Minocycline completely reverses mechanical hyperalgesia in diabetic rats through microglia-induced changes in the expression of the potassium chloride co-transporter 2 (KCC2) at the spinal cord.

Abstract

AIM:

neuronal hyperactivity at the spinal cord during mechanical hyperalgesia induced by diabetes may result from a decrease in the local expression of the potassium chloride co-transporter 2 (KCC2), which shifts the action of the neurotransmitter γ-amminobutiric acid (GABA) from inhibitory to excitatory. In this study, we evaluated the effects of spinal microglia inhibition or brain-derived neurotrophic factor (BDNF) blockade on KCC2 expression, spinal neuronal activity and mechanically induced pain responses of streptozotocin (STZ)-diabetic rats.

METHODS:

four weeks after induction of diabetes, the STZ-diabetic rats received daily intrathecal injections, for 3 days, of minocycline (microglia inhibitor), TrkB/Fc (BDNF sequester) or saline. Behavioural responses to mechanical nociceptive stimulation of STZ-diabetic rats were evaluated by the Randall-Selitto test. The lumbar spinal cord was immunoreacted against the Fos protein (marker of neuronal activation) or KCC2, which was also quantified by western blotting. BDNF levels at the spinal cord were quantified by an enzyme-linked immunosorbent assay (ELISA).

RESULTS:

minocycline treatment reversed the mechanical hyperalgesia, increased Fos expression and decreased the KCC2 expression detected in STZ-diabetic rats to control levels. Treatment with TrkB/Fc was less effective, inducing moderate effects in mechanical hyperalgesia and Fos expression and only a partial correction of KCC2 expression. BDNF levels were not increased in STZ-diabetic rats.

CONCLUSIONS:

this study demonstrates that the microglial activation at the spinal cord contributes to mechanical hyperalgesia and spinal neuronal hyperactivity induced by diabetes, apparently by regulating the KCC2 expression. These effects do not seem to be mediated by BDNF, which is an important difference from other chronic pain conditions. New targets directed to prevent spinal microglia activation should be considered for the treatment of mechanical hyperalgesia induced by diabetes.

• Authors: C Morgado, P Pereira-Terra, C D Cruz, I Tavares
• Journal: Diabetes, obesity & metabolism (Diabetes Obes Metab) Vol. 13 Issue 2 Pg. 150-9 (Feb 2011) ISSN: 1463-1326 [Electronic] England
• PMID: 21199267 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Symporters
• Potassium Chloride
• Minocycline

Topics

• Animals
• Diabetes Mellitus, Experimental
• Diabetic Neuropathies (diet therapy, metabolism, physiopathology)
• Hyperalgesia (drug therapy, metabolism, physiopathology)
• Male
• Microglia (drug effects)
• Minocycline (administration & dosage, pharmacology)
• Potassium Chloride (metabolism)
• Rats
• Rats, Wistar
• Spinal Cord (drug effects, metabolism, physiopathology)
• Symporters
• Synaptic Transmission (physiology)
• Up-Regulation (physiology)