Relationship between the firing frequency of injured peripheral neurons and inhibition of firing by sodium channel blockers.
Animal models of neuropathic pain in which a peripheral nerve is damaged result in spontaneous activity in primary afferents that can be inhibited by intravenous administration of sodium channel blockers. Many of these compounds exhibit use-dependent block of sodium current, leading to the prediction that they should more readily inhibit neurons that fire at higher frequencies. This prediction was tested in 2 rat models of nerve injury, L5 spinal nerve section and sciatic nerve section. Sciatic nerve section produced average firing frequencies that were higher than spinal nerve section and often manifested as high-frequency bursting. Inhibition of firing by intravenous sodium channel blockers was longer lasting in this model. Within each model, higher frequency of firing did not translate into more effective block. In the spinal nerve section model, there was a robust inverse correlation between frequency and inhibition. Within the sciatic section model, only neurons that fired in rhythmic bursts were inhibited, and again, those firing at lower mean frequencies were more effectively inhibited. These results indicate that the efficacy of sodium channel blockers depends on the nature of the injury and the pattern of the resulting activity rather than simply the frequency of action potentials generated.


CONCLUSIONS
This study examines the ability of frequency-dependent sodium channel blockers to inhibit spontaneous firing of injured peripheral nerves in vivo. It outlines the conditions under which inhibition is more and less effective and will provide insight into conditions under which sodium channel blockers are likely to be therapeutically useful.
Ritter
Amy M
AM
Department of Pharmacology, Merck Research Labs, Rahway, New Jersey 06075, USA. amy_ritter@merck.com
Ritchie
Courtney
C
Martin
William J
WJ
D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D003714:Denervation; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D000077213:Lamotrigine; D008012:Lidocaine / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000187:drug effects*; D017933:Peripheral Nervous System / Q000166:cytology / Q000187:drug effects* / Q000293:injuries*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000293:injuries / Q000473:pathology; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D013127:Spinal Nerves / Q000293:injuries / Q000473:pathology; D014227:Triazines / Q000494:pharmacology
D000779:Anesthetics, Local; D018691:Excitatory Amino Acid Antagonists; D026941:Sodium Channel Blockers; D014227:Triazines; D008012:Lidocaine; D000077213:Lamotrigine