Sleep disturbances in a neuropathic pain-like condition in the mouse are associated with altered GABAergic transmission in the cingulate cortex

Pain. 2011 Jun;152(6):1358-1372. doi: 10.1016/j.pain.2011.02.016. Epub 2011 Mar 10.


Insomnia is a common problem for people with chronic pain. Cortical GABAergic neurons are part of the neurobiological substrate that underlies homeostatic sleep regulation. In the present study, we confirmed that sciatic nerve ligation caused thermal hyperalgesia and tactile allodynia in mice. In this experimental model for neuropathic pain, we found an increase in wakefulness and a decrease in non-rapid eye movement sleep under a neuropathic pain-like state. Under these conditions, membrane-bound GABA (γ-aminobutyric acid) transporters (GATs) on activated glial fibrillary acidic protein-positive astrocytes were significantly increased in the cingulate cortex, and extracellular GABA levels in this area after depolarization were rapidly decreased by nerve injury. Furthermore, sleep disturbance induced by sciatic nerve ligation was improved by the intracingulate cortex injection of a GAT-3 inhibitor. These findings provide novel evidence that sciatic nerve ligation decreases extracellular-released GABA in the cingulate cortex of mice. These phenomena may, at least in part, explain the insomnia in patients with neuropathic pain. Neuropathic pain-like stimuli suppress the GABAergic transmission with increased GABA (γ-aminobutyric acid) transporters located on activated astrocytes in the cingulate cortex related to sleep disturbance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Anisoles / pharmacology
  • Disease Models, Animal
  • Electroencephalography
  • Electromyography
  • GABA Plasma Membrane Transport Proteins / genetics
  • GABA Plasma Membrane Transport Proteins / metabolism
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology
  • Glial Fibrillary Acidic Protein / metabolism
  • Gyrus Cinguli / drug effects
  • Gyrus Cinguli / metabolism*
  • Hyperalgesia / drug therapy
  • Hyperalgesia / physiopathology
  • Hypnotics and Sedatives / therapeutic use
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred ICR
  • Microdialysis
  • Midazolam / pharmacology
  • Midazolam / therapeutic use
  • Nipecotic Acids / pharmacology
  • Pain Measurement
  • Pain Threshold / physiology
  • Physical Stimulation / adverse effects
  • Pyridines / therapeutic use
  • RNA, Messenger / metabolism
  • Reflex / drug effects
  • Reflex / physiology
  • Sciatic Neuropathy / complications*
  • Sciatic Neuropathy / drug therapy
  • Sciatic Neuropathy / pathology*
  • Sleep Wake Disorders / etiology*
  • Zolpidem
  • gamma-Aminobutyric Acid / metabolism*


  • 1-(2-(tris(4-methoxyphenyl)methoxy)ethyl)-3-piperidinecarboxylic acid
  • Anisoles
  • GABA Plasma Membrane Transport Proteins
  • Glial Fibrillary Acidic Protein
  • Hypnotics and Sedatives
  • Nipecotic Acids
  • Pyridines
  • RNA, Messenger
  • gamma-Aminobutyric Acid
  • Zolpidem
  • Midazolam