Na_v1.7 and other voltage-gated sodium channels as drug targets for pain relief

ABSTRACT

Introduction: Chronic pain is a massive clinical problem. We discuss the potential of subtype selective sodium channel blockers that may provide analgesia with limited side effects.

Areas covered: Sodium channel subtypes have been linked to human pain syndromes through genetic studies. Gain of function mutations in Na_v1.7, 1.8 and 1.9 can cause pain, whilst loss of function Na_v1.7 mutations lead to loss of pain in otherwise normal people. Intriguingly, both human and mouse Na_v1.7 null mutants have increased opioid drive, because naloxone, an opioid antagonist, can reverse the analgesia associated with the loss of Na_v1.7 expression.

Expert Opinion: We believe there is a great future for sodium channel antagonists, particularly Na_v1.7 antagonists in treating most pain syndromes. This review deals with recent attempts to develop specific sodium channel blockers, the mechanisms that underpin the Na_v1.7 null pain-free phenotype and new routes to analgesia using, for example, gene therapy or combination therapy with subtype specific sodium channel blockers and opioids. The use of selective Na_v1.7 antagonists together with either enkephalinase inhibitors or low dose opioids has the potential for side effect-free analgesia, as well as an important opioid sparing function that may be clinically very significant.

KEYWORDS:

• SCN9A
• Na_v1.7
• sensory neurons
• pain
• opioids

Article highlights

• Non-specific sodium channel blockers are very effective analgesics for most pain syndromes.

• Sodium channel Na_v1.7 is essential for human pain, but specific antagonists have weak analgesic activity.

• Na_v1.7 not only propagates action potentials but has other actions, notably in control of the expression of opioid peptides.

• Animal models show that Na_v1.7 antagonists, when co-administered with low dose opioids do give effective analgesia.

• The role of Na_v1.8 and Na_v1.9 in pain syndromes is explored.

• Small molecule blockers and gene therapy approaches to down-regulating Na_v1.7 sodium channel expression are described.

This box summarizes the key points contained in the article.

Acknowledgement

The authors gratefully acknowledge the generous gift of Phlotoxin by Dr Pierre Escoubas.

Declaration of interest

E Emery and J Wood thank the Wellcome Trust, J Wood thanks the Medical Research Council and A Luiz and J Wood thank Arthritis UK. J Wood also thanks the BK21 Programme at SNU for generous support. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.