Targeting voltage-gated sodium channels for pain therapy

Abstract

Drugs inhibiting voltage-gated sodium channels have long been used as analgesics, beginning with the use of local anaesthetics for sensory blockade and then with the discovery that Nav-blocking anticonvulsants also have benefit for pain therapy. These drugs were discovered without knowledge of their molecular target, using traditional pharmacological methods, and their clinical utility is limited by relatively narrow therapeutic windows. Until recently, attempts to develop improved inhibitors using modern molecular-targeted screening approaches have met with limited success. However, in the last few years there has been renewed activity following the discovery of human Nav1.7 mutations that cause striking insensitivity to pain. Together with recent advances in the technologies required to prosecute ion channels as drug targets, this has led to significant progress being made. This article reviews these developments and summarises current findings with these emerging new Nav inhibitors, highlighting some of the unanswered questions and the challenges that remain before they can be developed for clinical use.

Keywords::

• automated electrophysiology
• disinhibition
• drug binding site
• frequency-dependence
• inhibitory antibodies
• pain
• subtype selectivity
• toxins
• use-dependence
• voltage-dependence
• voltage-gated sodium channels

Acknowledgements

The author would like to acknowledge R Helliwell and L Pym for their input in generating the data shown in Figure 4, and L Browne for the data in Figures 3 and 5.

Notes