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 43

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A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons.

A Akopian, L Sivilotti, J Wood (1996)

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.

L Stanfa, N Ogata, S. J. McMahon … (1999)

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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A-803467, a potent and selective Nav1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat.

Michael F Jarvis, Prisca Honore, Char-Chang Shieh … (2007)

Activation of tetrodotoxin-resistant sodium channels contributes to action potential electrogenesis in neurons. Antisense oligonucleotide studies directed against Na(v)1.8 have shown that this channel contributes to experimental inflammatory and neuropathic pain. We report here the discovery of A-803467, a sodium channel blocker that potently blocks tetrodotoxin-resistant currents (IC(50) = 140 nM) and the generation of spontaneous and electrically evoked action potentials in vitro in rat dorsal root ganglion neurons. In recombinant cell lines, A-803467 potently blocked human Na(v)1.8 (IC(50) = 8 nM) and was >100-fold selective vs. human Na(v)1.2, Na(v)1.3, Na(v)1.5, and Na(v)1.7 (IC(50) values >or=1 microM). A-803467 (20 mg/kg, i.v.) blocked mechanically evoked firing of wide dynamic range neurons in the rat spinal dorsal horn. A-803467 also dose-dependently reduced mechanical allodynia in a variety of rat pain models including: spinal nerve ligation (ED(50) = 47 mg/kg, i.p.), sciatic nerve injury (ED(50) = 85 mg/kg, i.p.), capsaicin-induced secondary mechanical allodynia (ED(50) approximately 100 mg/kg, i.p.), and thermal hyperalgesia after intraplantar complete Freund's adjuvant injection (ED(50) = 41 mg/kg, i.p.). A-803467 was inactive against formalin-induced nociception and acute thermal and postoperative pain. These data demonstrate that acute and selective pharmacological blockade of Na(v)1.8 sodium channels in vivo produces significant antinociception in animal models of neuropathic and inflammatory pain.

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Author and article information

Contributors

Xi-Yao Gu: gxykevin@gmail.com

Ben-Long Liu: 12210700026@fudan.edu.cn

Kai-Kai Zang: 13210700032@fudan.edu.cn

Liu Yang: ribaike@163.com

Hua Xu: pshhuaxu@163.com

Hai-Li Pan: panhaili@ncu.edu.cn

Zhi-Qi Zhao: zqzhao@fudan.edu.cn

Yu-Qiu Zhang: yuqiuzhang@fudan.edu.cn

Journal

Journal ID (nlm-ta): Mol Brain

Journal ID (iso-abbrev): Mol Brain

Title: Molecular Brain

Publisher: BioMed Central (London )

ISSN (Electronic): 1756-6606

Publication date (Electronic): 3 March 2015

Publication date PMC-release: 3 March 2015

Publication date Collection: 2015

Volume: 8

Electronic Location Identifier: 15

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

Article

Publisher ID: 105

DOI: 10.1186/s13041-015-0105-2

PMC ID: 4350947

PubMed ID: 25761941

SO-VID: 7eab5933-ce8e-4fd1-909b-0ca5b043bb70

License:

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.

History

Date received : 30 November 2014

Date accepted : 18 February 2015

Custom metadata

ScienceOpen disciplines: Neurosciences

Keywords: α2-adrenoceptor,dexmedetomidine,dorsal root ganglion,pain,tetrodotoxin-resistant (ttx-r) sodium channel nav1.8,whole-cell recording

Data availability:

ScienceOpen disciplines: Neurosciences

Keywords: α2-adrenoceptor, dexmedetomidine, dorsal root ganglion, pain, tetrodotoxin-resistant (ttx-r) sodium channel nav1.8, whole-cell recording