Analgesic Interaction between Intrathecal Midazolam and Glutamate Receptor Antagonists on Thermal-induced Pain in Rats

Abstract

Background Two major neurotransmitters, gamma-aminobutyric acid (GABA) and the excitatory amino acid, glutamate, may be involved in nociception in the spinal cord. GABA and glutamate receptors may operate in concert to modify signals in the central nervous system. The purpose of this study was to investigate the spinal analgesic interaction between midazolam, a benzodiazepine-GABA(A) receptor agonist, and two glutamate receptor antagonists on acute thermal nociception. Methods Sprague-Dawley rats were implanted with chronic lumbar intrathecal catheters and were tested for their tail withdrawal response by the tail flick test after intrathecal administration of saline, midazolam (1-100 microg), AP-5 (1-30 microg), or YM872 (0.3-30 microg). AP-5 is an N-methyl-D-aspartate (NMDA) receptor antagonist and YM872 is an alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor antagonist. The combination of midazolam and the other two agents were also tested by isobolographic analyses. Motor disturbance and behavioral changes were observed. Results Dose-dependent increases in the tail flick latency were observed with midazolam, AP-5, and YM872 with 50% effective dose values of 1.57+/-0.34 (SEM) microg, 5.54+/-0.19 microg, and 1.0+/-0.22 microg, respectively. A potent synergy in analgesia with decreased behavioral changes and motor disturbance was obtained when combining midazolam with AP-5 or YM872. Conclusions Spinally administered midazolam and an NMDA- or an AMPA-receptor antagonist exhibited potent synergistic analgesia on acute thermal nociception in rats. Side effects, shown by behavioral changes and motor disturbance, decreased with the combination of the agents. These results point out an important direction for the study of acute nociception.