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Sensory neuron-derived Na_V1.7 contributes to dorsal horn neuron excitability.

ABSTRACT: Expression of the voltage-gated sodium channel Na_V1.7 in sensory neurons is required for pain sensation. We examined the role of Na_V1.7 in the dorsal horn of the spinal cord using an epitope-tagged Na_V1.7 knock-in mouse. Immuno-electron microscopy showed the presence of Na_V1.7 in dendrites of superficial dorsal horn neurons, despite the absence of mRNA. Rhizotomy of L5 afferent nerves lowered the levels of Na_V1.7 in the dorsal horn. Peripheral nervous system-specific Na_V1.7 null mutant mice showed central deficits, with lamina II dorsal horn tonic firing neurons more than halved and single spiking neurons more than doubled. Na_V1.7 blocker PF05089771 diminished excitability in dorsal horn neurons but had no effect on Na_V1.7 null mutant mice. These data demonstrate an unsuspected functional role of primary afferent neuron-generated Na_V1.7 in dorsal horn neurons and an expression pattern that would not be predicted by transcriptomic analysis.

SUBMITTER: Alles SRA

PROVIDER: S-EPMC7030926 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Sensory neuron-derived NaV1.7 contributes to dorsal horn neuron excitability.

Alles Sascha R A SRA Nascimento Filipe F Luján Rafael R Luiz Ana P AP Millet Queensta Q Bangash M Ali MA Santana-Varela Sonia S Zhou Xuelong X Cox James J JJ Okorokov Andrei L AL Beato Marco M Zhao Jing J Wood John N JN

Science advances 20200219 8

Expression of the voltage-gated sodium channel NaV1.7 in sensory neurons is required for pain sensation. We examined the role of NaV1.7 in the dorsal horn of the spinal cord using an epitope-tagged NaV1.7 knock-in mouse. Immuno-electron microscopy showed the presence of NaV1.7 in dendrites of superficial dorsal horn neurons, despite the absence of mRNA. Rhizotomy of L5 afferent nerves lowered the levels of NaV1.7 in the dorsal horn. Peripher ...[more]

PMID: 32128393

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Project description:Postoperative pain remains a complex problem that is difficult to manage in the clinical context, seriously affecting rehabilitation and the quality of life of patients after surgery. Nociceptors, of which the cell bodies are located in the dorsal root ganglion, are crucial for initiating and conducting the pain signal. The peripheral voltage-gated sodium channels, including Nav1.7, which is mainly expressed in the dorsal root ganglion, are key to understanding the mechanism underlying postoperative pain. Nav1.7, in particular, of which mutations in the encoding gene ( SCN9A) can determine whether pain occurs, has aroused most attention. Previous studies have shown that Nav1.7 in dorsal root ganglion is critical for the development of inflammatory pain and some neuropathic pain. However, the expression of Nav1.7 in the dorsal root ganglion after surgery and its role in postoperative pain hypersensitivity remain unclear. Therefore, in this study, in order to gain a better understanding of the role of dorsal root ganglion Nav1.7 in pain hypersensitivity following operation, we dynamically examined the pain-related behavior and expression of Nav1.7 in L4-L6 dorsal root ganglion before and after plantar incision in rats (an acute postoperative pain model). After plantar incision, the mechanical and thermal pain threshold decreased significantly, the cumulative pain score was increased significantly, meanwhile quantitative polymerase chain reaction and Western blotting results showed that expression of Nav1.7 in L4-L6 dorsal root ganglion was enhanced significantly. After pretreatment using SCN9A-RNAi-LV delivered via an intrathecal tube, immunohistochemistry showed that increased expression of Nav1.7 in L4-L6 dorsal root ganglion after plantar incision was inhibited, as also confirmed by quantitative polymerase chain reaction and Western blotting. Moreover, pain hypersensitivity was alleviated. These results suggested that Nav1.7 of L4-L6 dorsal root ganglion plays an important role in the development of pain hypersensitivity after plantar incision.

Project description:Background and purposePharmacotherapy for pain currently involves trial and error. A previous study on inherited erythromelalgia (a genetic model of neuropathic pain due to mutations in the sodium channel, Nav 1.7) used genomics, structural modelling and biophysical and pharmacological analyses to guide pharmacotherapy and showed that carbamazepine normalizes voltage dependence of activation of the Nav 1.7-S241T mutant channel, reducing pain in patients carrying this mutation. However, whether this approach is applicable to other Nav channel mutants is still unknown.Experimental approachWe used structural modelling, patch clamp and multi-electrode array (MEA) recording to assess the effects of carbamazepine on Nav 1.7-I234T mutant channels and on the firing of dorsal root ganglion (DRG) sensory neurons expressing these mutant channels.Key resultsIn a reverse engineering approach, structural modelling showed that the I234T mutation is located in atomic proximity to the carbamazepine-responsive S241T mutation and that activation of Nav 1.7-I234T mutant channels, from patients who are known to respond to carbamazepine, is partly normalized with a clinically relevant concentration (30 μM) of carbamazepine. There was significantly higher firing in intact sensory neurons expressing Nav 1.7-I234T channels, compared with neurons expressing the normal channels (Nav 1.7-WT). Pre-incubation with 30 μM carbamazepine also significantly reduced the firing of intact DRG sensory neurons expressing Nav 1.7-I234T channels. Although the expected use-dependent inhibition of Nav 1.7-WT channels by carbamazepine was confirmed, carbamazepine did not enhance use-dependent inhibition of Nav 1.7-I234T mutant channels.Conclusion and implicationsThese results support the utility of a pharmacogenomic approach to treatment of pain in patients carrying sodium channel variants.Linked articlesThis article is part of a themed section on Recent Advances in Targeting Ion Channels to Treat Chronic Pain. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc.

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Sensory neuron-derived Na_V1.7 contributes to dorsal horn neuron excitability.

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Sensory neuron-derived Na<sub>V</sub>1.7 contributes to dorsal horn neuron excitability.

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