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      Spinal ephrinB/EphB signalling contributed to remifentanil-induced hyperalgesia via NMDA receptor


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          One of the major unresolved issues in treating pain is the paradoxical hyperalgesia produced by opiates, and accumulating evidence implicate that EphBs receptors and ephrinBs ligands are involved in mediation of spinal nociceptive information and central sensitization, but the manner in which ephrinB/EphB signalling acts on spinal nociceptive information networks to produce hyperalgesia remains enigmatic. The objective of this research was to investigate the role of ephrinB/EphB signalling in remifentanil-induced hyperalgesia (RIH) and its downstream effector.


          We characterized the remifentanil-induced pain behaviours by evaluating thermal hyperalgesia and mechanical allodynia in a rat hind paw incisional model. Protein expression of EphB1 receptor and ephrinB1 ligand in spinal dorsal horn cord was determined by Western blotting, and Fos was determined by immunohistochemistry assay, respectively. To figure out the manner in which ephrinB/EphB signalling acts with N-methyl- d-aspartic acid (NMDA) receptor, we used MK-801, an antagonist of NMDA receptor, trying to suppressed the hyperalgesia induced by ephrinB1-Fc, an agonist of ephrinB/EphB.


          Continuing infusion of remifentanil produced a thermal hyperalgesia and mechanical allodynia, which was accompanied with increased protein expression of spinal-level EphB1 receptor, ephrinB1 ligand and Fos; what appeared above was suppressed by pretreatment with EphB1-Fc, an antagonist of ephrinB/EphB or MK-801, and increased pain behaviours induced by intrathecal injection of ephrinB1-Fc, an agonist of ephrinB/EphB, were suppressed by MK-801.


          Our findings indicated that ephrinB/EphB signalling is involved in RIH. EphrinB/EphB signalling might be the upstream of NMDA receptor.

          What's already known about this topic?
          • EphBs receptors and ephrinBs ligands are involved in mediation of spinal nociceptive information and central sensitization.

          • The combination of EphB receptor and N-methyl- d-aspartic acid receptor induces long-term potentiation that is critical for causing excitation of spinal neuron and pain hyperalgesia.

          What does this study add?
          • EphrinB/EphB signalling is involved in remifentanil-induced hyperalgesia (RIH).

          • EphrinB/EphB signalling might be the upstream of N-methyl- d-aspartic acid receptor in RIH.

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          Most cited references26

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          A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia.

          A method to measure cutaneous hyperalgesia to thermal stimulation in unrestrained animals is described. The testing paradigm uses an automated detection of the behavioral end-point; repeated testing does not contribute to the development of the observed hyperalgesia. Carrageenan-induced inflammation resulted in significantly shorter paw withdrawal latencies as compared to saline-treated paws and these latency changes corresponded to a decreased thermal nociceptive threshold. Both the thermal method and the Randall-Selitto mechanical method detected dose-related hyperalgesia and its blockade by either morphine or indomethacin. However, the thermal method showed greater bioassay sensitivity and allowed for the measurement of other behavioral parameters in addition to the nociceptive threshold.
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            Models and mechanisms of hyperalgesia and allodynia.

            Hyperalgesia and allodynia are frequent symptoms of disease and may be useful adaptations to protect vulnerable tissues. Both may, however, also emerge as diseases in their own right. Considerable progress has been made in developing clinically relevant animal models for identifying the most significant underlying mechanisms. This review deals with experimental models that are currently used to measure (sect. II) or to induce (sect. III) hyperalgesia and allodynia in animals. Induction and expression of hyperalgesia and allodynia are context sensitive. This is discussed in section IV. Neuronal and nonneuronal cell populations have been identified that are indispensable for the induction and/or the expression of hyperalgesia and allodynia as summarized in section V. This review focuses on highly topical spinal mechanisms of hyperalgesia and allodynia including intrinsic and synaptic plasticity, the modulation of inhibitory control (sect. VI), and neuroimmune interactions (sect. VII). The scientific use of language improves also in the field of pain research. Refined definitions of some technical terms including the new definitions of hyperalgesia and allodynia by the International Association for the Study of Pain are illustrated and annotated in section I.
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              Mechanisms and functions of Eph and ephrin signalling.


                Author and article information

                Eur J Pain
                Eur J Pain
                European Journal of Pain (London, England)
                BlackWell Publishing Ltd (Oxford, UK )
                October 2014
                16 April 2014
                : 18
                : 9
                : 1231-1239
                [1 ]Department of Anesthesiology, Second Affiliated Hospital, School of Medicine, Zhejiang University Hangzhou, China
                [2 ]Jiangsu Province Key Laboratory of Anesthesiology and Center for Pain Research and Treatment, Xuzhou Medical College China
                [3 ]Department of Anesthesiology, The First Hospital of Jiaxing China
                Author notes
                Correspondence, Min Yan, E-mail: yanminnina@ 123456hotmail.com
                *These authors contributed equally to this work.

                Founding sources This work was supported by grants from medicine health project of Zhejiang Province (No. 2008A088).

                Conflicts of interest None declared.

                © 2014 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation - EFIC®.

                This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

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                Anesthesiology & Pain management
                Anesthesiology & Pain management


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