Blocking EphB1 Receptor Forward Signaling in Spinal Cord Relieves Bone Cancer Pain and Rescues Analgesic Effect of Morphine Treatment in Rodents

Su Liu,Yue-Peng Liu,Li-Ze Xiong,Wen-Tao Liu,Hai-Long Dong,Mark Henkemeyer,Xue-Jun Song

doi:10.1158/0008-5472.can-10-3870

Abstract

Treating bone cancer pain continues to be a clinical challenge and underlying mechanisms of bone cancer pain remain elusive. Here, we report that EphB1 receptor forward signaling in the spinal cord is critical to the development of bone cancer pain and morphine tolerance in treating bone cancer pain. Tibia bone cavity tumor cell implantation (TCI) produces bone cancer-related thermal hyperalgesia, mechanical allodynia, spontaneous and movement-evoked pain behaviors, and bone destruction. Production and persistence of these pain behaviors are well correlated with TCI-induced upregulation of EphB1 receptor and its ligand ephrinB2 in the dorsal horn and primary sensory neurons. Spinal administration of an EphB1 receptor blocking reagent EphB2-Fc prevents and reverses bone cancer pain behaviors and the associated induction of c-Fos and activation of astrocytes and microglial cells, NR1 and NR2B receptors, Src within the N-methyl-D-aspartate receptor complex, and the subsequent Ca(2+)-dependent signals. The exogenous ligand ephrinB2-Fc upregulates level of phosphorylation of NR1 and NR2B receptors depending on the activation of EphB1 receptor. Spinal administration of EphB2-Fc and ephrinB2-Fc induces downregulation of EphB1 and ephrinB2, respectively, accompanied with increased activity of matrix metalloproteinase (MMP)-2/9. Blocking MMP-2 or MMP-9 reverses EphB1-Fc treatment-induced downregulation of EphB1 receptor. In addition, spinal blocking or targeted mutation of EphB1 receptor reverses morphine tolerance in treating bone cancer pain in rats and defensive pain in mice. These findings show a critical mechanism underlying the pathogenesis of bone cancer pain and suggest a potential target for treating bone cancer pain and improving analgesic effect of morphine clinically.

Highlights

Bone cancer pain is one of the most common symptoms presented by patients with primary bone sarcomas and predominantly occurs as distant metastases of non-bone primary tumors, notably those in breast, prostate, and lung [1, 2]
Given that EphB1 receptor may be a potential target for treating bone cancer pain, we extended our experiments to examine whether morphine tolerance in treating bone cancer pain would be involved in the activation of ephrinB–EphB signaling
Our study reveals a critical role for the ephrinB–EphB receptor signaling in bone cancer pain and morphine tolerance in treating bone cancer pain

Summary

Introduction

Bone cancer pain is one of the most common symptoms presented by patients with primary bone sarcomas and predominantly occurs as distant metastases of non-bone primary tumors, notably those in breast, prostate, and lung [1, 2]. Tumor cells act to cause pain in many ways. Authors' Affiliations: 1Departments of Neurobiology, Parker University Research Institute, Dallas, Texas; 2Department of Anesthesiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China; and 3Developmental Biology, The University of Texas Southwestern Medical Center, Dallas, Texas. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). This work should be attributed to the Department of Neurobiology, Parker University Research Institute, Dallas, Texas, and Department of Anesthesiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China

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