title: Interaction between midazolam and epibatidine in spinally mediated antinociception in rats.
abstract: OBJECTIVE
  Both gamma-aminobutyric acid (GABA)(A) receptors and nicotinic cholinergic receptors have important roles in antinociception in the spinal cord. The antinociceptive effects of midazolam (a GABA(A) agonist) and epibatidine (a nicotinic cholinergic agonist) in the spinal cord have been reported. The present study was performed to investigate the interaction between intrathecal midazolam and epibatidine.
  
  
  METHODS
  Sprague-Dawley rats with lumbar intrathecal catheters were tested for their tail withdrawal response to thermal stimulation (tail-flick test) or for their paw flinches in response to formalin injection (formalin test) after the intrathecal administration of epibatidine or a combination of midazolam and epibatidine. The combination doses were 1/16, 1/8, 1/4, 1/2, 1, 2, and 4 times the 50% effective dose (ED50) of each agent in each test. The interaction of midazolam and epibatidine was investigated by isobolographic analysis. Behavioral side effects were also investigated.
  
  
  RESULTS
  In the tail-flick test, the ED50 values of the combination were significantly higher than the theoretical additive values. In the formalin test, the ED50 values of the combination were significantly lower than the theoretical additive values in phase 1, but were not different from the theoretical additive values in phase 2.
  
  
  CONCLUSIONS
  The intrathecal combination of midazolam and epibatidine had antagonistic effects on thermal acute nociception, while the combination had synergistic effects on acute inflammatory nociception, with only additive effects on inflammatory-facilitated nociceptive responses.
authors.affiliation: Department of Anesthesiology and Critical Care, Kamagaya General Hospital, 926-6 Hatsutomi, Kamagaya 273-0121, Japan.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Nishiyama
mesh_terms: D018712:Analgesics, Non-Narcotic / Q000494:pharmacology*; D000775:Anesthesia, Spinal; D018686:Anesthetics, Intravenous / Q000494:pharmacology*; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D005557:Formaldehyde; D007278:Injections, Spinal; D008297:Male; D008874:Midazolam / Q000494:pharmacology*; D010147:Pain Measurement / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D011963:Receptors, GABA-A / Q000187:drug effects
chemical_list: D018712:Analgesics, Non-Narcotic; D018686:Anesthetics, Intravenous; D019086:Bridged Bicyclo Compounds, Heterocyclic; D011725:Pyridines; D011963:Receptors, GABA-A; D005557:Formaldehyde; C082748:epibatidine; D008874:Midazolam
references.citation: Pain. 1999 Mar;80(1-2):291-9
references.pmid: 10204742
references.citation: Br J Pharmacol. 1994 Dec;113(4):1487-93
references.pmid: 7889306
references.citation: Neuropharmacology. 1987 Dec;26(12):1715-20
references.pmid: 2449625
references.citation: Can J Anaesth. 1998 Jun;45(6):551-5
references.pmid: 9669009
references.citation: Pain. 1992 Jan;48(1):61-71
references.pmid: 1738576
references.citation: J Pharmacol Exp Ther. 1993 Oct;267(1):341-9
references.pmid: 7901397
references.citation: Neuropharmacology. 1996 Apr;35(4):393-405
references.pmid: 8793901
references.citation: Acta Physiol Acad Sci Hung. 1973;44(1):85-93
references.pmid: 4804571
references.citation: Eur J Pharmacol. 2003 May 30;470(1-2):27-31
references.pmid: 12787827
references.citation: Pain. 1999 Jan;79(1):75-82
references.pmid: 9928779
references.citation: Anesthesiology. 1990 Aug;73(2):273-7
references.pmid: 2166454
references.citation: J Pharmacol Exp Ther. 1998 Dec;287(3):847-53
references.pmid: 9864263
references.citation: Brain Res. 1997 Apr 11;753(2):269-82
references.pmid: 9125412
references.citation: Pain. 1992 Jan;48(1):5-12
references.pmid: 1531383
references.citation: Can J Anaesth. 2006 Oct;53(10):1004-9
references.pmid: 16987855
references.citation: Mol Pharmacol. 1994 Apr;45(4):563-9
references.pmid: 8183234
references.citation: Pharmacogenetics. 1999 Oct;9(5):619-25
references.pmid: 10591542
references.citation: J Pharmacol Exp Ther. 1995 Mar;272(3):1199-203
references.pmid: 7891333
references.citation: Pain. 1996 Feb;64(2):345-355
references.pmid: 8740613
references.citation: J Physiol. 2000 Oct 1;528 Pt 1:1
references.pmid: 11018098
references.citation: Neurosci Lett. 1988 Jul 19;90(1-2):197-202
references.pmid: 3137509
references.citation: Neuroscience. 1994 Jul;61(1):123-32
references.pmid: 7526265
references.citation: Pharmacol Biochem Behav. 1995 Aug;51(4):855-60
references.pmid: 7675869
references.citation: Anesthesiology. 2006 Feb;104(2):338-43
references.pmid: 16436854
references.citation: Neuroscience. 1991;44(3):741-6
references.pmid: 1754057
references.citation: J Pharmacol Exp Ther. 1994 Nov;271(2):624-31
references.pmid: 7965777
references.citation: Life Sci. 1989;45(11):947-61
references.pmid: 2677570