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      Sonic Hedgehog Signaling Contributes to Chronic Post-Thoracotomy Pain via Activating BDNF/TrkB Pathway in Rats

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          Abstract

          Purpose

          Some patients undergoing thoracotomy may suffer from chronic post-thoracotomy pain (CPTP). Treatment of CPTP has been a clinical challenge and the underlying mechanisms of CPTP remain elusive. Recently, sonic hedgehog (Shh) signaling has been shown to be associated with various pain states but its role in the pathogenesis of CPTP is still unclear.

          Methods

          CPTP was induced in rats by thoracotomy. Rats were divided into CPTP group and non-CPTP group based on the mechanical withdrawal threshold (MWT). Rats were administered with Shh signaling inhibitor cyclopamine and activator smoothened agonist (SAG), and then evaluated by MWT and cold allodynia testing. The expressions of Shh signaling (Shh ligand, patched and smoothened receptor, Gli transcription factors), brain-derived neurotrophic factor (BDNF), tropomyosin-related kinase receptor B (Trk-B), phosphatidylinositol 3-kinase (PI3K) and protein kinase B (Akt) in rat T4-5 spinal cord dorsal horn (SDH) were detected by Western blotting and immunohistochemistry.

          Results

          The expression of Shh signaling significantly increased and the BDNF/TrkB pathway was activated in T4-5 SDH of CPTP rats. Cyclopamine attenuated hyperalgesia and down-regulated the expressions of Gil1, BDNF, p-TrkB, p-PI3K and p-Akt in CPTP rats. SAG induced hyperalgesia in non-CPTP rats and elevated the expressions of Gil1, BDNF, p-TrkB, p-PI3K and p-Akt.

          Conclusion

          Shh signaling may contribute to CPTP via activating BDNF/TrkB signaling pathway, and inhibition of Shh signaling may effectively alleviate CPTP.

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          Most cited references 37

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          Chronic catheterization of the spinal subarachnoid space.

          To administer drugs into the spinal subarachnoid space of unanesthetized and intact rats and rabbits, a procedure is described whereby a polyethylene catheter (PE-10) may be inserted through a puncture of the atlanto-occipital membrane and secured to the skull. Calibration experiments carried out with bromophenol blue dye, 3H-naloxone and 14C-urea revealed first, that there was little rostro-caudal diffusion of the injectate along the spinal axis and secondly, that even for compounds such as naloxone which can rapidly permeate neural tissues, the levels which do appear in the brain are small following the spinal subarachnoid administration of the drug. Control injections, administered either acutely or repeatedly over a prolonged period of time, had no detectable effect on the animal's behavior. These observations, as well as the lack of pathology in the spinal cords of rats having such catheters for periods of up to 4 months suggests that the implant is well tolerated.
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            Chronic post-thoracotomy pain: a critical review of pathogenic mechanisms and strategies for prevention.

            Chronic pain complaints after thoracic surgery represent a significant clinical problem in 25-60% of patients. Results from thoracic and other surgical procedures suggest multiple pathogenic mechanisms that include pre-, intra-, and postoperative factors. This review attempts to analyse the methodology and systematics of the studies on the post-thoracotomy pain syndrome (PTPS) after lung cancer surgery in adults, in order to clarify the relative role of possible pathogenic factors and to define future strategies for prevention. Literature published from 2000 to 2008 together with studies included in previous systematic reviews was searched recursively using PubMed and OVID by combining three categories of search terms. The available data have major inconsistencies in collection of pre-, intra- and postoperative data that may influence PTPS, thereby hindering precise conclusions as well as preventive and treatment strategies. However, intercostal nerve injury seems to be the most important pathogenic factor. Since there is a general agreement on the clinical relevance of PTPS, a proposal for design of future trials is presented.
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              Nociceptor-derived brain-derived neurotrophic factor regulates acute and inflammatory but not neuropathic pain.

              Conditional mouse knock-outs provide an informative approach to drug target validation where no pharmacological blockers exist or global knock-outs are lethal. Here, we used the Cre-loxP system to delete BDNF in most nociceptive sensory neurons. Conditional null animals were healthy with no sensory neuron loss. However, pain-related behavior was substantially altered. Baseline thermal thresholds were reduced. Carrageenan-induced thermal hyperalgesia was inhibited. Formalin-induced pain behavior was attenuated in the second phase, and this correlated with abolition of NMDA receptor NR1 Ser896/897 phosphorylation and ERK1 and ERK2 activation in the dorsal horn; AMPA receptor phosphorylation (GluR1/Ser831) was unaffected. NGF-induced thermal hyperalgesia was halved, and mechanical secondary hyperalgesia caused by intramuscular NGF was abolished. By contrast, neuropathic pain behavior developed normally. Nociceptor-derived BDNF thus plays an important role in regulating inflammatory pain thresholds and secondary hyperalgesia, but BDNF released only from nociceptors plays no role in the development of neuropathic pain.
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                Author and article information

                Journal
                J Pain Res
                J Pain Res
                JPR
                jpainres
                Journal of Pain Research
                Dove
                1178-7090
                10 July 2020
                2020
                : 13
                : 1737-1746
                Affiliations
                [1 ]Anesthesia and Operation Center, The First Medical Center of Chinese PLA General Hospital, Medical School of Chinese PLA , Beijing 100853, People’s Republic of China
                [2 ]Department of Anesthesiology, The Fourth Medical Center of Chinese PLA General Hospital, Medical School of Chinese PLA , Beijing 100037, People’s Republic of China
                [3 ]Department of Anesthesiology, Tianjin Cancer Institute & Hospital, Tianjin Medical University , Tianjin 300060, People’s Republic of China
                [4 ]Department of Anesthesiology, Air Force Medical Center , Beijing 100142, People’s Republic of China
                Author notes
                Correspondence: Hong Zhang; Yitian Yang Email mazuimao301@163.com; yangyitiansdu@126.com
                [*]

                These authors contributed equally to this work

                Article
                245515
                10.2147/JPR.S245515
                7360429
                © 2020 Yang 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: 5, References: 44, Pages: 10
                Categories
                Original Research

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