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The differential effects of two sodium channel modulators on the conductive properties of C-fibers in pig skin in vivo.
Anesth Analg. 2012 Sep; 115(3):560-71.A&A

Abstract

BACKGROUND

Axonal sodium channels are attractive targets for chronic pain treatment, and recent evidence suggests that specific targeting of the slow inactivation of sodium channels (NaV) might exert analgesic effects. Using a human-like animal model, the pig, we compared changes in the conductive properties of different C-fiber classes on acute administration of lidocaine (nonselective NaV blocker) and lacosamide (selective enhancer of NaV slow inactivation).

METHODS

Single-fiber extracellular recordings from saphenous nerves were performed. We classified C-fibers according to mechanical responsiveness and amount of activity-dependent slowing (ADS) of conduction velocity. Lidocaine (4 mM; 100 μL), lacosamide (4 mM; 100 μL), or saline was injected intradermally at the stimulation site, and changes of fibers' conductive properties were assessed.

RESULTS

Conduction latencies evoked by lidocaine were more prominent in mechanosensitive (5.5%± 2.1%) than in mechano-insensitive nociceptors (2.5% ± 1%), whereas lacosamide increased conduction latencies to a greater extent in the mechano-insensitive (3% ± 1%) than in mechanosensitive C-nociceptors (2% ± 0.9%). Lidocaine, but not lacosamide, increased electrical thresholds in all mechanosensitive, but not in the mechano-insensitive, C-fibers. Lacosamide blocked conduction and, in addition, reduced ADS in mechano-insensitive nociceptors significantly more than in mechanosensitive nociceptors (ΔADS: 2.4% ± 0.5% vs 1.6% ± 0.5%), whereas lidocaine had opposite effects. Saline had no significant effect on the conductive properties of C-fibers.

CONCLUSION

Local application of test compounds in pig skin allows for functional assessment of steady-state and use-dependent modulation of sodium channels in nociceptive and nonnociceptive C-fibers. Increased analgesic specificity might derive from selective enhancement of slow inactivation of sodium channels.

Authors+Show Affiliations

Department of Anesthesiology and Operative Intensive Care, Heidelberg University, Mannheim, Germany. otilia.obreja@medma.uni-heidelberg.deNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

22575571

Citation

Obreja, Otilia, et al. "The Differential Effects of Two Sodium Channel Modulators On the Conductive Properties of C-fibers in Pig Skin in Vivo." Anesthesia and Analgesia, vol. 115, no. 3, 2012, pp. 560-71.
Obreja O, Hirth M, Turnquist B, et al. The differential effects of two sodium channel modulators on the conductive properties of C-fibers in pig skin in vivo. Anesth Analg. 2012;115(3):560-71.
Obreja, O., Hirth, M., Turnquist, B., Rukwied, R., Ringkamp, M., & Schmelz, M. (2012). The differential effects of two sodium channel modulators on the conductive properties of C-fibers in pig skin in vivo. Anesthesia and Analgesia, 115(3), 560-71. https://doi.org/10.1213/ANE.0b013e3182542843
Obreja O, et al. The Differential Effects of Two Sodium Channel Modulators On the Conductive Properties of C-fibers in Pig Skin in Vivo. Anesth Analg. 2012;115(3):560-71. PubMed PMID: 22575571.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The differential effects of two sodium channel modulators on the conductive properties of C-fibers in pig skin in vivo. AU - Obreja,Otilia, AU - Hirth,Michael, AU - Turnquist,Brian, AU - Rukwied,Roman, AU - Ringkamp,Matthias, AU - Schmelz,Martin, Y1 - 2012/05/10/ PY - 2012/5/12/entrez PY - 2012/5/12/pubmed PY - 2012/11/6/medline SP - 560 EP - 71 JF - Anesthesia and analgesia JO - Anesth Analg VL - 115 IS - 3 N2 - BACKGROUND: Axonal sodium channels are attractive targets for chronic pain treatment, and recent evidence suggests that specific targeting of the slow inactivation of sodium channels (NaV) might exert analgesic effects. Using a human-like animal model, the pig, we compared changes in the conductive properties of different C-fiber classes on acute administration of lidocaine (nonselective NaV blocker) and lacosamide (selective enhancer of NaV slow inactivation). METHODS: Single-fiber extracellular recordings from saphenous nerves were performed. We classified C-fibers according to mechanical responsiveness and amount of activity-dependent slowing (ADS) of conduction velocity. Lidocaine (4 mM; 100 μL), lacosamide (4 mM; 100 μL), or saline was injected intradermally at the stimulation site, and changes of fibers' conductive properties were assessed. RESULTS: Conduction latencies evoked by lidocaine were more prominent in mechanosensitive (5.5%± 2.1%) than in mechano-insensitive nociceptors (2.5% ± 1%), whereas lacosamide increased conduction latencies to a greater extent in the mechano-insensitive (3% ± 1%) than in mechanosensitive C-nociceptors (2% ± 0.9%). Lidocaine, but not lacosamide, increased electrical thresholds in all mechanosensitive, but not in the mechano-insensitive, C-fibers. Lacosamide blocked conduction and, in addition, reduced ADS in mechano-insensitive nociceptors significantly more than in mechanosensitive nociceptors (ΔADS: 2.4% ± 0.5% vs 1.6% ± 0.5%), whereas lidocaine had opposite effects. Saline had no significant effect on the conductive properties of C-fibers. CONCLUSION: Local application of test compounds in pig skin allows for functional assessment of steady-state and use-dependent modulation of sodium channels in nociceptive and nonnociceptive C-fibers. Increased analgesic specificity might derive from selective enhancement of slow inactivation of sodium channels. SN - 1526-7598 UR - https://www.unboundmedicine.com/medline/citation/22575571/The_differential_effects_of_two_sodium_channel_modulators_on_the_conductive_properties_of_C_fibers_in_pig_skin_in_vivo_ L2 - https://doi.org/10.1213/ANE.0b013e3182542843 DB - PRIME DP - Unbound Medicine ER -