Midazolam administration reverses thermal hyperalgesia and prevents gamma-aminobutyric acid transporter loss in a rodent model of neuropathic pain.
BACKGROUND
Loss of gamma-aminobutyric acid (GABA) inhibition in the spinal dorsal horn may contribute to neuropathic pain. Here we examined whether systemic administration of the benzodiazepine midazolam would alleviate thermal hyperalgesia due to chronic constriction injury (CCI) of the sciatic nerve.


METHODS
Hyperalgesia was evaluated with the thermal paw withdrawal latency test before, and 3 and 7 days after CCI. Animals randomly received, via osmotic minipump infusion, midazolam (2.0 mg x kg(-1) x h(-1)), flumazenil (0.004 mg x kg(-1) x h(-1)), midazolam plus flumazenil at the same doses, or saline (0.01 mg x kg(-1) x h(-1)). Four groups of sham-operated rats (surgery without nerve ligation) received matched treatments. Levels of the GABA transporter 1 (GAT-1) in the lumbar spinal dorsal horn were estimated using western immunoblots 7 days after surgery.


RESULTS
Saline-treated CCI rats developed thermal hyperalgesia on Day 3 with a more pronounced effect on Day 7. Continuous midazolam infusion prevented thermal hyperalgesia on both days. The antihyperalgesic effect of midazolam was reversed by the coadministration of flumazenil. Infusion of flumazenil alone had no effect on the thermal hyperalgesia in CCI rats. Sham-operated rats treated with saline, midazolam, or midazolam plus flumazenil exhibited no thermal hyperalgesia. Unexpectedly, thermal paw withdrawal latency in sham animals treated with flumazenil alone was significantly decreased. Changes in GAT-1 levels paralleled the behavior. Midazolam prevented the CCI-associated decreases, and flumazenil reversed midazolam's effect. Flumazenil alone did not modify GAT-1 levels in CCI animals but in sham animals the transporter levels were significantly reduced.


CONCLUSIONS
GABA inhibition plays an important role in neuropathic pain. Continuous systemic benzodiazepine administration may prove effective in alleviating neuropathic pain.
Shih
Andre
A
Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, Florida, USA.
Miletic
Vjekoslav
V
Miletic
Gordana
G
Smith
Lesley J
LJ
D000818:Animals; D004195:Disease Models, Animal; D050485:GABA Plasma Membrane Transport Proteins / Q000378:metabolism*; D006358:Hot Temperature; D006930:Hyperalgesia / Q000517:prevention & control*; D008297:Male; D008874:Midazolam / Q000627:therapeutic use*; D009443:Neuritis / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley
D050485:GABA Plasma Membrane Transport Proteins; D008874:Midazolam