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ANALGESIA

Midazolam Administration Reverses Thermal Hyperalgesia and Prevents -Aminobutyric Acid Transporter Loss in a Rodent Model of Neuropathic Pain

Andre Shih, DVM^*, Vjekoslav Miletic, PhD, Gordana Miletic, PhD, and Lesley J. Smith, DVM

From the *Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, Florida; Department of Anesthesiology, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin; and Department of Surgical Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, Wisconsin.

Address correspondence and reprint requests to Dr. L. J. Smith, Department of Surgical Sciences, School of Veterinary Medicine, University of Wisconsin, 2015 Linden Dr., Madison, WI 53706. Address e-mail to smithl{at}svm.vetmed.wisc.edu.

Abstract

BACKGROUND: Loss of -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 · kg^–1 · h^–1), flumazenil (0.004 mg · kg^–1 · h^–1), midazolam plus flumazenil at the same doses, or saline (0.01 mg · kg^–1 · 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.

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