Antinociceptive effects of RB101, a complete inhibitor of enkephalin-catabolizing enzymes, are enhanced by a cholecystokinin type B receptor antagonist, as revealed by noxiously evoked spinal c-Fos expression in rats.
The effects of RB101, a complete inhibitor of enkephalin-catabolizing enzymes, alone or with a selective cholecystokinin (CCK)B receptor antagonist (CI988) or CCK(A) receptor antagonist (devazepide), on carrageenin-induced spinal c-Fos expression were investigated. Spinal c-Fos expression was observed 90 min after intraplantar carrageenin (6 mg/150 microl saline), with Fos-like-immunoreactive neurons preferentially located in the superficial laminae of the spinal dorsal horn. Intravenous RB101 (10, 20 and 40 mg/kg) dose-dependently reduced the number of superficial Fos-like-immunoreactive neurons (r2 = 0.739, P < .0001), with 63 +/- 2% (P < .0001) reduction for the highest dose. These effects were completely blocked by coadministered naloxone. Coadministration of inactive doses of i.v. RB101 (5 mg/kg) and i.p. CI988 (3 mg/kg) significantly and strongly reduced the number of carrageenin-induced, superficial, Fos-like-immunoreactive neurons (55 +/- 5% reduction of control carrageenin c-Fos expression, P < .0001). This effect was blocked by coadministered naloxone. It is important to note that coadministered RB101 and devazepide did not influence spinal c-Fos expression. None of the various drug combinations influenced the carrageenin-induced peripheral edema. These results show that RB101 dose-dependently decreases carrageenin-evoked spinal c-Fos expression. In addition, the effectiveness of RB101 can be revealed by preadministration of the CCK(B) receptor antagonist CI988. Considering the weak opioid side effects obtained with RB101 treatment and the strong increase of its effects by the CCK(B) receptor antagonist, this type of drug combination could have promising therapeutic application in the management of pain in humans.
Honore
P
P
Physiopharmacologie du Système Nerveux, l'Institut National de la Santé et de la Recherche Médicale U161, and Ecole Pratique des HautesEtudes, Paris, France.
Buritova
J
J
Fournié-Zaluski
M C
MC
Roques
B P
BP
Besson
J M
JM
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology; D020109:Devazepide; D004220:Disulfides / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000188:drug therapy; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D008536:Meglumine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy / Q000378:metabolism*; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000032:analysis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors*; D013116:Spinal Cord / Q000737:chemistry / Q000187:drug effects*
D000700:Analgesics; D001570:Benzodiazepinones; D004220:Disulfides; D004791:Enzyme Inhibitors; D007211:Indoles; D016760:Proto-Oncogene Proteins c-fos; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin; C065599:PD 134308; C074024:RB 101; D010649:Phenylalanine; D008536:Meglumine; D020109:Devazepide