Original Article
Cholecystokinin-B Antagonist could Prevent and Reverse Repeated Morphine Injection-induced Antinociceptive Tolerance
Volume 30,Issue 1,Pages 7-18
Yu-Cheng Liu1 , Shang-Yi Lee1 , Hsin-Han Ouyang1 , Kuen Bao Chen1.2 , Yeong-Ray Wen1.2.3.4

1Pain Management and Research Center, Department of Anesthesiology, China Medical University Hospital, Taichung, Taiwan

2School of Medicine, China Medical University, Taichung, Taiwan

3Graduate Institute of Acupuncture Science, College of Chinese Medicine, China Medical University, Taichung, Taiwan

4Acupuncture Research Center, China Medical University, Taichung, Taiwan





Paradoxical opioid-induced pain, an unusual hyperesthesia and allodynia, appears in human and animals after exposure to long-term morphine uses. Cholecystokinin (CCK) is an endogenous anti-opioid peptide and presumed to be involved in this phenomenon. In this study, we tested if CCK-B antagonist could ameliorate nociceptive hyperalgesia in the morphine-tolerant rats.
Materials and Methods: Male Sprague-Dawley rats subjective to morphine 4 mg/kg, s.c. twice daily for 4 days and another injection in the morning of the fifth day, developed morphine analgesic tolerance. LY225,910 (0.1, or 1 mg/kg, s.c.), a CCK-B receptor antagonist, or saline at 1.0 ml was injected 30 min before morphine treatment in separate groups. Two control groups of rats received saline or LY225,910 (1 mg/kg, s.c.) alone twice daily for 5 days. Intraplantar formaline injection at the left hind paw was conducted after the last morphine or saline injection on the 5th day morning. Formalin-induced paw hyperalgesic responses were evaluated and calculated by a weighted pain scoring software. Fos expression by immunohistochemistry at the L4-5 spinal dorsal horn were also analyzed.


The morphine-tolerant rats showed significantly stronger formalininjection induced hyperalgesia compared to the normal rats, and co-treatment of LY225,910 with morphine attenuated morphine tolerance in a dose-dependent manner. The high-dose co-treatment group (1.0 mg/kg) showed a significant reduction in formalin-induced paw hyperalgesia, especially at the late phase response. Induction of Fos expression after formalin injection was higher in the morphine-treated rats compared to those in the saline or LY225,910 injection rats. Co-administration with LY225,910 at the high dose could decrease the Foslike immunoreactivity, but the low-dose group did not show difference from the morphine group.


We concluded that CCK-B antagonist LY225,910 could attenuate morphine tolerance-induced behavioral hyperalgesia and spinal Fos reactivity in the rats. The inhibition of Formalin-induced hyperalgesia may be mediated through reduction of spinal mechanism of the CCKergic pathway

Cholecystokinin, CCK antagonist, Formalin test, Morphine tolerance, Opioid-induced hyperalgesia

Key Words

Cholecystokinin, CCK antagonist, Formalin test, Morphine tolerance, Opioid-induced hyperalgesia

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