Bidirectional signaling between ephrins and Eph receptor tyrosine kinases was first found to play important roles during development, but recently has been implicated in synaptic plasticity and pain processing in the matured nervous system. We show that ephrinB-EphB receptor signaling plays a critical role is induction and maintenance of neuropathic pain by regulating neural excitability and synaptic plasticity in the dorsal root ganglion (DRG) and the spinal dorsal horn (DH). Intrathecal application of blocking reagents for EphB-receptors, EphB1-Fc and EphB2-Fc chimeras inhibits the induction and maintenance of nerve injury-induced thermal hyperalgesia and mechanical allodynia. These blockers also prevent and suppress the nerve injury-induced hyperexcitability of nociceptive small DRG neurons, sensitization of DH neurons and long-term potentiation (LTP) of synapses between C fibers and DH neurons. In naïve, uninjured animals intrathecal administration of EphB-receptor activators ephrinB1-Fc and ephrinB2-Fc, respectively, induces thermal hypersensitivity and lowers the threshold for LTP, while EphB1-Fc prevents induction of the LTP. Western Blot analysis shows that nerve injury triggers an upregulation of the ephrinB1 and EphB1 receptor proteins in DRG and the spinal cord. These results indicate that, by regulating excitability of nociceptive-related neurons in DRG and DH and the synaptic plasticity at the spinal level, ephrinB-EphB receptor signaling contributes to neuropathic pain. This novel role for ephrinB-EphB receptor signaling suggests that these molecules may be useful therapeutic targets for treating pain after nerve injury.

Aim: To investigate whether activation and translocation of extracellular signalregulated kinase (ERK) is involved in the induction and maintenance of neuropathic pain, and effects of activation and translocation of ERK on expression of pCREB and Fos in the chronic neuropathic pain. Methods: Lumbar intrathecal catheters were chronically implanted in male Sprague-Dawley rats. The left sciatic nerve was loosely ligated proximal to the sciatica's trifurcation at approximately 1.0 mm intervals with 4-0 silk sutures. The mitogen-activated protein kinase kinase (MEK) inhibitor U0126 or phosphorothioate-modified antisense oligonucleotides (ODN) were intrathecally administered every 12 h, 1 d pre-chronic constriction injury (CCI) and 3 d post-CCI. Thermal and mechanical nociceptive thresholds were assessed with the paw withdrawal latency (PWL) to radiant heat and von Frey filaments. The expression of pERK, pCREB, and Fos were assessed by both Western blotting and immunohistochemical analysis. Results: Intrathecal injection of U0126 or ERK antisense ODN significantly attenuated CCI-induced mechanical allodynia and thermal hyperalgesia. CCI significantly increased the expression of p-ERK-IR neurons in the ipsilateral spinal dorsal horn to injury, not in the contralateral spinal dorsal horn. The time courses of pERK expression showed that the levels of both cytosol and nuclear pERK, but not total ERK, were increased at all points after CCI and reached a peak level on postoperative d 5. CCI also significantly increased the expression of pCREB and Fos. Phospho-CREBpositive neurons were distributed in all laminae of the bilateral spinal cord and Fos was expressed in laminae I and II of the ipsilateral spinal dorsal horn. Intrathecal injection of U0126 or ERK antisense ODN markedly suppressed the increase of CCI-induced pERK, pCREB and c-Fos expression in the spinal cord. Conclusion: The activation of ERK pathways contributes to neuropathic pain in CCI rats, and the function of pERK may partly be accomplished via the cAMP response element binding protein (CREB)-dependent gene expression.

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EphrinB-EphB receptor signaling plays diverse roles during development, but recently has been implicated in synaptic plasticity in the matured nervous system and in pain processes. The present study investigated the correlation between expression of ephrinB and EphB receptor proteins and chronic constriction injury (CCI) of the sciatic nerve and dorsal rhizotomy (DR) in dorsal root ganglion (DRG) and spinal cord (SC); and interaction of CCI and DR on expression of these signals. Adult, male Sprague-Dawley rats were employed and thermal sensitivity was determined in the sham operated CCI and DR rats. Western blot and immunobiochemistry analysis and immunofluorescence staining techniques were used to detect the expression and location of the ephrinB-EphB receptor proteins in DRG and SC. The results showed that expression of ephrinB1 and EphB1 receptor proteins was significantly upregulated in DRG and SC in a time-dependent manner corresponding to the development of thermal hyperalgesia after CCI. The increased expression is predominately located in the medium- and small-sized DRG neurons, the superficial layers of spinal dorsal horn (DH) neurons, and the IB4 positive nociceptive terminals. DR increases ephrinB1 in DRG, not SC and EphB receptor in SC, not DRG. DR suppressed CCI-induced upregulation of ephrinB1 in SC and EphB1 receptor in DRG and SC. These findings indicate that ephrinB-EphB receptor activation and redistribution in DRG and DH neurons after nerve injury could contribute to neuropathic pain. This study may also provide a new mechanism underlying DR-induced analgesia in clinic.

Thiamine can reduce hyperexcitability and lessen alterations of Na currents in injured DRG neurons, in addition to suppressing thermal hyperalgesia.

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.

MicroRNAs (miRNAs) are small non-coding RNAs that play critical roles in cervical carcinogenesis and progression. microRNA-133a (miR-133a) has been reported to play a tumor-suppressor role in a range of cancers. However, the role and underlying molecular mechanism of miR-133a in cervical cancer have not been investigated. In the present study, we investigated the role of miR-133a in the tumorigenicity of cervical cancer cells in vivo and in vitro. The expression of miR-133a was investigated using real-time reverse transcription-polymerase chain reaction (qRT-PCR) in 30 cervical specimens and matched adjacent normal tissues and cervical cancer cell lines. We found that the expression level of miR‑133a was significantly downregulated in cervical cancer tissues and cervical cancer cell lines, and the aberrant expression of miR-133a was correlated with lymph node metastasis, histological grade and FIGO stage. The role of miR-133a in tumorigenicity of cervical cancer cells was assessed by the restoration of miR-133a. We found that restoration of miR‑133a inhibited cell proliferation, colony formation, migration and invasion, promoted cell apoptosis in vitro and suppressed tumorigenicity in vivo. The epidermal growth factor receptor (EGFR) was confirmed to be a direct target of miR-133a in cervical cancer cells using luciferase assay and western blotting. Restoration of miR-133a inhibited EGFR expression and activated the AKT and ERK signaling pathways. These results showed that miR-133a suppresses cervical cancer growth in vitro and in vivo through targeting EGFR, suggesting that miR-133a can be a potential target for the treatment of cervical cancer.

Background:Sufentanil is widely used for patient-controlled intravenous analgesia (PCIA). Oxycodone has a powerful analgesic effect and mild side effects. We conducted this study to compare the efficacy of oxycodone and sufentanil for PCIA on postoperative pain after laparoscopic radical gastrectomy.Methodology:A total of fifty patients scheduled for laparoscopic radical gastrectomy were equally randomized to receive postoperative pain treatment with either oxycodone (Group O) or sufentanil (Group S) for 48 h postoperatively. PCIA was set on demand mode without loading dose or background infusion. Postoperative cumulative sufentanil or oxycodone consumption, pain intensity, sedation status, and side effects were assessed.Results:No significant differences were detected in visual analog scale score at rest and during coughing in the two groups at various time points after operation. Group S was associated with more doses delivered by PCIA than Group O. The overall satisfaction degree was higher in Group O. The incidences of side effects were comparable between the two groups.Conclusion:Oxycodone is a valuable alternative for PCIA in patients undergoing laparoscopic radical gastrectomy.