Dose-independent antinociceptive interaction of endogenous ligands at the spinal level.
Adenosine, agmatine and kynurenic acid are endogenous ligands acting on different (e.g. adenosine, NMDA, alpha(2)-adrenergic and imidazoline) receptors with a potential role in nociception at the spinal level. Their antinociceptive effects have already been investigated as monotherapy, but only a few studies have reported on their effects on the potency of other drugs. The purpose of the present study was carried out to analyse their interactions during continuous intrathecal co-administration in a carrageenan-induced thermal hyperalgesia model in rats. A paw withdrawal test was used for nociceptive testing. The intrathecal infusion (60 min) of these three drugs was administered alone or in combinations (kynurenic acid+adenosine or agmatine; adenosine+agmatine), which was followed by an additional 60-min observation period. Kynurenic acid alone was ineffective, while adenosine and agmatine alone caused a slight increase in pain threshold. However, independently of the applied doses all of the combinations significantly (p<0.05) increased the paw withdrawal latencies on the inflamed side during and after the infusion, but were almost ineffective on the normal side. The adenosine+kynurenic acid combination was the most effective: namely, that it relieved thermal hyperalgesia in all the applied dose combinations. Treatment with the kynurenic acid-containing combinations also caused dose-dependent side-effects (motor impairment and excitation), despite the fact that monotherapy with kynurenic acid in the applied dose (0.1 microg/min) did not result in adverse effects.
Kekesi
Gabriella
G
Department of Physiology, Faculty of Medicine, University of Szeged, P.O. Box 427, H-6701, Szeged, Hungary.
Joo
Gabriella
G
Csullog
Emese
E
Peter-Szabo
Mihaly
M
Benedek
Gyorgy
G
Horvath
Gyongyi
G
D000241:Adenosine / Q000008:administration & dosage*; D000376:Agmatine / Q000008:administration & dosage*; D000700:Analgesics / Q000008:administration & dosage*; D000818:Animals; D002351:Carrageenan; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004357:Drug Synergism; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage; D006930:Hyperalgesia / Q000139:chemically induced; D007278:Injections, Spinal; D007736:Kynurenic Acid / Q000008:administration & dosage*; D008024:Ligands; D008297:Male; D017288:Pain Threshold / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects
D000700:Analgesics; D004338:Drug Combinations; D018691:Excitatory Amino Acid Antagonists; D008024:Ligands; D000376:Agmatine; D002351:Carrageenan; D007736:Kynurenic Acid; D000241:Adenosine