Vol. 281, Issue 1, 208-217, 1997

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 Rats¹

Prisca Honoré, Jaroslava Buritova, Marie-Claude Fournié-Zaluski, Bernard P. Roques and Jean-Marie Besson

Physiopharmacologie du Système Nerveux, l'Institut National de la Santé et de la Recherche Médicale U161, and Ecole Pratique des Hautes Etudes, Paris, France (P.H., J.B., J.-M.B.), and Laboratoire de Pharmacochimie Moléculaire et Structurale, l'Institut National de la Santé et de la Recherche Médicale U266, CNRS URA D1500, Paris, France (M.-C.F.-Z., B.P.R.)

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 µl 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.