Effects of midazolam in the spinal nerve ligation model of neuropathic pain in rats.
Potential changes in the spinal GABAergic activity after nerve injury were studied by comparing the effects of systemic administration of the benzodiazepine midazolam on the noxious evoked responses of dorsal horn in rats with spinal nerve ligation of neuropathy and control animals. The tight ligation of the L(5) and L6 spinal nerves was performed in adult male Sprague-Dawley rats and resulting mechanical and cold allodynia were assessed with von Frey hairs and the acetone drop test. Single unit extracellular recordings of dorsal horn neurones were performed 15-18 days after the surgery under halothane anaesthesia using transcutaneous electrical stimulation of the receptive field at three times the C-fibre threshold. The rats in the spinal nerve ligation group, but not in the sham-operated control group developed mechanical and cold allodynia. Subcutaneous administration of midazolam 0.1-3.0 mg/kg reduced the Adelta-fibre evoked activity in a dose-related manner in all study groups, but the C-fibre evoked activity was significantly reduced only in the spinal nerve ligation group. The inhibitory effects of s.c. midazolam were significantly reversed by i.t. administration of flumazenil, suggesting a spinal site of action. Midazolam reduced C-fibre evoked firing significantly more in the spinal nerve ligation model than in the non-operated or sham controls. These results indicate changes in the spinal GABAergic system in the neuropathic animals and could be of importance in the development of new treatments for neuropathic pain.
Kontinen
Vesa K
VK
Department of Pharmacology, University College London, Gower Street, London WC1E 6BT, UK Department of Pharmacology and Toxicology, Institute of Biomedicine, Siltavuorenpenger 10, FIN-00014 University of Helsinki, Finland.
Dickenson
Anthony H
AH
D000818:Animals; D003080:Cold Temperature; D004594:Electrophysiology; D005071:Evoked Potentials / Q000502:physiology; D005442:Flumazenil / Q000494:pharmacology; D018757:GABA Modulators / Q000008:administration & dosage / Q000627:therapeutic use*; D007278:Injections, Spinal; D007279:Injections, Subcutaneous; D008026:Ligation; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000627:therapeutic use*; D009412:Nerve Fibers / Q000187:drug effects; D009413:Nerve Fibers, Myelinated / Q000187:drug effects; D010146:Pain / Q000188:drug therapy* / Q000209:etiology; D010147:Pain Measurement / Q000187:drug effects; D010812:Physical Stimulation; D020671:Posterior Horn Cells / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013127:Spinal Nerves / Q000293:injuries*
D018757:GABA Modulators; D005442:Flumazenil; D008874:Midazolam