WEAK TOLERANCE TO THE ANTINOCICEPTIVE EFFECT INDUCED BY THE ASSOCIATION OF A PEPTIDASE INHIBITOR AND A CCKB RECEPTOR ANTAGONIST

We have recently shown that CCKB receptor antagonists such as PD-134,3 08, }-4-oxo[R-(R,R*)]-butanoate-N-methyl-D-glucamine, are able to str ongly potentiate antinociception induced by endogenous enkephalins, pr otected from degrading enzymes by the mixed inhibitor RE 101, thylthio )butyldithio]-1-oxopropyl}-L-phenylalanine benzyl ester, at both spina l and supraspinal levels. In this study, the duration of this facilita tory response and the possible development of tolerance to this synerg istic effect were investigated in the rat tail-flick test after acute and chronic treatment with PD-134,308 and RE 101. PD-134,308 facilitat ed and prolonged the antinociceptive responses induced by RE 101 (20 m g/kg, i.v.). The duration of the effect induced by PD-134,308 was also investigated by injecting this compound at different times before RE 101 administration. In the case of the tail-flick test, the improvemen t of RE 101 antinociceptive response was still significant 6 h after P D-134,308 (3 mg/kg, i.p.), whereas in the hot-plate test, this enhance ment was only effective for 3 h after CCKB receptor antagonist adminis tration. In the case of a repeated administration of RE 101, the poten tiation induced by PD-134,308 on the antinociceptive effect produced b y the first injection of RE 101 (20 mg/kg, i.v.), was found almost ide ntical after a second administration of RE 101 performed 190 min later . Chronic administration of RB 101 (20 mg/kg, i.v.) plus PD-134,308 (3 mg/kg, i.p.) administered for 5 days both once or twice per day, did not induce the development of tolerance to antinociception at the peak effect time. However, a decrease in the duration of the antinocicepti ve response was observed. These results indicate that the potent and l ong-lasting antinociceptive response induced by the coadministration o f the peptidase inhibitor and the CCK, receptor antagonist could have interesting perspectives in the clinical treatment of pain.