Allodynia and hyperalgesia in diabetic rats are mediated by GABA and depletion of spinal potassium-chloride co-transporters.

Abstract

Diabetic rats show behavioral indices of painful neuropathy that may model the human condition. Hyperalgesia during the formalin test in diabetic rats is accompanied by the apparently paradoxical decrease in spinal release of excitatory neurotransmitters and increase in the inhibitory neurotransmitter GABA. Decreased expression of the potassium-chloride co-transporter, KCC2, in the spinal cord promotes excitatory properties of GABA. We therefore measured spinal KCC2 expression and explored the role of the GABA(A) receptor in rats with painful diabetic neuropathy. KCC2 protein levels were significantly reduced in the spinal cord of diabetic rats, while levels of NKCC1 and the GABA(A) receptor were unchanged. Spinal delivery of the GABA(A) receptor antagonist bicuculline reduced formalin-evoked flinching in diabetic rats and also dose-dependently alleviated tactile allodynia. GABA(A) receptor-mediated rate-dependent depression of the spinal H reflex was absent in the spinal cord of diabetic rats. Control rats treated with the KCC2 blocker DIOA, mimicked diabetes by showing increased formalin-evoked flinching and diminished rate- dependent depression. The ability of bicuculline to alleviate allodynia and formalin-evoked hyperalgesia in diabetic rats is consistent with a reversal of the properties of GABA predicted by reduced spinal KCC2 and suggests that reduced KCC2 expression and increased GABA release contribute to spinally mediated hyperalgesia in diabetes.

• Authors: Corinne G Jolivalt, Corinne A Lee, Khara M Ramos, Nigel A Calcutt
• Journal: Pain (Pain) Vol. 140 Issue 1 Pg. 48-57 (Nov 15 2008) ISSN: 1872-6623 [Electronic] United States
• PMID: 18755547 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Symporters
• potassium-chloride symporters
• gamma-Aminobutyric Acid
• Streptozocin

Topics

• Animals
• Diabetes Mellitus, Experimental (chemically induced, metabolism)
• Hyperalgesia (metabolism)
• Hyperesthesia (metabolism)
• Male
• Neuralgia (metabolism)
• Rats
• Rats, Sprague-Dawley
• Spinal Cord (metabolism)
• Streptozocin
• Symporters (metabolism)
• Touch
• gamma-Aminobutyric Acid (metabolism)