title: Experimental and computational evidence for an essential role of NaV1.6 in spike initiation at stretch-sensitive colorectal afferent endings.
abstract: Stretch-sensitive afferents comprise ∼33% of the pelvic nerve innervation of mouse colorectum, which are activated by colorectal distension and encode visceral nociception. Stretch-sensitive colorectal afferent endings respond tonically to stepped or ramped colorectal stretch, whereas dissociated colorectal dorsal root ganglion neurons generally fail to spike repetitively upon stepped current stimulation. The present study investigated this difference in the neural encoding characteristics between the soma and afferent ending using pharmacological approaches in an in vitro mouse colon-nerve preparation and complementary computational simulations. Immunohistological staining and Western blots revealed the presence of voltage-gated sodium channel (NaV) 1.6 and NaV1.7 at sensory neuronal endings in mouse colorectal tissue. Responses of stretch-sensitive colorectal afferent endings were significantly reduced by targeting NaV1.6 using selective antagonists (μ-conotoxin GIIIa and μ-conotoxin PIIIa) or tetrodotoxin. In contrast, neither selective NaV1.8 (A803467) nor NaV1.7 (ProTX-II) antagonists attenuated afferent responses to stretch. Computational simulation of a colorectal afferent ending that incorporated independent Markov models for NaV1.6 and NaV1.7, respectively, recapitulated the experimental findings, suggesting a necessary role for NaV1.6 in encoding tonic spiking by stretch-sensitive afferents. In addition, computational simulation of a dorsal root ganglion soma showed that, by adding a NaV1.6 conductance, a single-spiking neuron was converted into a tonic spiking one. These results suggest a mechanism/channel to explain the difference in neural encoding characteristics between afferent somata and sensory endings, likely caused by differential expression of ion channels (e.g., NaV1.6) at different parts of the neuron.
authors: Department of Anesthesiology, Center for Pain Research, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; and feng@engr.uconn.edu.
authors: Bin
authors: B
authors: Feng
authors: Department of Anesthesiology, Center for Pain Research, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; and.
authors: Yi
authors: Y
authors: Zhu
authors: Department of Anesthesiology, Center for Pain Research, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; and.
authors: Jun-Ho
authors: JH
authors: La
authors: Department of Neurobiology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors: Zachary P
authors: ZP
authors: Wills
authors: Department of Anesthesiology, Center for Pain Research, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; and.
authors: G F
authors: GF
authors: Gebhart
mesh_terms: D000200:Action Potentials; D000818:Animals; D003106:Colon / Q000294:innervation / Q000378:metabolism / Q000502:physiology*; D005727:Ganglia, Spinal / Q000378:metabolism / Q000502:physiology*; D008297:Male; D008465:Mechanoreceptors / Q000378:metabolism / Q000502:physiology*; D008564:Membrane Potentials; D051379:Mice; D008810:Mice, Inbred C57BL; D062557:NAV1.6 Voltage-Gated Sodium Channel / Q000378:metabolism / Q000502:physiology*; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000378:metabolism / Q000502:physiology; D062559:NAV1.8 Voltage-Gated Sodium Channel / Q000502:physiology; D010812:Physical Stimulation; D012007:Rectum / Q000294:innervation / Q000378:metabolism / Q000502:physiology*
chemical_list: D062557:NAV1.6 Voltage-Gated Sodium Channel; D062556:NAV1.7 Voltage-Gated Sodium Channel; D062559:NAV1.8 Voltage-Gated Sodium Channel; C568318:Scn10a protein, mouse; C491046:Scn8a protein, mouse; C503479:Scn9a protein, mouse
keywords: colon; computational model; single fiber; sodium channel; visceral pain
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