Gabapentin reverses microglial activation in the spinal cord of streptozotocin-induced diabetic rats.
Diabetes mellitus is the leading cause of peripheral neuropathy worldwide. Despite this high level of incidence, underlying mechanisms of the development and maintenance of neuropathic pain are still poorly understood. Evidence supports a prominent role of glial cells in neuropathic pain states. Gabapentin is used clinically and shows some efficacy in the treatment of neuropathic pain. Here we investigate the distribution and activation of spinal microglia and astrocytes in streptozotocin (STZ)-diabetic rats and the effect of the gold standard analgesic, Gabapentin, on these cells. Mechanical allodynia was observed in four week-diabetic rats. Oral administration of Gabapentin significantly attenuated mechanical allodynia. Quantification of cell markers Iba-1 for microglia and GFAP for astrocytes revealed extensive activation of microglia in the dorsal horn of diabetic rats, whereas a reduction in the number of astrocytes could be observed. In addition, an attenuation of microglial activation correlated with reduced allodynia following Gabapentin treatment, while Gabapentin had no effect on the number of astrocytes. Here we show a role of microglia in STZ-induced mechanical allodynia and furthermore, that the anti-allodynic effect of Gabapentin may be linked to a reduction of spinal microglial activation. Astrocytic activation in this model appears to be limited and is unaffected by Gabapentin treatment. Consequently, spinal microglial activation is a key mechanism underlying diabetic neuropathy. Furthermore, we suggest that Gabapentin may exert its anti-allodynic actions partially through alterations of microglial cell function.
Wodarski
Rachel
R
Neurorestoration Group, Wolfson Centre for Age Related Diseases, King's College London, London SE1 1UL, UK.
Clark
Anna K
AK
Grist
John
J
Marchand
Fabien
F
Malcangio
Marzia
M
D000588:Amines / Q000494:pharmacology* / Q000627:therapeutic use; D000700:Analgesics / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001253:Astrocytes / Q000187:drug effects; D002452:Cell Count; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000473:pathology*; D003929:Diabetic Neuropathies / Q000150:complications; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D000077206:Gabapentin; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D017628:Microglia / Q000187:drug effects*; D010146:Pain / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D010147:Pain Measurement / Q000187:drug effects; D017288:Pain Threshold / Q000187:drug effects; D010812:Physical Stimulation; D051381:Rats; D017208:Rats, Wistar; D013116:Spinal Cord / Q000473:pathology*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology* / Q000627:therapeutic use
D000588:Amines; D000700:Analgesics; D003509:Cyclohexanecarboxylic Acids; D018691:Excitatory Amino Acid Antagonists; D005904:Glial Fibrillary Acidic Protein; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin