hypersensitivity

Pain. 2015 Jun;156(6):1084-1091. doi: 10.1097/j.pain.0000000000000152.

Abstract

Decreased spinal cord GABAergic inhibition is a major contributor to the persistent neuropathic pain that can follow peripheral nerve injury. Recently, we reported that restoring spinal cord GABAergic signaling by intraspinal transplantation of cortical precursors of GABAergic interneurons from the embryonic medial ganglionic eminence (MGE) can reverse the mechanical hypersensitivity (allodynia) that characterizes a neuropathic pain model in the mouse. We show that MGE cell transplants are also effective against both the mechanical allodynia and the heat hyperalgesia produced in a paclitaxel-induced chemotherapy model of neuropathic pain. To test the necessity of GABA release by the transplants, we also studied the utility of transplanting MGE cells from mice with a deletion of VGAT, the vesicular GABA transporter. Transplants from these mice, in which GABA is synthesized but cannot be stored or released, had no effect on mechanical hypersensitivity or heat hyperalgesia in the paclitaxel model. Taken together, these results demonstrate the therapeutic potential of GABAergic precursor cell transplantation in diverse neuropathic pain models and support our contention that restoration of inhibitory controls through release of GABA from the transplants is their mode of action.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 3 / metabolism
  • Animals
  • Antineoplastic Agents, Phytogenic / toxicity*
  • Cell Count
  • Cell Transplantation / methods*
  • Disease Models, Animal
  • Glutamate Decarboxylase / genetics
  • Glutamate Decarboxylase / metabolism
  • Hyperalgesia* / chemically induced
  • Hyperalgesia* / metabolism
  • Hyperalgesia* / surgery
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Paclitaxel / toxicity*
  • Pain Measurement
  • Pain Threshold
  • Spinal Cord / metabolism*
  • Vesicular Inhibitory Amino Acid Transport Proteins / genetics
  • Vesicular Inhibitory Amino Acid Transport Proteins / metabolism
  • gamma-Aminobutyric Acid / metabolism*

Substances

  • Activating Transcription Factor 3
  • Antineoplastic Agents, Phytogenic
  • Atf3 protein, mouse
  • Vesicular Inhibitory Amino Acid Transport Proteins
  • Viaat protein, mouse
  • gamma-Aminobutyric Acid
  • Glutamate Decarboxylase
  • glutamate decarboxylase 1
  • glutamate decarboxylase 2
  • Paclitaxel