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 a ntagonist (CI988) or CCKA receptor antagonist (devazepide), on carrage enin-induced spinal c-Fos expression were investigated. Spinal c-Fos e xpression was observed 90 min after intraplantar carrageenin (6 mg/150 mu l saline), with Fos-like-immunoreactive neurons preferentially loc ated in the superficial laminae of the spinal dorsal horn. Intravenous RB101 (10, 20 and 40 mg/kg) dose-dependently reduced the number of su perficial Fos-like-immunoreactive neurons (r(2) = 0.739, P < .0001), w ith 63 +/- 2% (P < .0001) reduction for the highest dose. These effect s were completely blocked by coadministered naloxone. Coadministration of inactive doses of i.v. RB101 (5 mg/kg) and i.p. CI988 (3 mg/kg) si gnificantly and strongly reduced the number of carrageenin-induced, su perficial, Fos-like-immunoreactive neurons (55 +/- 5% reduction of con trol carrageenin c-Fos expression, P < .0001). This effect was blocked by coadministered naloxone. It is important to note that coadminister ed RB101 and devazepide did not influence spinal c-Fos expression. Non e of the various drug combinations influenced the carrageenin-induced peripheral edema. These results show that RB101 dose-dependently decre ases carrageenin-evoked spinal c-Fos expression. In addition, the effe ctiveness of RB101 can be revealed by preadministration of the CCKB re ceptor antagonist CI988. Considering the weak opioid side effects obta ined with RB101 treatment and the strong increase of its effects by th e CCKB receptor antagonist, this type of drug combination could have p romising therapeutic application in the management of pain in humans.