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      Proteomics analysis of the amygdala in rats with CFA-induced pain aversion with electro-acupuncture stimulation

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          Clinical patients suffering from pain usually exhibit aversion to pain-associated environments (pain aversion). Electro-acupuncture (EA) has been proven to be effective for the treatment of pain aversion in our previous studies. The amygdala could have substantial consequences on emotion and pain consolidation as well as general pain aversion behavior, however, the underlying mechanism remains unclear.


          The current study was performed to investigate Isobaric tags for relative and absolute quantitation (iTRAQ) based quantitative proteomic analysis of the amygdala in rats with complete Freund’s adjuvant (CFA)-induced pain aversion, and comprehensive analysis of protein expression were performed to explore the underlying mechanism by which EA affects pain aversion.

          Materials and methods

          Inflammatory pain was induced with an intraplantar injection of 100 μL of CFA in the plantar surface of the left hind paw of the male Spragure-Dawley (SD) rats. Then the CFA-induced conditioned place aversion (C-CPA) test was performed. EA stimulation on the bilateral Zusanli and Sanyinjiao acu-points was used for 14 days and the EA stimulation frequency is 2 Hz. Based on iTRAQ-based proteomics analysis, we investigated the protein expression in the amygdala.


          EA can increase the paw withdrawal threshold in inflammatory pain induced by noxious stimulation. A total of 6319 proteins were quantified in amygdala. Of these identified proteins, 123 were identified in the pain aversion group relative to those in the saline group, and 125 significantly altered proteins were identified in the pain aversion + EA group relative to the pain aversion group. A total of 11 proteins were found to be differentially expressed in the amygdala of pain aversion and EA-treated rats. The expression of three proteins, glyceraldehyde-3-phosphate dehydrogenase, glutamate transporter-1, and p21-activated kinase 6, were confirmed to be consistent with the results of the proteome.


          Our investigation demonstrated the possible mechanism of central nerve system by which EA intervetion on pain aversion.

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          Most cited references 42

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          Hydrogen sulfide and cell signaling.

          Hydrogen sulfide (H₂S) is a gaseous mediator synthesized from cysteine by cystathionine γ lyase (CSE) and other naturally occurring enzymes. Pharmacological experiments using H₂S donors and genetic experiments using CSE knockout mice suggest important roles for this vasodilator gas in the regulation of blood vessel caliber, cardiac response to ischemia/reperfusion injury, and inflammation. That H₂S inhibits cytochrome c oxidase and reduces cell energy production has been known for many decades, but more recently, a number of additional pharmacological targets for this gas have been identified. H₂S activates K(ATP) and transient receptor potential (TRP) channels but usually inhibits big conductance Ca²(+)-sensitive K(+) (BK(Ca)) channels, T-type calcium channels, and M-type calcium channels. H₂S may inhibit or activate NF-κB nuclear translocation while affecting the activity of numerous kinases including p38 mitogen-activated protein kinase (p38 MAPK), extracellular signal-regulated kinase (ERK), and Akt. These disparate effects may be secondary to the well-known reducing activity of H₂S and/or its ability to promote sulfhydration of protein cysteine moieties within the cell.
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            Psychological aspects of persistent pain: current state of the science.

            This article provides an overview of current research on psychological aspects of persistent pain. It is divided into 3 sections. In section 1, recent studies are reviewed that provide evidence that psychological factors are related to adjustment to persistent pain. This section addresses research on factors associated with increased pain and poorer adjustment to pain (ie, pain catastrophizing, pain-related anxiety and fear of pain, and helplessness) and factors associated with decreased pain and improved adjustment to pain (ie, self-efficacy, pain coping strategies, readiness to change, and acceptance). In section 2, we review recent research on behavioral and psychosocial interventions for patients with persistent pain. Topics addressed include early intervention, tailoring treatment, telephone/Internet-based treatment, caregiver-assisted treatment, and exposure-based protocols. In section 3, we conclude with a general discussion that highlights steps needed to advance this area of research including developing more comprehensive and integrative conceptual models, increasing attention to the social context of pain, examining the link of psychological factors to pain-related brain activation patterns, and investigating the mechanisms underlying the efficacy of psychological treatments for pain. This is one of several invited commentaries to appear in The Journal of Pain in recognition of The Decade of Pain Research. This article provides an overview of current research on psychological aspects of persistent pain, and highlights steps needed to advance this area of research. Copyright 2004 American Pain Society
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              The amygdala and persistent pain.

              A reciprocal relationship exists between persistent pain and negative affective states such as fear, anxiety, and depression. Accumulating evidence points to the amygdala as an important site of such interaction. Whereas a key role of the amygdala in the neuronal mechanisms of emotionality and affective disorders has been well established, the concept of the amygdala as an important contributor to pain and its emotional component is still emerging. This article will review and discuss evidence from anatomical, neuroimaging, behavioral, electrophysiological, pharmacological, and biochemical data that implicate the amygdala in pain modulation and emotional responses to pain. The latero-capsular division of the central nucleus of the amygdala is now defined as the "nociceptive amygdala" and integrates nociceptive information with poly-modal information about the internal and external bodily environment. Dependent on environmental conditions and affective states, the amygdala appears to play a dual facilitatory and inhibitory role in the modulation of pain behavior and nociceptive processing at different levels of the pain neuraxis. Only recently, electrophysiological, pharmacological, and biochemical neuroplastic changes were shown in the nociceptive amygdala in persistent pain. It is conceivable, however, that amygdala plasticity plays an important role in emotional pain behavior and its modulation by affective state.

                Author and article information

                J Pain Res
                J Pain Res
                Journal of Pain Research
                13 November 2019
                : 12
                : 3067-3078
                [1 ]Key Laboratory of Acupuncture and Neurology of Zhejiang Province, The Third Clinical Medical College, Zhejiang Chinese Medical University , Hangzhou, People’s Republic of China
                [2 ]Department of Acupuncture and Moxibustion, The Fourth Clinical Medical College, Zhejiang Chinese Medical University , Hangzhou, People’s Republic of China
                [3 ]Zhejiang Chinese Medical University , Hangzhou, People’s Republic of China
                Author notes
                Correspondence: Jianqiao FangZhejiang Chinese Medical University , Hangzhou, Zhejiang310053, People’s Republic of ChinaTel +86 5 718 667 3000 Email fangjianqiao7532@163.com
                © 2019 Wu et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 6, Tables: 2, References: 48, Pages: 12
                Original Research

                Anesthesiology & Pain management

                pain, pain aversion, amygdala, electro-acupuncture, proteomics


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