Antinociceptive effects of RB101(S), a complete inhibitor of enkephalin-catabolizing enzymes, are enhanced by (+)-HA966, a functional NMDA receptor antagonist: a c-Fos study in the rat spinal cord.
The effects of the S enantiomer of RB101, a complete inhibitor of enkephalin-catabolizing enzymes, alone or in combination with a functional NMDA receptor antagonist, (+)-HA966 were studied on the spinal c-Fos protein expression in the carrageenan model of inflammatory nociception. One hour 30min after intraplantar carrageenan in awake rats, c-Fos immunoreactive (c-Fos-IR) nuclei were preferentially located in the laminae I-II and V-VI of the spinal dorsal horn, i.e., spinal areas containing numerous neurons responding exclusively, or not, to peripheral nociceptive stimuli. RB101(S) (5, 10, 20 and 40mg/kg i.v.) dose-dependently reduced the total number of carrageenan-evoked c-Fos-IR nuclei (r=0.63, P<0.01), with 49+/-3% reduction (P<0.001) for the highest dose. Two highest doses of RB101(S) (20 and 40mg/kg) significantly reduced the number of carrageenan-evoked c-Fos-IR nuclei in both superficial I-II (32+/-7% and 36+/-5% reduction, respectively, P<0.05 for both) and deep V-VI (42+/-6% and 61+/-2% reduction, respectively, P<0.001 for both) laminae. The effects of RB101(S) were naloxone-reversible. Combination of low doses of RB101(S) (2.5 or 10mg/kg i.v.) and an inactive dose of (+)-HA966 (2.5mg/kg s.c.) produced supra-additive effects (39+/-4% and 51+/-5% reduction of the total number of c-Fos-IR nuclei, respectively, P<0.001 for both). These effects were partially reversed by naloxone. These results provide evidence for the potent effects of combination of RB101(S) and (+)-HA966. Considering the absence of major opioid side effects of RB101(S) and the marked increase of its antinociceptive effects by NMDA receptor antagonist, this type of drug combination could have beneficial therapeutical application.
Buritova
Jaroslava
J
Physiopharmacologie du Système Nerveux, INSERM U161, 2 rue d'Alésia, 75014 Paris, France. jaroslava.buritova@pierre-fabre.com
Le Guen
Stéphanie
S
Fournié-Zaluski
Marie-Claude
MC
Roques
Bernard P
BP
Besson
Jean-Marie
JM
D000700:Analgesics / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D002351:Carrageenan; D004220:Disulfides / Q000494:pharmacology* / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D004745:Enkephalins / Q000819:agonists / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D007150:Immunohistochemistry; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D011760:Pyrrolidinones / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism
D000700:Analgesics; D004220:Disulfides; D004745:Enkephalins; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D009292:Narcotic Antagonists; D016760:Proto-Oncogene Proteins c-fos; D011760:Pyrrolidinones; D016194:Receptors, N-Methyl-D-Aspartate; C074024:RB 101; D009270:Naloxone; D010649:Phenylalanine; D002351:Carrageenan; C001369:1-hydroxy-3-amino-2-pyrrolidone