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      Activation of the P2X 7 receptor in midbrain periaqueductal gray participates in the analgesic effect of tramadol in bone cancer pain rats

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          Abstract

          Background

          Cancer pain is a well-known serious complication in metastatic or terminal cancer patients. Current pain management remains unsatisfactory. The activation of spinal and supraspinal P2X 7 receptors plays a crucial role in the induction and maintenance mechanisms of various kinds of acute or chronic pain. The midbrain periaqueductal gray is a vital supraspinal site of the endogenous descending pain-modulating system. Tramadol is a synthetic, centrally acting analgesic agent that exhibits considerable efficacy in clinically relieving pain. The purpose of this study was to determine whether the activation of P2X 7 receptor in the ventrolateral region of the periaqueductal gray (vlPAG) participates in the analgesic mechanisms of tramadol on bone cancer pain in rats. The bone cancer pain rat model was established by intratibial cell inoculation of SHZ-88 mammary gland carcinoma cells. The analgesic effects of different doses of tramadol (10, 20, and 40 mg/kg) were assessed by measuring the mechanical withdrawal threshold and thermal withdrawal latency values in rats by using an electronic von Frey anesthesiometer and radiant heat stimulation, respectively. Alterations in the number of P2X 7 receptor-positive cells and P2X 7 protein levels in vlPAG were separately detected by using immunohistochemistry and Western blot assay. The effect of intra-vlPAG injection of A-740003 (100 nmol), a selective competitive P2X 7 receptor antagonist, on the analgesic effect of tramadol was also observed.

          Results

          The expression of P2X 7 receptor in the vlPAG on bone cancer pain rats was mildly elevated, and the tramadol (10, 20, and 40 mg/kg) dose dependently relieved pain-related behaviors in bone cancer pain rats and further upregulated the expression of P2X 7 receptor in the vlPAG. The intra-vlPAG injection of A-740003 pretreatment partly but significantly antagonized the analgesic effect of tramadol on bone cancer pain rats.

          Conclusions

          The injection of tramadol can dose dependently elicit analgesic effect on bone cancer pain rats by promoting the expression of the P2X 7 receptor in vlPAG.

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          Most cited references59

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          Ethical guidelines for investigations of experimental pain in conscious animals.

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            Descending control of pain.

            Upon receipt in the dorsal horn (DH) of the spinal cord, nociceptive (pain-signalling) information from the viscera, skin and other organs is subject to extensive processing by a diversity of mechanisms, certain of which enhance, and certain of which inhibit, its transfer to higher centres. In this regard, a network of descending pathways projecting from cerebral structures to the DH plays a complex and crucial role. Specific centrifugal pathways either suppress (descending inhibition) or potentiate (descending facilitation) passage of nociceptive messages to the brain. Engagement of descending inhibition by the opioid analgesic, morphine, fulfils an important role in its pain-relieving properties, while induction of analgesia by the adrenergic agonist, clonidine, reflects actions at alpha(2)-adrenoceptors (alpha(2)-ARs) in the DH normally recruited by descending pathways. However, opioids and adrenergic agents exploit but a tiny fraction of the vast panoply of mechanisms now known to be involved in the induction and/or expression of descending controls. For example, no drug interfering with descending facilitation is currently available for clinical use. The present review focuses on: (1) the organisation of descending pathways and their pathophysiological significance; (2) the role of individual transmitters and specific receptor types in the modulation and expression of mechanisms of descending inhibition and facilitation and (3) the advantages and limitations of established and innovative analgesic strategies which act by manipulation of descending controls. Knowledge of descending pathways has increased exponentially in recent years, so this is an opportune moment to survey their operation and therapeutic relevance to the improved management of pain.
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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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                Author and article information

                Journal
                Mol Pain
                Mol Pain
                MPX
                spmpx
                Molecular Pain
                SAGE Publications (Sage CA: Los Angeles, CA )
                1744-8069
                10 September 2018
                2018
                : 14
                : 1744806918803039
                Affiliations
                [1 ]Graduate School, Zunyi Medical University, Zunyi, Guizhou, China
                [2 ]Key Laboratory of Brain Science, Zunyi Medical University, Zunyi, Guizhou, China
                [3 ]Research Center for Medicine and Biology, Zunyi Medical University, Zunyi, Guizhou, China
                Author notes

                The first two authors contributed equally to this work.

                [*]Zhi Xiao, Key Laboratory of Brain Science, Zunyi Medical University, No.6 West Xuefu Road, Xinpu District, Zunyi, Guizhou, China. Email: xiaozhi1971@ 123456163.com
                Article
                10.1177_1744806918803039
                10.1177/1744806918803039
                6176534
                30198382
                77a9c322-dd92-491b-b1b6-de37f69153fc
                © The Author(s) 2018

                Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

                History
                : 19 June 2018
                : 21 July 2018
                : 28 August 2018
                Funding
                Funded by: Guizhou Provincial Science and Technology Planning Project, FundRef ;
                Award ID: QianKeHe JiChu [2017]1214
                Funded by: National Natural Science Foundation of China, FundRef https://doi.org/10.13039/501100001809;
                Award ID: 81760214
                Categories
                Research Article
                Custom metadata
                January-December 2018

                Molecular medicine
                bone cancer pain,tramadol,midbrain periaqueductal gray,p2x7 receptor,analgesic effect

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