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Selective spider toxins reveal a role for the Nav1.1 channel in mechanical pain.

ABSTRACT: Voltage-gated sodium (Nav) channels initiate action potentials in most neurons, including primary afferent nerve fibres of the pain pathway. Local anaesthetics block pain through non-specific actions at all Nav channels, but the discovery of selective modulators would facilitate the analysis of individual subtypes of these channels and their contributions to chemical, mechanical, or thermal pain. Here we identify and characterize spider (Heteroscodra maculata) toxins that selectively activate the Nav1.1 subtype, the role of which in nociception and pain has not been elucidated. We use these probes to show that Nav1.1-expressing fibres are modality-specific nociceptors: their activation elicits robust pain behaviours without neurogenic inflammation and produces profound hypersensitivity to mechanical, but not thermal, stimuli. In the gut, high-threshold mechanosensitive fibres also express Nav1.1 and show enhanced toxin sensitivity in a mouse model of irritable bowel syndrome. Together, these findings establish an unexpected role for Nav1.1 channels in regulating the excitability of sensory nerve fibres that mediate mechanical pain.

SUBMITTER: Osteen JD

PROVIDER: S-EPMC4919188 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Selective spider toxins reveal a role for the Nav1.1 channel in mechanical pain.

Osteen Jeremiah D JD Herzig Volker V Gilchrist John J Emrick Joshua J JJ Zhang Chuchu C Wang Xidao X Castro Joel J Garcia-Caraballo Sonia S Grundy Luke L Rychkov Grigori Y GY Weyer Andy D AD Dekan Zoltan Z Undheim Eivind A B EA Alewood Paul P Stucky Cheryl L CL Brierley Stuart M SM Basbaum Allan I AI Bosmans Frank F King Glenn F GF Julius David D

Nature 20160606 7608

Voltage-gated sodium (Nav) channels initiate action potentials in most neurons, including primary afferent nerve fibres of the pain pathway. Local anaesthetics block pain through non-specific actions at all Nav channels, but the discovery of selective modulators would facilitate the analysis of individual subtypes of these channels and their contributions to chemical, mechanical, or thermal pain. Here we identify and characterize spider (Heteroscodra maculata) toxins that selectively activate th ...[more]

PMID: 27281198

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Project description:BackgroundPrevious research has demonstrated the efficacy of cognitive engagement in reducing concurrent pain. However, little is known about the role of individual differences in inhibitory control abilities and negative pain-related cognitions in modulating the magnitude of this type of distraction from pain.MethodsIn a pain distraction paradigm, 41 participants completed a working memory task with both a demanding high load condition (2-back) and an easy low load condition (0-back), while receiving warm or painful thermal stimuli to their left forearm. To control for individual differences in sensitivity to pain and perceived task difficulty, nociceptive stimulus intensity and task speed were individually calibrated. Additionally, participants completed a set of cognitive inhibition tasks (flanker, go/nogo, Stroop) and questionnaires about negative pain-related cognitions (fear of pain, pain catastrophizing) prior to the distraction paradigm.ResultsAs expected, engaging in the high load condition significantly reduced perceived intensity and unpleasantness of nociceptive stimuli, compared to the low load condition. The size of the distraction effect correlated significantly with better cognitive inhibition and selective attention abilities, as measured by the flanker task. A moderation analysis revealed a significant interaction between pain catastrophizing and performance in the flanker task in predicting the distraction effect size: Participants who performed well on the flanker task showed more pain reduction, but only when they were average to high pain catastrophizers.ConclusionsSelective attention abilities and pain catastrophizing seem to be important factors in explaining individual differences in the size of the analgesic response to a distractive task.SignificanceUnderstanding which factors influence the effectiveness of cognitive engagement in distracting from pain could help to optimize its therapeutic application in patient care. This study shows that a complex interplay of cognitive inhibition abilities, specifically selective attention, and negative pain-related cognitions, such as pain catastrophizing, modulate the magnitude of the distraction effect.

Project description:Objective: An overwhelming majority of the genetic variants associated with genetic disorders are missense. The association between the nature of substitution and the functional alteration, which is critical in determining the pathogenicity of variants, remains largely unknown. With a novel missense variant (E1623A) identified from two epileptic cases, which occurs in the extracellular S3-S4 loop of Nav1.1, we studied functional changes of all latent mutations at residue E1623, aiming to understand the relationship between substitution nature and functional alteration. Methods: Six latent mutants with amino acid substitutions at E1623 were generated, followed by measurements of their electrophysiological alterations. Different computational analyses were used to parameterize the residue alterations. Results: Structural modeling indicated that the E1623 was located in the peripheral region far from the central pore, and contributed to the tight turn of the S3-S4 loop. The E1623 residue exhibited low functional tolerance to the substitutions with the most remarkable loss-of-function found in E1623A, including reduced current density, less steady-state availability of activation and inactivation, and slower recovery from fast inactivation. Correlation analysis between electrophysiological parameters and the parameterized physicochemical properties of different residues suggested that hydrophilicity of side-chain at E1623 might be a crucial contributor for voltage-dependent kinetics. However, none of the established algorithms on the physicochemical variations of residues could well predict changes in the channel conductance property indicated by peak current density. Significance: The results established the important role of the extracellular S3-S4 loop in Nav1.1 channel gating and proposed a possible effect of local conformational loop flexibility on channel conductance and kinetics. Site-specific knowledge of protein will be a fundamental task for future bioinformatics.

Dataset Information

Selective spider toxins reveal a role for the Nav1.1 channel in mechanical pain.

Publications

Selective spider toxins reveal a role for the Nav1.1 channel in mechanical pain.

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