1Department of Anesthesiology, China Medical University Hospital, Taichung, Taiwan
2School of Medicine, China Medical University, Taichung, Taiwan
3 Graduate Institute of Acupuncture Science, College of Chinese Medicine, China Medical University, Taichung, Taiwan
Opioids are a class of the most effective analgesics for treating many forms of acute and chronic pain. However, prolonged use of opioid causes analgesic tolerance, withdrawal syndrome, and paradoxical opioid-induced hyperalgesia, which attenuates benefits and hinder the effective use of opioids in human and in animals. Cholecystokinin (CCK) is an anti-opioid endogenous peptide and presumed to be involved in this tolerant-related phenomenon. In this study, we tested if combination with CCK-B receptor antagonist could ameliorate and/or treat the side effects after prolonged morphine treatment.
Materials and Methods
SD rats were subjective to morphine 4 mg/kg, s.c. twice daily for 5 days and developed morphine analgesic tolerance. The morphine-treated rats were allocated into four groups to respectively co-injected with LY225,910 (0.1, 0.5, or 1 mg/kg, s.c.), a potent CCK-B antagonist, or saline 1.0 ml 30 min before every morphine injection. Another two control groups are rats injected with either saline or LY225,910 (1 mg/kg, s.c.) alone for comparison. To test if LY225,910 could reverse opioid tolerance, the morphine-tolerant rats, which had been treated as abovementioned, were divided into three groups to receive single injection of saline, or high-dose LY225,910 (1 mg/kg or 5 mg/kg) on the 5th day. Tail-flick tests were measured every morning after each morphine injection, and “Maximal Possible Effects (MPE)” were calculated for analysis.
Co-treatment with LY225,910 and morphine significantly attenuatedmorphine tolerance in a dose-dependent manner. Besides, the rats which showed
Cholecystokinin, CCK antagonist, Morphine tolerance, Tail-flick test
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