J Anesth Perioper Med. 2014;1(2):79-89. https://doi.org/10.24015/ebcmed.japm.2014.0013

Activation of Spinal EphrinBs/EphBs Contributes to Morphine Dependence and Tolerance

He Liu1,2,3*, Di-Yang Ling1,2*, Yan Yuan1,2,3*, Xue-Hai Guan1,2, Jia-Ping Ruan1,2, Hong-Xing Zhang1,2, Hai-Lei Ding1,2, and Jun-Li Cao1,2,3

From the 1Jiangsu Province Key Laboratory of Anesthesiology, 2Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou, China; 3Department of Anesthesiology, Affiliated Hospital of Xuzhou Medical College, Xuzhou, China.

*These authors contributed equally to this work.

Correspondence to Dr. Jun-Li Cao at caojl0310@aliyun.com.

EBCMED ID: ebcmed.japm.2014.0013 DOI: 10.24015/ebcmed.japm.2014.0013


Previous studies have demonstrated that spinal ephrinBs/EphBs system plays a critical role in the development and maintenance of chronic pain, and neuropathic pain and opiate dependence may share some common mechanisms. The aim of this study was to further explore the role of the spinal ephrinBs/EphBs system in opiate dependence and tolerance.

Adult male kunming mice were randomly allocated into treatment group and control group. Four different models including acute/chronic morphine dependence and acute/chronic morphine tolerance were set up in treatment group and control group individually. Withdrawal syndromes were precipitated by naloxone (4mg/kg, intraperitoneal), the inhibitory or reversal role of EphB1-Fc in acute/chronic morphine withdrawal or tolerance was assessed by injecting 0.5 μg/5 μl EphB1-Fc intrathecally prior to the treatment of morphine. In control group, equal value of vehicle (saline) was substituted for morphine. In behavior part, morphine physical dependence was assessed by "withdrawal jumping" counting; and morphine induced antinociceptive tolerance was evaluated by "paw withdrawal latency" in hot- plate test. PERK and C-Fos expression in the spinal cord were detected by western blot and immunohistochemistry individually.

Acute and chronic morphine treatment increased the expression of spinal ephrinB1, which was further increased by acute morphine withdrawal precipitated by administration of naloxone; however, chronic morphine withdrawal precipitated by administration of naloxone decreased the expression of ephrinB1, which was significantly higher than that in saline group. Intrathecal pretreatment of EphB1-Fc inhibited or reversed morphine tolerance-induced antinociceptive tolerance and naloxoneprecipitated withdrawal jumping, which was accompanied with the decreased expression of spinal Fos protein and p-ERK.

These results demonstrated that activation of spinal ephrinBs/EphBs contributed to morphine dependence and tolerance.

Article Type
Original Article

Declaration of Interests
All authors have no other financial support and potential conflicts of interest for this work.

This study was supported in part by grants from the National Natural Science Foundation of China (NSFC81070888, 81230025 to Prof. Cao, NSFC 22100201 to Prof. Ding, NSFC81200862 to Dr. Zhang, NSFC81300957 to Dr. Liu), Jiangsu Province Nature Science Foundation (BK2004029 to Prof. Cao), and “Xing-Wei” project of Jiangsu Province Department of Health (RC2007094 to Prof. Cao).

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