title: Dexmedetomidine inhibits Tetrodotoxin-resistant Nav1.8 sodium channel activity through Gi/o-dependent pathway in rat dorsal root ganglion neurons.
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 Nav1.8 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 Nav1.8 currents in acutely dissociated small-diameter DRG neurons.
  
  
  RESULTS
  Whole-cell patch-clamp recordings demonstrated that DEX concentration-dependently suppressed TTX-R Nav1.8 currents in small-diameter lumbar DRG neurons. DEX also shifted the steady-state inactivation curves of Nav1.8 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 α2A-AR antagonist BRL44408 but not α2B-AR antagonist imiloxan blocked the inhibition of Nav1.8 currents by DEX. Immunohistochemistry results showed that Nav1.8 was predominantly expressed in peripherin-positive small-diameter DRG neurons, and some of them were α2A-AR-positive ones. Our electrophysiological recordings also demonstrated that DEX-induced inhibition of Nav1.8 currents was prevented by intracellular application of G-protein inhibitor GDPβ-s or Gi/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 Nav1.8 currents.
  
  
  CONCLUSIONS
  We established a functional link between α2-AR and Nav1.8 in primary sensory neurons utilizing the Gi/o/AC/cAMP/PKA pathway, which probably mediating peripheral analgesia of DEX.
authors.affiliation: 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. gxykevin@gmail.com.
authors.forename: Xi-Yao
authors.initials: XY
authors.lastname: Gu
authors.affiliation: 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. 12210700026@fudan.edu.cn.
authors.forename: Ben-Long
authors.initials: BL
authors.lastname: Liu
authors.affiliation: 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. 13210700032@fudan.edu.cn.
authors.forename: Kai-Kai
authors.initials: KK
authors.lastname: Zang
authors.affiliation: 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. ribaike@163.com.
authors.forename: Liu
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Anesthesiology, Changhai Hospital, The Second Military Medical University, Shanghai, 200433, China. pshhuaxu@163.com.
authors.forename: Hua
authors.initials: H
authors.lastname: Xu
authors.affiliation: Center for Neuropsychiatric Diseases, Institute of Life Science, Nanchang University, Nanchang, 330031, China. panhaili@ncu.edu.cn.
authors.forename: Hai-Li
authors.initials: HL
authors.lastname: Pan
authors.affiliation: 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. zqzhao@fudan.edu.cn.
authors.forename: Zhi-Qi
authors.initials: ZQ
authors.lastname: Zhao
authors.affiliation: 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. yuqiuzhang@fudan.edu.cn.
authors.forename: Yu-Qiu
authors.initials: YQ
authors.lastname: Zhang
mesh_terms: D000200:Action Potentials; D000818:Animals; D020927:Dexmedetomidine / Q000494:pharmacology*; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism*; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism*; D015640:Ion Channel Gating / Q000187:drug effects*; D008297:Male; D062559:NAV1.8 Voltage-Gated Sodium Channel / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D017208:Rats, Wistar; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013779:Tetrodotoxin / Q000494:pharmacology*
chemical_list: D062559:NAV1.8 Voltage-Gated Sodium Channel; D018341:Receptors, Adrenergic, alpha-2; C568319:Scn10a protein, rat; D013779:Tetrodotoxin; D020927:Dexmedetomidine; D019206:GTP-Binding Protein alpha Subunits, Gi-Go