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      Journal of Pain Research (submit here)

      This international, peer-reviewed Open Access journal by Dove Medical Press focuses on reporting of high-quality laboratory and clinical findings in all fields of pain research and the prevention and management of pain. Sign up for email alerts here.

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      Substance P modulates electroacupuncture analgesia in humanized mice with sickle cell disease

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          Abstract

          Purpose: Chronic pain is a major comorbidity of sickle cell disease (SCD). Acupuncture, a non-opioid and non-addictive therapy to treat pain, was found to reduce pain in the majority (80%) of SCD patients in an earlier retrospective review. We observed that electroacupuncture (EA) decreased hyperalgesia in transgenic mice with SCD with varied analgesia from high to moderate to no response. Interestingly, poor responders exhibited high levels of substance P (SP), a mediator of chronic pain, as well as active p38 MAPK in spinal cords. The present study aimed to investigate the roles of inhibition of SP and SP-activated p38 MAPK in chronic pain in sickle mice that are poorly responsive to EA intervention (moderate/non-responders).

          Materials and methods: Humanized mouse model with SCD defined as moderate- and non-responders to EA were intraperitoneally administered with antagonist of SP receptor NK1R (netupitant, 10 mg/kg/day, i.p.) or p38 MAPK inhibitor (SB203580, 10 mg/kg/day, i.p.) alone or in combination with EA (acupoint GB30, every 3rd day until day 12). Hyperalgesia to mechanical, thermal and cold stimuli, as well as deep tissue were measured. Phosphorylated p38 MAPK (phospho-p38 MAPK) in the lumbar spinal cord was quantified using western blotting. Phospho-p38 MAPK nuclear translocation in spinal dorsal horn was examined using immunohistochemical staining and confocal microscopy.

          Results: In EA poor-responders, combined treatment with EA and netupitant significantly enhanced the analgesic effects of EA in poor-responders on mechanical, heat, cold, and deep tissue pain, and decreased phosphorylation of p38 MAPK in lumbar spinal cords and its nuclear translocation in the spinal dorsal horn. Furthermore, combined treatment with EA and SB203580 significantly improved analgesic effects of EA on mechanical and heat hyperalgesia, but not cold or deep tissue hyperalgesia. However, additional EA treatment only, or administration of either netupitant or SB203580 alone did not lead to analgesic effects.

          Conclusions: These results suggest a pivotal role of SP in maintaining the chronic pain in SCD via spinal phospho-p38 MAPK signaling, which may hinder the effect of EA in poor responders. Inhibition of SP signaling pathway or activity of p38 MAPK significantly improved the EA analgesia In EA poor-responders with SCD, which provides a promising way to treat the chronic pain in patients with SCD.

          Most cited references16

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          Transgenic knockout mice with exclusively human sickle hemoglobin and sickle cell disease.

          To create mice expressing exclusively human sickle hemoglobin (HbS), transgenic mice expressing human alpha-, gamma-, and betaS-globin were generated and bred with knockout mice that had deletions of the murine alpha- and beta-globin genes. These sickle cell mice have the major features (irreversibly sickled red cells, anemia, multiorgan pathology) found in humans with sickle cell disease and, as such, represent a useful in vivo system to accelerate the development of improved therapies for this common genetic disease.
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            NK1 (substance P) receptor antagonists--why are they not analgesic in humans?

            Ray Hill (2000)
            Tachykinin NK1 receptor antagonists have failed to exhibit efficacy in clinical trials of a variety of clinical pain states. By contrast, in preclinical studies in animals NK1 receptor antagonists have been shown to attenuate nociceptive responses sensitized by inflammation or nerve damage, although they exhibit little effect on baseline nociception. Other agents with this profile of activity in animal tests, typically nonsteroidal anti-inflammatory drugs (NSAIDs), are analgesic in humans. Thus, NK1 receptor antagonists appear able to block behavioural responses to noxious and other stressful sensory stimuli at a level detectable in animal tests but fail to provide the level of sensory blockade required to produce clinical analgesia in humans.
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              Mast cell activation contributes to sickle cell pathobiology and pain in mice.

              Sickle cell anemia (SCA) is an inherited disorder associated with severe lifelong pain and significant morbidity. The mechanisms of pain in SCA remain poorly understood. We show that mast cell activation/degranulation contributes to sickle pain pathophysiology by promoting neurogenic inflammation and nociceptor activation via the release of substance P in the skin and dorsal root ganglion. Mast cell inhibition with imatinib ameliorated cytokine release from skin biopsies and led to a correlative decrease in granulocyte-macrophage colony-stimulating factor and white blood cells in transgenic sickle mice. Targeting mast cells by genetic mutation or pharmacologic inhibition with imatinib ameliorates tonic hyperalgesia and prevents hypoxia/reoxygenation-induced hyperalgesia in sickle mice. Pretreatment with the mast cell stabilizer cromolyn sodium improved analgesia following low doses of morphine that were otherwise ineffective. Mast cell activation therefore underlies sickle pathophysiology leading to inflammation, vascular dysfunction, pain, and requirement for high doses of morphine. Pharmacological targeting of mast cells with imatinib may be a suitable approach to address pain and perhaps treat SCA.
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                Author and article information

                Journal
                J Pain Res
                J Pain Res
                JPR
                jpainres
                Journal of Pain Research
                Dove
                1178-7090
                01 August 2019
                2019
                : 12
                : 2419-2426
                Affiliations
                [1 ] Vascular Biology Center, Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota , Minneapolis, MN, USA
                Author notes
                Correspondence: Ying Wang; Kalpna GuptaMedicine-Hematology , MMC 480, 420 Delaware Street SE, Minneapolis, MN55455, USATel +1 612 301 2640; +1 612 625 9604Email wang5729@ 123456umn.edu ; gupta014@ 123456umn.edu
                Article
                210196
                10.2147/JPR.S210196
                6682765
                aeb0d66d-67e3-46cb-9e87-19dfed8a3e12
                © 2019 Wang 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).

                History
                : 27 March 2019
                : 05 June 2019
                Page count
                Figures: 3, References: 17, Pages: 8
                Categories
                Original Research

                Anesthesiology & Pain management
                acupuncture,pain,neuromodulator,p38 mapk,neurokinin 1 receptor,neuroinflammation

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