Synergistic analgesic effects of intrathecal midazolam and NMDA or AMPA receptor antagonists in rats.
OBJECTIVE
To investigate the interaction of midazolam and N-methyl-D-aspartate (NMDA) receptor or -amino-3-hydroxy-5-methyl isoxazole-4-propionic acid (AMPA) receptor antagonist on the effects of persistent inflammatory nociceptive activation.


METHODS
Male Sprague-Dawley rats were implanted with lumbar intrathecal catheters and were tested for their responses to subcutaneous formalin injection into the hindpaw. Saline, midazolam (1 to 100 microg), AP-5 (I to 30 microg), a NMDA receptor antagonist, or YM872 (0.3 to 30 microg), an AMPA receptor antagonist was injected intrathecally 10 min before formalin injection. The combinations of midazolam and AP-5 or YM872 in a constant dose ratio based on the 50% effective dose (ED50) were also tested and were analysed with an isobologram.


RESULTS
Dose-dependent effects were observed with midazolam (ED50 was 1.34 microg and 1.21 microg in phase 1 and 2 of the formalin test, respectively), AP-5 (7.64 microg and 1.4 microg) and YM872 (0.24 microg and 0.21 microg). Synergistic effects in both phases were obtained when combining midazolam with AP-5 or YM872. The ED50 of midazolam decreased to 0.012 microg (phase 1) and 0.27 microg (phase 2) with AP-5 and to 0.09 microg (phase 1) and 0.35 microg (phase 2) with YM872 (P < 0.01).


CONCLUSIONS
These results suggest a functional coupling of benzodiazepine-aminobutyric acid (GABA)A receptor with NMDA and AMPA receptors in acute and persistent inflammatory nociceptive mechanisms in the spinal cord.
Nishiyama
T
T
Department of Surgical Center, Institute of Medical Science, University of Tokyo, Japan. nishiyam@ims.u-tokyo.ac.jp
Gyermek
L
L
Lee
C
C
Kawasaki-Yatsugi
S
S
Yamaguchi
T
T
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000759:Adjuvants, Anesthesia / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005557:Formaldehyde; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D008874:Midazolam / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D011963:Receptors, GABA-A / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
D000759:Adjuvants, Anesthesia; D018691:Excitatory Amino Acid Antagonists; D007093:Imidazoles; D018696:Neuroprotective Agents; D011810:Quinoxalines; D018091:Receptors, AMPA; D011963:Receptors, GABA-A; D016194:Receptors, N-Methyl-D-Aspartate; C110629:YM 872; D005557:Formaldehyde; D015763:2-Amino-5-phosphonovalerate; D008874:Midazolam