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      • Record: found
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      Dexmedetomidine inhibits Tetrodotoxin-resistant Nav1.8 sodium channel activity through Gi/o-dependent pathway in rat dorsal root ganglion neurons

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          Abstract

          Background

          Systemically administered dexmedetomidine (DEX), a selective α2 adrenergic receptor (α2-AR) agonists, produces analgesia and sedation. Peripherally restricted α2-AR antagonist could block the analgesic effect of systemic DEX on neuropathic pain, with no effect on sedation, indicating peripheral analgesic effect of DEX. Tetrodotoxin-resistant (TTX-R) sodium channel Na v1.8 play important roles in the conduction of nociceptive sensation. Both α2-AR and Nav1.8 are found in small nociceptive DRG neurons. We, therefore, investigated the effects of DEX on the Na v1.8 currents in acutely dissociated small-diameter DRG neurons.

          Results

          Whole-cell patch-clamp recordings demonstrated that DEX concentration-dependently suppressed TTX-R Na v1.8 currents in small-diameter lumbar DRG neurons. DEX also shifted the steady-state inactivation curves of Na v1.8 in a hyperpolarizing direction and increased the threshold of action potential and decrease electrical and chemical stimuli-evoked firings in small-diameter DRG neurons. The α2-AR antagonist yohimbine or α2 A-AR antagonist BRL44408 but not α2 B-AR antagonist imiloxan blocked the inhibition of Na v1.8 currents by DEX. Immunohistochemistry results showed that Na v1.8 was predominantly expressed in peripherin-positive small-diameter DRG neurons, and some of them were α2 A-AR-positive ones. Our electrophysiological recordings also demonstrated that DEX-induced inhibition of Na v1.8 currents was prevented by intracellular application of G-protein inhibitor GDPβ-s or G i/o proteins inhibitor pertussis toxin (PTX), and bath application of adenylate cyclase (AC) activator forskolin or membrane-permeable cAMP analogue 8-Bromo-cAMP (8-Br-cAMP). PKA inhibitor Rp-cAMP could mimic DEX-induced inhibition of Na v1.8 currents.

          Conclusions

          We established a functional link between α2-AR and Na v1.8 in primary sensory neurons utilizing the G i/o/AC/cAMP/PKA pathway, which probably mediating peripheral analgesia of DEX.

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          Most cited references 45

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          Sodium channels in normal and pathological pain.

          Nociception is essential for survival whereas pathological pain is maladaptive and often unresponsive to pharmacotherapy. Voltage-gated sodium channels, Na(v)1.1-Na(v)1.9, are essential for generation and conduction of electrical impulses in excitable cells. Human and animal studies have identified several channels as pivotal for signal transmission along the pain axis, including Na(v)1.3, Na(v)1.7, Na(v)1.8, and Na(v)1.9, with the latter three preferentially expressed in peripheral sensory neurons and Na(v)1.3 being upregulated along pain-signaling pathways after nervous system injuries. Na(v)1.7 is of special interest because it has been linked to a spectrum of inherited human pain disorders. Here we review the contribution of these sodium channel isoforms to pain.
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            A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons.

            Dorsal root ganglion sensory neurons associated with C-fibres, many of which are activated by tissue-damage, express an unusual voltage-gated sodium channel that is resistant to tetrodotoxin. We report here that we have identified a 1,957 amino-acid sodium channel in these cells that shows 65% identity with the rat cardiac tetrodotoxin-insensitive sodium channel, and is not expressed in other peripheral and central neurons, glia or non-neuronal tissues. In situ hybridization shows that the channel is expressed only by small-diameter sensory neurons in neonatal and adult dorsal root and trigeminal ganglia. The channel is resistant to tetrodotoxin when expressed in Xenopus oocytes. The electrophysiological and pharmacological properties of the expressed channel are similar to those described for the small-diameter sensory neuron tetrodotoxin-resistant sodium channels. As some noxious input into the spinal cord is resistant to tetrodotoxin, block of expression or function of such a C-fibre-restricted sodium channel may have a selective analgesic effect.
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              The tetrodotoxin-resistant sodium channel SNS has a specialized function in pain pathways.

              Many damage-sensing neurons express tetrodotoxin (TTX)-resistant voltage-gated sodium channels. Here we examined the role of the sensory-neuron-specific (SNS) TTX-resistant sodium channel alpha subunit in nociception and pain by constructing sns-null mutant mice. These mice expressed only TTX-sensitive sodium currents on step depolarizations from normal resting potentials, showing that all slow TTX-resistant currents are encoded by the sns gene. Null mutants were viable, fertile and apparently normal, although lowered thresholds of electrical activation of C-fibers and increased current densities of TTX-sensitive channels demonstrated compensatory upregulation of TTX-sensitive currents in sensory neurons. Behavioral studies demonstrated a pronounced analgesia to noxious mechanical stimuli, small deficits in noxious thermoreception and delayed development of inflammatory hyperalgesia. These data show that SNS is involved in pain pathways and suggest that blockade of SNS expression or function may produce analgesia without side effects.
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                Author and article information

                Contributors
                gxykevin@gmail.com
                12210700026@fudan.edu.cn
                13210700032@fudan.edu.cn
                ribaike@163.com
                pshhuaxu@163.com
                panhaili@ncu.edu.cn
                zqzhao@fudan.edu.cn
                yuqiuzhang@fudan.edu.cn
                Journal
                Mol Brain
                Mol Brain
                Molecular Brain
                BioMed Central (London )
                1756-6606
                3 March 2015
                3 March 2015
                2015
                : 8
                Affiliations
                [ ]Institute of Neurobiology, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Collaborative Innovation Center for Brain Science, Fudan University, 138 Yi Xue Yuan Road, Shanghai, 200032 China
                [ ]Department of Anesthesiology, Changhai Hospital, The Second Military Medical University, Shanghai, 200433 China
                [ ]Center for Neuropsychiatric Diseases, Institute of Life Science, Nanchang University, Nanchang, 330031 China
                105
                10.1186/s13041-015-0105-2
                4350947
                © Gu et al.; licensee BioMed Central. 2015

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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                Research
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                © The Author(s) 2015

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