The selective CCK-B receptor antagonist L-365,260 enhances morphine analgesia and prevents morphine tolerance in the rat.

Journal article

The effects of the selective CCK-A antagonist L-365,031 and the selective CCK-B antagonist L-365,260 on morphine analgesia and opiate tolerance and dependence in rats were examined. L-365,031 and L-365,260 had no effect on baseline pain thresholds in the radiant heat tail flick test but enhanced analgesia induced by a submaximal dose of morphine (4 mg/kg). Similarly, L-365,260 did not effect pain thresholds in the paw pressure test but enhanced morphine analgesia in this model. Rats injected twice daily for 6 days with incremental doses of morphine became tolerant to the analgesic effects of the drug. Twice daily injections of either 8 mg/kg L-365,031 or 0.2 mg/kg L-365,260 prevented the development of tolerance to morphine analgesia. In contrast, L-365,260 had no influence on the development of opiate dependence in these animals, as assessed by naloxone-precipitated withdrawal. The results of the present study, when considered together with previous data, indicate that the rank order of potency of non-peptide CCK antagonists for enhancing morphine analgesia is L-365,260 greater than MK-329 greater than L-365,031. This rank order correlates well with the potency of the antagonists in blocking CCK-B receptors in rodents and suggests that CCK/opiate interactions in this species are mediated by CCK-B receptors.

Authors: Dourish, C; O'Neill, M; Coughlan, J; Kitchener, S; Hawley, D

• Publication status: Published
• Journal: European journal of pharmacology
• Volume: 176
• Issue: 1
• Pages: 35-44
• Publication date: 1990-01-01
• DOI: 10.1016/0014-2999(90)90129-t
• EISSN: 1879-0712
• ISSN: 0014-2999
• Language: English
• Keywords: Rats, Inbred Strains; Morphine; Analgesia; Naloxone; Drug Tolerance; Phenylurea Compounds; Benzodiazepines; Pain Measurement; Rats; Pain; Reaction Time; Animals; Receptors, Cholecystokinin; Male; Substance Withdrawal Syndrome; Substance-Related Disorders; Benzodiazepinones