<p>Voltage gated sodium channels as therapeutic targets for chronic pain</p>

Abstract

Being maladaptive and frequently unresponsive to pharmacotherapy, chronic pain presents a major unmet clinical need. While an intact central nervous system is required for conscious pain perception, nociceptor hyperexcitability induced by nerve injury in the peripheral nervous system (PNS) is sufficient and necessary to initiate and maintain neuropathic pain. The genesis and propagation of action potentials is dependent on voltage-gated sodium channels, in particular, Nav1.7, Nav1.8 and Nav1.9. However, nerve injury triggers changes in their distribution, expression and/or biophysical properties, leading to aberrant excitability. Most existing treatment for pain relief acts through non-selective, state-dependent sodium channel blockage and have narrow therapeutic windows. Natural toxins and developing subtype-specific and molecular-specific sodium channel blockers show promise for treatment of neuropathic pain with minimal side effects. New approaches to analgesia include combination therapy and gene therapy. Here, we review how individual sodium channel subtypes contribute to pain, and the attempts made to develop more effective analgesics for the treatment of chronic pain.

Rapid tolerance to morphine in the myenteric neurons of the small intestine is independent of β-arrestin-2 and mediated by PKC

“…PKC is known to cause homologous or heterologous desensitization of ion channels such as voltage-gated sodium channels-pivotal to action potential generation (Levitt and Williams, 2012;Ma et al, 2019). However, we did not observe altered active action potential properties after Bis XI-induced PKC inhibition.…”

Centipede Venom Peptides Acting on Ion Channels

“…Pharmacologically, Navs may be classified by their sensitivity to the neurotoxin tetrodotoxin (TTX). Nav1.5, Nav1.8 and Nav1.9 are TTX-resistant (TTX-R), while other subtypes are TTX-sensitive (TTX-S) [60]. Nav1.7, Nav1.8, and Nav1.9, predominantly expressed in peripheral neurons, are important targets for chronic pain therapy [61][62][63][64].…”

Novel Analgesics with Peripheral Targets

“…Therefore, it seems valuable to pursue selective pharmacological tools targeting Na v subtypes. However, this development is ongoing for a considerable time and with substantial effort, indicating the difficulty to generate such subtype-specific and effective drugs [136][137][138]. Clinical trials have been exploring the utility of lidocaine patches in arthritis [139] and also alternatives to small-molecule antagonists, e.g., peptides (AM-6120, AM-8145, AM-0422) or Na v 1.7 monoclonal antibodies [140].…”