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Differential axonal conduction patterns of mechano-sensitive and mechano-insensitive nociceptors--a combined experimental and modelling study.
PLoS One. 2014; 9(8):e103556.Plos

Abstract

Cutaneous pain sensations are mediated largely by C-nociceptors consisting of both mechano-sensitive (CM) and mechano-insensitive (CMi) fibres that can be distinguished from one another according to their characteristic axonal properties. In healthy skin and relative to CMi fibres, CM fibres show a higher initial conduction velocity, less activity-dependent conduction velocity slowing, and less prominent post-spike supernormality. However, after sensitization with nerve growth factor, the electrical signature of CMi fibres changes towards a profile similar to that of CM fibres. Here we take a combined experimental and modelling approach to examine the molecular basis of such alterations to the excitation thresholds. Changes in electrical activation thresholds and activity-dependent slowing were examined in vivo using single-fibre recordings of CM and CMi fibres in domestic pigs following NGF application. Using computational modelling, we investigated which axonal mechanisms contribute most to the electrophysiological differences between the fibre classes. Simulations of axonal conduction suggest that the differences between CMi and CM fibres are strongly influenced by the densities of the delayed rectifier potassium channel (Kdr), the voltage-gated sodium channels NaV1.7 and NaV1.8, and the Na+/K+-ATPase. Specifically, the CM fibre profile required less Kdr and NaV1.8 in combination with more NaV1.7 and Na+/K+-ATPase. The difference between CM and CMi fibres is thus likely to reflect a relative rather than an absolute difference in protein expression. In support of this, it was possible to replicate the experimental reduction of the ADS pattern of CMi nociceptors towards a CM-like pattern following intradermal injection of nerve growth factor by decreasing the contribution of Kdr (by 50%), increasing the Na+/K+-ATPase (by 10%), and reducing the branch length from 2 cm to 1 cm. The findings highlight key molecules that potentially contribute to the NGF-induced switch in nociceptors phenotype, in particular NaV1.7 which has already been identified clinically as a principal contributor to chronic pain states such as inherited erythromelalgia.

Authors+Show Affiliations

School of Computer Science and Communication, KTH Royal Institute of Technology, Stockholm, Sweden; Stockholm Brain Institute, KTH Royal Institute of Technology, Stockholm, Sweden.Dept. of Anaesthesiology, Universitaetsmedizin Mannheim, Univ. of Heidelberg, Mannheim, Germany.Institute of Physiology and Pathophysiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.Dept. of Anaesthesiology, Universitaetsmedizin Mannheim, Univ. of Heidelberg, Mannheim, Germany.Dept. of Anaesthesiology, Universitaetsmedizin Mannheim, Univ. of Heidelberg, Mannheim, Germany.School of Computer Science and Communication, KTH Royal Institute of Technology, Stockholm, Sweden; Stockholm Brain Institute, KTH Royal Institute of Technology, Stockholm, Sweden.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25136824

Citation

Petersson, Marcus E., et al. "Differential Axonal Conduction Patterns of Mechano-sensitive and Mechano-insensitive Nociceptors--a Combined Experimental and Modelling Study." PloS One, vol. 9, no. 8, 2014, pp. e103556.
Petersson ME, Obreja O, Lampert A, et al. Differential axonal conduction patterns of mechano-sensitive and mechano-insensitive nociceptors--a combined experimental and modelling study. PLoS One. 2014;9(8):e103556.
Petersson, M. E., Obreja, O., Lampert, A., Carr, R. W., Schmelz, M., & Fransén, E. (2014). Differential axonal conduction patterns of mechano-sensitive and mechano-insensitive nociceptors--a combined experimental and modelling study. PloS One, 9(8), e103556. https://doi.org/10.1371/journal.pone.0103556
Petersson ME, et al. Differential Axonal Conduction Patterns of Mechano-sensitive and Mechano-insensitive Nociceptors--a Combined Experimental and Modelling Study. PLoS One. 2014;9(8):e103556. PubMed PMID: 25136824.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Differential axonal conduction patterns of mechano-sensitive and mechano-insensitive nociceptors--a combined experimental and modelling study. AU - Petersson,Marcus E, AU - Obreja,Otilia, AU - Lampert,Angelika, AU - Carr,Richard W, AU - Schmelz,Martin, AU - Fransén,Erik, Y1 - 2014/08/19/ PY - 2013/07/03/received PY - 2014/07/02/accepted PY - 2014/8/20/entrez PY - 2014/8/20/pubmed PY - 2015/10/27/medline SP - e103556 EP - e103556 JF - PloS one JO - PLoS One VL - 9 IS - 8 N2 - Cutaneous pain sensations are mediated largely by C-nociceptors consisting of both mechano-sensitive (CM) and mechano-insensitive (CMi) fibres that can be distinguished from one another according to their characteristic axonal properties. In healthy skin and relative to CMi fibres, CM fibres show a higher initial conduction velocity, less activity-dependent conduction velocity slowing, and less prominent post-spike supernormality. However, after sensitization with nerve growth factor, the electrical signature of CMi fibres changes towards a profile similar to that of CM fibres. Here we take a combined experimental and modelling approach to examine the molecular basis of such alterations to the excitation thresholds. Changes in electrical activation thresholds and activity-dependent slowing were examined in vivo using single-fibre recordings of CM and CMi fibres in domestic pigs following NGF application. Using computational modelling, we investigated which axonal mechanisms contribute most to the electrophysiological differences between the fibre classes. Simulations of axonal conduction suggest that the differences between CMi and CM fibres are strongly influenced by the densities of the delayed rectifier potassium channel (Kdr), the voltage-gated sodium channels NaV1.7 and NaV1.8, and the Na+/K+-ATPase. Specifically, the CM fibre profile required less Kdr and NaV1.8 in combination with more NaV1.7 and Na+/K+-ATPase. The difference between CM and CMi fibres is thus likely to reflect a relative rather than an absolute difference in protein expression. In support of this, it was possible to replicate the experimental reduction of the ADS pattern of CMi nociceptors towards a CM-like pattern following intradermal injection of nerve growth factor by decreasing the contribution of Kdr (by 50%), increasing the Na+/K+-ATPase (by 10%), and reducing the branch length from 2 cm to 1 cm. The findings highlight key molecules that potentially contribute to the NGF-induced switch in nociceptors phenotype, in particular NaV1.7 which has already been identified clinically as a principal contributor to chronic pain states such as inherited erythromelalgia. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/25136824/Differential_axonal_conduction_patterns_of_mechano_sensitive_and_mechano_insensitive_nociceptors__a_combined_experimental_and_modelling_study_ L2 - https://dx.plos.org/10.1371/journal.pone.0103556 DB - PRIME DP - Unbound Medicine ER -