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 Nav1.7, 1.8 and 1.9 can cause pain, whilst loss of function Nav1.7 mutations lead to loss of pain in otherwise normal people. Intriguingly, both human and mouse Nav1.7 null mutants have increased opioid drive, because naloxone, an opioid antagonist, can reverse the analgesia associated with the loss of Nav1.7 expression. Expert Opinion: We believe there is a great future for sodium channel antagonists, particularly Nav1.7 antagonists in treating most pain syndromes. This review deals with recent attempts to develop specific sodium channel blockers, the mechanisms that underpin the Nav1.7 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 Nav1.7 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.

Pharmacological characterisation of the highly NaV1.7 selective spider venom peptide Pn3a

“…In the transcriptome of sensory neurons from Advillin-Cre Na V 1.7 knockout mice, no changes in endogenous opioid receptor transcripts were reported, only upregulation of Penk mRNA and Met-Enkephalin protein21. It therefore appears that Na V 1.7 inhibition in combination with opioid receptor activation, whether through upregulation of endogenous opioids, such as the enkephalins as demonstrated in the knockout experiments, or administration of exogenous opioids, as described here, can elicit profound analgesia53. Opioid receptors are expressed on peripheral sensory neurons, both on the peripheral and central projections, as well as along the axon, where they are involved in regulating neuronal excitability, action potential propagation, and neurotransmitter release through inhibition of calcium currents5455.…”

Neuropathic pain

“…These include, in particular, subtype selective sodium channel-blocking agents, particularly Na v 1.7 antagonists 114 , and EMA401, a novel angiotensin type II antagonist that has been found to be effective in a phase II clinical trial in postherpetic neuralgia 115 . Although still in the preclinical phase, studies show promising results of stem cell treatment for neuropathic pain 116,117 .…”

Emerging Targets for the Management of Osteoarthritis Pain

“…The mechanism of action of these substances, however, may not be completely clear as it has also been recently demonstrated that strong antagonism of Na V 1.7 activity leads to strongly increased expression of opioid peptide levels, which may contribute to the analgesic effects of loss of Na V 1.7 function. Whatever their precise mechanism, several of these substances have entered the drug development pipeline (for recent review, see [30]).…”