Loss of Inhibitory Tone on Spinal Cord Dorsal Horn Spontaneously and Nonspontaneously Active Neurons in a Mouse Model of Neuropathic Pain

Pain. 2016 Jul;157(7):1432-42. doi: 10.1097/j.pain.0000000000000538.

Abstract

Plasticity of inhibitory transmission in the spinal dorsal horn (SDH) is believed to be a key mechanism responsible for pain hypersensitivity in neuropathic pain syndromes. We evaluated this plasticity by recording responses to mechanical stimuli in silent neurons (nonspontaneously active [NSA]) and neurons showing ongoing activity (spontaneously active [SA]) in the SDH of control and nerve-injured mice (cuff model). The SA and NSA neurons represented 59% and 41% of recorded neurons, respectively, and were predominantly wide dynamic range (WDR) in naive mice. Nerve-injured mice displayed a marked decrease in the mechanical threshold of the injured paw. After nerve injury, the proportion of SA neurons was increased to 78%, which suggests that some NSA neurons became SA. In addition, the response to touch (but not pinch) was dramatically increased in SA neurons, and high-threshold (nociceptive specific) neurons were no longer observed. Pharmacological blockade of spinal inhibition with a mixture of GABAA and glycine receptor antagonists significantly increased responses to innocuous mechanical stimuli in SA and NSA neurons from sham animals, but had no effect in sciatic nerve-injured animals, revealing a dramatic loss of spinal inhibitory tone in this situation. Moreover, in nerve-injured mice, local spinal administration of acetazolamide, a carbonic anhydrase inhibitor, restored responses to touch similar to those observed in naive or sham mice. These results suggest that a shift in the reversal potential for anions is an important component of the abnormal mechanical responses and of the loss of inhibitory tone recorded in a model of nerve injury-induced neuropathic pain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetazolamide / pharmacology
  • Action Potentials / drug effects
  • Action Potentials / physiology*
  • Animals
  • Carbonic Anhydrase Inhibitors / pharmacology
  • Disease Models, Animal
  • Mice
  • Neuralgia / physiopathology*
  • Pain Threshold / drug effects
  • Pain Threshold / physiology
  • Physical Stimulation
  • Posterior Horn Cells / drug effects
  • Posterior Horn Cells / physiology*
  • Spinal Cord Dorsal Horn / drug effects
  • Spinal Cord Dorsal Horn / physiopathology*

Substances

  • Carbonic Anhydrase Inhibitors
  • Acetazolamide