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

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.

PKA is required for the modulation of spinal nociceptive information related to ephrinB–EphB signaling in mice

“…We speculate that species differences may account for these differences as we examined pain behaviors in mice and the previous study used rats. Indeed, in other study, the activation of spinal EphB receptors by using another reagent, ephrinB1-Fc, also produced thermal hyperalgesia and mechanical allodynia in mice (Ruan et al, 2010;Yu et al, 2012). Nevertheless, other factors, such as the use of different doses and different nociception tests, also potentially contributed to the discrepancies between our results and those of the previous study.…”

COX‐2 is required for the modulation of spinal nociceptive information related to ephrinB/EphB signalling

“…These findings demonstrate that ephrinB/EphB signalling is a key regulator of physiological and pathological processes underlying pain, suggesting that it may act as a new molecular target for pain prevention and relief. Indeed, in other study, activation of spinal EphB receptors using another reagent, eph-rinB1-Fc, also produced thermal hyperalgesia and mechanical allodynia in mice (Ruan et al, 2010;Yu et al, 2012). Spinal application of ephrinB2-Fc, which can activate EphB receptors, caused thermal hyperalgesia and mechanical allodynia.…”

“…The induction and maintenance of central sensitization are dependent on maladaptive alterations in the expression, distribution, and activity of ion channels, receptors and intracellular signal transduction pathways. For instance, ephrinB/EphB signalling can modulate spinal nociceptive processing through MAPKs-and PI3K-dependent mechanisms (Ruan et al, 2010;Yu et al, 2012). Exogenous ephrinB-Fc or increased expression of ephrinB proteins induced by tissue injury or inflammation directly activates EphB receptors in nociceptors or sensory neurons.…”

“…Our recent studies showed that spinal administration of ephrinB1-Fc, an EphB1 receptor activator, induced rapid extracellular signal-regulated kinase (ERK) activation mainly in spinal cord neurons (Ruan et al, 2010;Yu et al, 2012). The ERK activation plays an important role in neuronal plasticity and central sensitization (Ji et al, 1999;Karim et al, 2001).…”

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

“…Recently, our and other studies also demonstrated that activation of spinal ephrinBs/EphBs system played a critical role in the development and maintenance of chronic pain after peripheral nerve injury (18)(19)(20)(21)(22). There are striking similarities between neuropathic pain and opiate dependence and tolerance, and neuropathic pain and opiate dependence may share some common mechanisms (23,24).…”