Voltage-gated sodium channel blockers for the treatment of neuropathic pain

Abstract

Pain serves a crucial physiological function, warning the body of impending or actual tissue damage, preventing further damage and aiding the healing process. Neuropathic pain, resulting from nervous system injury or dysfunction, can be a serious medical problem and especially difficult to treat. Although sodium channel blockers are clinically useful for treating pain, they often provide only partial relief and adverse effects associated with nonspecific actions can limit their use. Research on the roles of sodium channels in neuronal excitability and pain shows that specific sodium channel isoforms are crucial determinants of nociception and neuropathic pain, indicating that it should be possible to develop sodium channel blockers with lower toxicity and enhanced efficacy for treating neuropathic pain.

Tarantula Huwentoxin-IV Inhibits Neuronal Sodium Channels by Binding to Receptor Site 4 and Trapping the Domain II Voltage Sensor in the Closed Configuration

“…Of the VGSCs that we tested, Nav1.7 showed the highest sensitivity for HWTX-IV. This is intriguing as Nav1.7 plays crucial roles in the pathophysiology of pain (29, 39 -41), and Nav1.7 blockers could aid the development of new drugs that can effectively treat pain (42). Indeed our preliminary experiments suggest that HWTX-IV can reduce pain behaviors in rats (14) (data not shown).…”

Conus Venom Peptide Pharmacology

“…As summarized in Table 6, Na v 1.7, -1.8, -1.9, and perhaps -1.3 are potential candidate targets for pain therapeutics because of their established role in pain, selective expression in nociceptive neurons and nerve terminals, and/or their regulation in pain states (see reviews by Catterall et al, 2005a;Cummins and Rush, 2007;Dib-Hajj et al, 2009;England and de Groot, 2009;Catterall, 2010;Dib-Hajj et al, 2010). Other Na v types are also expressed in sensory neurons, including Na v 1.1, -1.6, and (at low levels) -1.5 (Catterall et al, 2005a;Catterall, 2010;DibHajj et al, 2010), but inhibition studies with -conotoxins have suggested that Na v 1.6 and Na v 1.7 are the major contributors to peripheral nerve action potentials (Wilson et al, 2011a).…”

“…It is expressed predominantly in small nociceptive primary afferent nerves (Catterall et al, 2005a;Cummins and Rush, 2007;Catterall, 2010;Dib-Hajj et al, 2010). Na v 1.8 contributes to the action potential and repetitive firing in small, nociceptive sensory neurons (Catterall et al, 2005a;Cummins and Rush, 2007;Catterall, 2010;Dib-Hajj et al, 2010).…”

Sodium Channel Blockers for the Treatment of Neuropathic Pain

“…This topic is of great ongoing interest in the field, and the reader is referred to additional recent reviews for further reading. [155][156][157][158][159][160][161][162][163][164] …”