PI3K Contributed to Modulation of Spinal Nociceptive Information Related to ephrinBs/EphBs

Li-Na Yu,Xue-Long Zhou,Li-Shan Jiang,Hao Huang,Jing Yu,Feng-Jiang Zhang,Min Yan,Jun-Li Cao,Mark L Baccei

doi:10.1371/journal.pone.0040930

Abstract

There is accumulating evidence to implicate the importance of EphBs receptors and ephrinBs ligands were involved in modulation of spinal nociceptive information. However, the downstream mechanisms that control this process are not well understood. In the present study, we investigated whether phosphatidylinositol 3-kinase (PI3K), as the downstream effectors, participates in modulation of spinal nociceptive information related to ephrinBs/EphBs. Intrathecal injection of ephrinB1-Fc produced a dose- and time-dependent thermal and mechanical hyperalgesia, accompanied by the increase of spinal PI3K-p110γ, phosphorylation of AKT (p-AKT) and c-Fos expression. Pre-treatment with PI3K inhibitor wortmannin or LY294002 prevented activation of spinal AKT induced by ephrinB1-Fc. Inhibition of spinal PI3K signaling dose-dependently prevented and reversed pain behaviors and spinal c-Fos protein expression induced by intrathecal injection of ephrinB1-Fc. Inhibition of EphBs receptors by intrathecal injection of EphB1-Fc reduced formalin-induced inflammation and chronic constrictive injury-induced neuropathic pain behaviors accompanied by decreased expression of spinal PI3K,p-AKT and c-Fos protein. Furthermore, pre-treatment with PI3K inhibitor wortmannin or LY294002 prevented ephrinB1-Fc-induced ERK activation in spinal. These data demonstrated that PI3K and PI3K crosstalk to ERK signaling contributed to modulation of spinal nociceptive information related to ephrinBs/EphBs.

Highlights

Central sensitization, an activity-dependent functional plasticity in spinal cord neurons, is one of the main causes of behavior hyperalgesia under pathologic conditions and has been under intensive investigation [1,2,3]
We found that intrathecal injection of ephrinB1-Fc (0.02, 0.1, and 0.5 mg in 5 ml saline), not control Fc, induced a dose-dependent thermal hyperalgesia and mechanical allodynia in mice, which can last at least up to 24 h and return to baseline level on 48 h after injection of ephrinB1-Fc (P,0.05, from 0.5 to 24 h time point, ephrinB1-Fc 0.1 or ephrinB1-Fc 0.5 group compared with saline or Fc group; fig. 1A)
Compared with saline and Fc groups, the calculated area under the curve (22– 48 h) in paw-withdrawal latency (PWL) and paw-withdrawal threshold (PWT) tests was significantly decreased in a dosedependent manner in ephrinB1-Fc group.To rule out a nonspecific effect through the Fc portion, human Fc was used as a control

Summary

Introduction

An activity-dependent functional plasticity in spinal cord neurons, is one of the main causes of behavior hyperalgesia under pathologic conditions and has been under intensive investigation [1,2,3]. Recent advances indicate that Eph receptors and ephrin ligands are present in the adult brain and peripheral tissue and play a critical role in modulating multiple aspects of physiology and pathophysiology(e.g., activity-dependent synaptic plasticity, regulation of pain threshold, epileptogenesis, inflammation response, and excitotoxic neuronal death) [8,9,10,11]. Some studies demonstrated that activation of spinal ephrinBs/EphBs system played a critical role in the development and maintenance of chronic pain after peripheral nerve injury [15,16,17].These studies indicated that Ephrin/Eph system may be involved in physiologic and pathologic pain modulation in the spinal cord level. The downstream mechanisms that control this process are not well understood

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Conclusion