Pharmacological modulation of peripheral nerve excitability-a novel way to investigate sodium channel subtypes in humans.

Abstract

Despite considerable progress in pain management, recommended systemic pharmacotherapy often comes with a high risk of serious side effects adversely affecting quality of life. Hence, topical routes of drug administration are currently gaining popularity in painful conditions such as diabetic peripheral neuropathy. Voltage-gated sodium channels (Nav) are expressed in peripheral nerves and are crucial for development and maintenance of neuropathic pain. Subtypes Nav1.7, 1.8, and 1.9 are highly expressed in nociceptors and are therefore interesting targets for topical pharmacotherapeutics. The aim of this study was to assess pharmacologically modulated excitability of peripheral sensory nerves using the human experimental perception threshold tracking technique, an indirect method for measuring the excitability of peripheral nerves. This randomized, placebo-controlled, and double-blinded study included 20 healthy participants. A novel electrical stimulation protocol-the Sodium channel Excitability Nociceptor Testing protocol-was used to identify alterations in Nav1.7, 1.8, and 1.9 after applying 3 (5% lidocaine, 10% phenytoin, and 2% mepyramine) topical pharmacological drugs. There was a significant difference in the relative increase in the perception threshold after drug application between drugs (P < 0.01) and between drugs and placebo (P < 0.01), except for phenytoin (P = 0.22). The computational model suggests that lidocaine and mepyramine caused different alterations of the Nav1.7, 1.8, and 1.9 currents. The Sodium channel Excitability Nociceptor Testing protocol can be used to investigate differential pharmacological alterations of specific Nav subtypes. This may lead to better insight of neurophysiological mechanisms of sensory afferents, forming the basis for targeted drug development, leading the way to stratified treatment regimens of peripheral pain.