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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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      Ulinastatin Exhibits Antinociception in Rat Models of Acute Somatic and Visceral Pain Through Inhibiting the Local and Central Inflammation

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          Abstract

          Introduction

          Ulinastatin, a broad-spectrum serine protease inhibitor, has been widely used to treat various diseases clinically. However, so far, the antinociceptive effect of ulinastatin remains less studied experimentally and the underlying mechanisms of ulinastatin for pain relief remain unclear. This study aimed to find evidence of the analgesic effect of ulinastatin on acute somatic and visceral pain.

          Methods

          The analgesic effect of ulinastatin on acute somatic and visceral pain was evaluated by using formalin and acetic acid-induced writhing test. The analgesic mechanism of ulinastatin was verified by detecting the peripheral inflammatory cell infiltration and spinal glial activation with hematoxylin-eosin (H&E) and immunohistochemistry staining.

          Results

          We found that both of intraperitoneal (i.p.) pre-administration and post-administration of ulinastatin could reduce the total number of flinching and the licking duration following intraplantar formalin injection in a dose-related manner. However, the inhibitory effect of ulinastatin existed only in the second phase (Phase 2) of formalin-induced spontaneous pain response, with no effect in the first phase (Phase 1). The formalin-induced edema and ulcer were also improved by i.p. administration of ulinastatin. Moreover, i.p. administration of ulinastatin was also able to delay the occurrence of acetic acid-induced writhing and reduced the total number of writhes dose-dependently. We further demonstrated that ulinastatin significantly decreased the local inflammatory cell infiltration in injured paw and peritoneum tissue under formalin and acetic acid test separately. The microglial and astrocytic activation in the spinal dorsal horn induced by intraplantar formalin and i.p. acetic acid injection were also dramatically inhibited by i.p. administration of ulinastatin.

          Conclusion

          Our results for the first time provided a new line of evidence showing that ulinastatin could attenuate acute somatic and visceral pain by inhibiting the peripheral and spinal inflammatory reaction.

          Most cited references69

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          Pain as a global public health priority

          Background Pain is an enormous problem globally. Estimates suggest that 20% of adults suffer from pain globally and 10% are newly diagnosed with chronic pain each year. Nevertheless, the problem of pain has primarily been regarded as a medical problem, and has been little addressed by the field of public health. Discussion Despite the ubiquity of pain, whether acute, chronic or intermittent, public health scholars and practitioners have not addressed this issue as a public health problem. The importance of viewing pain through a public health lens allows one to understand pain as a multifaceted, interdisciplinary problem for which many of the causes are the social determinants of health. Addressing pain as a global public health issue will also aid in priority setting and formulating public health policy to address this problem, which, like most other chronic non-communicable diseases, is growing both in absolute numbers and in its inequitable distribution across the globe. Summary The prevalence, incidence, and vast social and health consequences of global pain requires that the public health community give due attention to this issue. Doing so will mean that health care providers and public health professionals will have a more comprehensive understanding of pain and the appropriate public health and social policy responses to this problem.
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            Role for protease activity in visceral pain in irritable bowel syndrome.

            Mediators involved in the generation of symptoms in patients with irritable bowel syndrome (IBS) are poorly understood. Here we show that colonic biopsy samples from IBS patients release increased levels of proteolytic activity (arginine cleavage) compared to asymptomatic controls. This was dependent on the activation of NF-kappaB. In addition, increased proteolytic activity was measured in vivo, in colonic washes from IBS compared with control patients. Trypsin and tryptase expression and release were increased in colonic biopsies from IBS patients compared with control subjects. Biopsies from IBS patients (but not controls) released mediators that sensitized murine sensory neurons in culture. Sensitization was prevented by a serine protease inhibitor and was absent in neurons lacking functional protease-activated receptor-2 (PAR2). Supernatants from colonic biopsies of IBS patients, but not controls, also caused somatic and visceral hyperalgesia and allodynia in mice, when administered into the colon. These pronociceptive effects were inhibited by serine protease inhibitors and a PAR2 antagonist and were absent in PAR2-deficient mice. Our study establishes that proteases are released in IBS and that they can directly stimulate sensory neurons and generate hypersensitivity symptoms through the activation of PAR2.
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              The crucial roles of inflammatory mediators in inflammation: A review

              The inflammatory response is a crucial aspect of the tissues’ responses to deleterious inflammogens. This complex response involves leukocytes cells such as macrophages, neutrophils, and lymphocytes, also known as inflammatory cells. In response to the inflammatory process, these cells release specialized substances which include vasoactive amines and peptides, eicosanoids, proinflammatory cytokines, and acute-phase proteins, which mediate the inflammatory process by preventing further tissue damage and ultimately resulting in healing and restoration of tissue function. This review discusses the role of the inflammatory cells as well as their by-products in the mediation of inflammatory process. A brief insight into the role of natural anti-inflammatory agents is also discussed. The significance of this study is to explore further and understand the potential mechanism of inflammatory processes to take full advantage of vast and advanced anti-inflammatory therapies. This review aimed to reemphasize the importance on the knowledge of inflammatory processes with the addition of newest and current issues pertaining to this phenomenon.
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                Author and article information

                Journal
                J Pain Res
                J Pain Res
                jpr
                jpainres
                Journal of Pain Research
                Dove
                1178-7090
                04 May 2021
                2021
                : 14
                : 1201-1214
                Affiliations
                [1 ]Department of Anesthesiology and Perioperative Medicine, Clinical Medical College, (900 Hospital of the Joint Logistic Support Force), Fujian Medical University , Fuzhou, Fujian, 350025, People’s Republic of China
                [2 ]Department of Anesthesiology and Perioperative Medicine, Dongfang Hospital, Xiamen University , Fuzhou, Fujian, 350025, People’s Republic of China
                [3 ]Department of Stomatology, Beijing Friendship Hospital, Capital Medical University , Beijing, 100050, People’s Republic of China
                [4 ]Department of Anesthesiology, Fifth Medical Center of Chinese PLA General Hospital , Beijing, 100039, People’s Republic of China
                [5 ]Laboratory of Pain Research, School of Basic Medical Sciences, Fujian Medical University , Fuzhou, Fujian, 350122, People’s Republic of China
                Author notes
                Correspondence: Guo-Zhong Chen; Fei Yang Department of Anesthesiology and Perioperative Medicine, 900 Hospital of the Joint Logistic Support Force, Fujian Medical University , #156 West 2 nd Ring Road North, Gulou District, Fuzhou, 350025, People’s Republic of China Email cgzssq2000@sina.com; yangfeimedbrain@outlook.com
                [*]

                These authors contributed equally to this work

                Article
                303595
                10.2147/JPR.S303595
                8106509
                33976570
                36c1b29e-c585-4216-9669-4a0858f147f0
                © 2021 Zhan 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
                : 28 January 2021
                : 31 March 2021
                Page count
                Figures: 8, References: 69, Pages: 14
                Categories
                Original Research

                Anesthesiology & Pain management
                ulinastatin,formalin,somatic pain,visceral pain,inflammation,antinociception

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