Reverse pharmacogenomics: carbamazepine normalizes activation and attenuates thermal hyperexcitability of sensory neurons due to Na v 1.7 mutation I234T

Abstract

Background and Purpose: Pharmacotherapy for pain currently involves trial and error. A previous study on inherited erythromelalgia (a genetic model of neuropathic pain due to mutations in the sodium channel, Na v 1.7) used genomics, structural modelling and biophysical and pharmacological analyses to guide pharmacotherapy and showed that carbamazepine normalizes voltage dependence of activation of the Na v 1.7-S241T mutant channel, reducing pain in patients carrying this mutation. However, whether this approach is applicable to other Na v channel mutants is still unknown. Experimental Approach: We used structural modelling, patch clamp and multi-electrode array (MEA) recording to assess the effects of carbamazepine on Na v 1.7-I234T mutant channels and on the firing of dorsal root ganglion (DRG) sensory neurons expressing these mutant channels. Key Results: In a reverse engineering approach, structural modelling showed that the I234T mutation is located in atomic proximity to the carbamazepine-responsive S241T mutation and that activation of Na v 1.7-I234T mutant channels, from patients who are known to respond to carbamazepine, is partly normalized with a clinically relevant concentration (30 μM) of carbamazepine. There was significantly higher firing in intact sensory neurons expressing Na v 1.7-I234T channels, compared with neurons expressing the normal channels (Na v 1.7-WT). Pre-incubation with 30 μM carbamazepine also significantly reduced the firing of intact DRG sensory neurons expressing Na v 1.7-I234T channels. Although the expected use-dependent inhibition of Na v 1.7-WT channels by carbamazepine was confirmed, carbamazepine did not enhance use-dependent inhibition of Na v 1.7-I234T mutant channels. Conclusion and Implications: These results support the utility of a pharmacogenomic approach to treatment of pain in patients carrying sodium channel variants. Linked Articles: This article is part of a themed section on Recent Advances in Targeting Ion Channels to Treat Chronic Pain. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc.