title: Control of somatic membrane potential in nociceptive neurons and its implications for peripheral nociceptive transmission.
abstract: Peripheral sensory ganglia contain somata of afferent fibres conveying somatosensory inputs to the central nervous system. Growing evidence suggests that the somatic/perisomatic region of sensory neurons can influence peripheral sensory transmission. Control of resting membrane potential (Erest) is an important mechanism regulating excitability, but surprisingly little is known about how Erest is regulated in sensory neuron somata or how changes in somatic/perisomatic Erest affect peripheral sensory transmission. We first evaluated the influence of several major ion channels on Erest in cultured small-diameter, mostly capsaicin-sensitive (presumed nociceptive) dorsal root ganglion (DRG) neurons. The strongest and most prevalent effect on Erest was achieved by modulating M channels, K2P and 4-aminopiridine-sensitive KV channels, while hyperpolarization-activated cyclic nucleotide-gated, voltage-gated Na(+), and T-type Ca(2+) channels to a lesser extent also contributed to Erest. Second, we investigated how varying somatic/perisomatic membrane potential, by manipulating ion channels of sensory neurons within the DRG, affected peripheral nociceptive transmission in vivo. Acute focal application of M or KATP channel enhancers or a hyperpolarization-activated cyclic nucleotide-gated channel blocker to L5 DRG in vivo significantly alleviated pain induced by hind paw injection of bradykinin. Finally, we show with computational modelling how somatic/perisomatic hyperpolarization, in concert with the low-pass filtering properties of the t-junction within the DRG, can interfere with action potential propagation. Our study deciphers a complement of ion channels that sets the somatic Erest of nociceptive neurons and provides strong evidence for a robust filtering role of the somatic and perisomatic compartments of peripheral nociceptive neuron.
authors.affiliation: Department of Pharmacology, Hebei Medical University, Shijiazhuang, PR China. Electronic address: du_xiaona@hotmail.com.
authors.forename: Xiaona
authors.initials: X
authors.lastname: Du
authors.affiliation: Department of Pharmacology, Hebei Medical University, Shijiazhuang, PR China.
authors.forename: Han
authors.initials: H
authors.lastname: Hao
authors.affiliation: Faculty of Biological Sciences, School of Biomedical Sciences, University of Leeds, Leeds, UK.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Gigout
authors.affiliation: Department of Pharmacology, Hebei Medical University, Shijiazhuang, PR China.
authors.forename: Dongyang
authors.initials: D
authors.lastname: Huang
authors.affiliation: Department of Pharmacology, Hebei Medical University, Shijiazhuang, PR China.
authors.forename: Yuehui
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, Hebei Medical University, Shijiazhuang, PR China.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Hebei Medical University, Shijiazhuang, PR China.
authors.forename: Caixue
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Biology, University of Texas at San Antonio, San Antonio, TX, USA.
authors.forename: Danielle
authors.initials: D
authors.lastname: Sundt
authors.affiliation: Department of Biology, University of Texas at San Antonio, San Antonio, TX, USA.
authors.forename: David B
authors.initials: DB
authors.lastname: Jaffe
authors.affiliation: Department of Pharmacology, Hebei Medical University, Shijiazhuang, PR China.
authors.forename: Hailin
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Hebei Medical University, Shijiazhuang, PR China; Faculty of Biological Sciences, School of Biomedical Sciences, University of Leeds, Leeds, UK. Electronic address: N.Gamper@leeds.ac.uk.
authors.forename: Nikita
authors.initials: N
authors.lastname: Gamper
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001920:Bradykinin / Q000494:pharmacology; D020747:Calcium Channels, T-Type / Q000235:genetics / Q000378:metabolism; D002219:Carbamates / Q000494:pharmacology; D002478:Cells, Cultured; D003412:Cricetulus; D005727:Ganglia, Spinal / Q000166:cytology; D006801:Humans; D066298:In Vitro Techniques; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D051658:KCNQ2 Potassium Channel / Q000235:genetics / Q000378:metabolism; D051659:KCNQ3 Potassium Channel / Q000235:genetics / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology*; D049990:Membrane Transport Modulators; D008959:Models, Neurological; D009619:Nociceptors / Q000187:drug effects / Q000502:physiology*; D010655:Phenylenediamines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013054:Spectrophotometry, Atomic
chemical_list: C509958:Cacna1h protein, rat; D020747:Calcium Channels, T-Type; D002219:Carbamates; D007473:Ion Channels; D051658:KCNQ2 Potassium Channel; D051659:KCNQ3 Potassium Channel; D049990:Membrane Transport Modulators; D010655:Phenylenediamines; C101866:ezogabine; D001920:Bradykinin
keywords: DRG; Ion channel; K2P; KCNQ; M channel; Nociceptor; Pain