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EphB receptor signaling in mouse spinal cord contributes to physical dependence on morphine

Wen-Tao Liu^*, Hao-Chuan Li^*, Xue-Song Song^*, Zhi-Jiang Huang^* and Xue-Jun Song^*,,1

^* Department of Neurobiology, Parker University Research Institute, Dallas, Texas, USA; and

Jiangsu Province Key Laboratory of Anesthesiology and Center for Pain Research and Treatment, Xuzhou Medical College, Xuzhou, Jiangsu, China

¹ Correspondence: Department of Neurobiology, Parker University Research Institute, 2500 Walnut Hill Lane, Dallas, TX 75229, USA. E-mail: song{at}parkercc.edu

Cellular and molecular mechanisms underlying opioid tolerance and dependence remain elusive. We investigated roles of EphB receptor tyrosine kinases—which play important roles in synaptic connection and plasticity during development and in the matured nervous system—in development and maintenance of physical dependence on morphine in the mouse spinal cord (SC). Spinal administration of an EphB receptor blocking reagent EphB2-Fc prevents and/or suppresses behavioral responses to morphine withdrawal and associated induction of c-Fos and depletion of calcitonin gene-related peptide. Western blotting and immunohistochemical fluorescence staining demonstrates that EphB1 receptor protein is significantly up-regulated in the spinal dorsal horn following escalating morphine treatment. Chronic morphine exposure and withdrawal significantly increased phosphorylation of N-methyl-D-aspartate receptor subunit NR2B as well as the activated forms of extracellular signal-regulated kinase and the cAMP response element binding protein in SC. The increased levels of phosphorylation of these molecules, however, are significantly inhibited by the EphB receptor blocker. These findings indicate that EphB receptor signaling, probably by interacting with NR2B in SC, contributes to the development of opioid physical dependence and withdrawal effects. This novel role for EphB receptor signaling suggests that these molecules may be useful therapeutic targets for preventing, minimizing, or reversing the development of opiate dependence.—Liu, W.-T., Li, H.-C., Song, X.-S., Huang, Z.-J., Song, X.-J. EphB receptor signaling in mouse spinal cord contributes to physical dependence on morphine.

Key Words: opiate withdrawal • NR2B • ERK • CREB • c-Fos