Enhancement of the effects of a complete inhibitor of enkephalin-catabolizing enzymes, RB 101, by a cholecystokinin-B receptor antagonist in diabetic rats.
1. RB 101, a complete inhibitor of enkephalin-catabolizing enzymes, has been previously shown to produce antinociception in normal rats after systemic administration. Moreover, its coadministration with a cholecystokinin-B (CCK-B) receptor antagonist has been shown to strongly enhance its antinociceptive effect in normal rats. In this work, we determined whether RB 101 was able to reduce hyperalgesia and allodynia in diabetic rats, a model of neuropathic pain. The type of opioid receptors (mu or delta) involved was determined using naloxone and naltrindole, respectively, and the interactions between endogenous enkephalins and CCK on nociception control was investigated using coadministration of RB 101 and the CCK-B receptor antagonist CI-988. 2. RB 101 suppressed mechanical hyperalgesia (paw pressure-induced vocalization test), partially alleviated mechanical allodynia (von Frey hair test), and was ineffective in thermal allodynia (tail immersion test). The analgesic effect was completely cancelled by naloxone or naltrindole, suggesting that is requires the availability of mu- and/or delta-opioid receptors. 3. The combination of an inactive dose of CI-988 with the lowest effective dose of RB 101 resulted in a stronger increase in the vocalization threshold comparatively to RB 101 alone. 4. The present study demonstrates that the antinociception generated by RB 101 induced by elevation of extracellular levels of endogenous enkephalins, can be extended to neuropathic pain in diabetic rats and that blockade of CCK-B receptors potentiated antinociceptive effects elicited by RB 101.
Coudoré-Civiale
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MA
INSERM EPI 9904, Laboratoire de Physiologie, Faculté de Pharmacie. INSERM EPI 9904, Laboratoire de Pharmacologie Médicale, Faculté de Médecine, 63001 Clermont-Ferrand Cedex 1, France.
Méen
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Fournié-Zaluski
M C
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Boucher
M
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Roques
B P
BP
Eschalier
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A
D000626:Aminopeptidases / Q000037:antagonists & inhibitors*; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000378:metabolism*; D004220:Disulfides / Q000819:agonists* / Q000494:pharmacology / Q000627:therapeutic use*; D004357:Drug Synergism; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008536:Meglumine / Q000031:analogs & derivatives / Q000494:pharmacology; D009270:Naloxone / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology; D015260:Neprilysin / Q000037:antagonists & inhibitors; D010146:Pain / Q000188:drug therapy*; D010147:Pain Measurement / Q000187:drug effects; D010649:Phenylalanine / Q000819:agonists* / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D011312:Pressure; D051381:Rats; D017207:Rats, Sprague-Dawley; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors*; D013997:Time Factors; D014828:Vocalization, Animal / Q000187:drug effects; D015431:Weight Loss
D004220:Disulfides; D007211:Indoles; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin; C065599:PD 134308; C074024:RB 101; D009270:Naloxone; D010649:Phenylalanine; D009271:Naltrexone; D008536:Meglumine; D000626:Aminopeptidases; C025579:enkephalin degrading enzyme; D015260:Neprilysin; C055382:naltrindole