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

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 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 1.7-S241T mutant channel, reducing pain in patients carrying this mutation. However, whether this approach is applicable to other Na 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 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 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 1.7-I234T channels, compared with neurons expressing the normal channels (Na 1.7-WT). Pre-incubation with 30 μM carbamazepine also significantly reduced the firing of intact DRG sensory neurons expressing Na 1.7-I234T channels. Although the expected use-dependent inhibition of Na 1.7-WT channels by carbamazepine was confirmed, carbamazepine did not enhance use-dependent inhibition of Na 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.

© 2017 The British Pharmacological Society.