Targeting voltage-gated sodium channels for treatment for chronic visceral pain

Abstract

Voltage-gated sodium channels (VGSCs) play a fundamental role in controlling cellular excitability, and their abnormal activity is related to several pathological processes, including cardiac arrhythmias, epilepsy, neurodegenerative diseases, spasticity and chronic pain. In particular, chronic visceral pain, the central symptom of functional gastrointestinal disorders such as irritable bowel syndrome, is a serious clinical problem that affects a high percentage of the world population. In spite of intense research efforts and after the dedicated decade of pain control and research, there are not many options to treat chronic pain conditions. However, there is a wealth of evidence emerging to give hope that a more refined approach may be achievable. By using electronic databases, available data on structural and functional properties of VGSCs in chronic pain, particularly functional gastrointestinal hypersensitivity, were reviewed. We summarize the involvement and molecular bases of action of VGSCs in the pathophysiology of several organic and functional gastrointestinal disorders. We also describe the efficacy of VGSC blockers in the treatment of these neurological diseases, and outline future developments that may extend the therapeutic use of compounds that target VGSCs. Overall, clinical and experimental data indicate that isoform-specific blockers of these channels or targeting of their modulators may provide effective and novel approaches for visceral pain therapy.

Neonatal colonic inflammation sensitizes voltage-gated Na+channels via upregulation of cystathionine β-synthetase expression in rat primary sensory neurons

“…with previous reports that Na ϩ current is involved in somatic pain (16,26) and visceral pain (7,17,27,42). The increase in Na ϩ current density is attributed to more Na ϩ influx.…”

Colonic Hypersensitivity and Sensitization of Voltage-gated Sodium Channels in Primary Sensory Neurons in Rats with Diabetes

“…VGSCs have important roles in nociception 8 and visceral pain. 38 Many of the published data suggest that voltage-gated sodium channel subtypes are expressed in primary sensory neurons where they influence excitability via their role in the generation and propagation of APs. 39 Nerve damage leads to alterations in expression and function of α-subunits that in turn can enhance the excitability of sensory neurons.…”

“…This is in agreement with previous reports that VGSCs have important roles in nociception and visceral pain. 38,[43][44][45] Based on multifarious sensitivity to tetrodotoxin (TTX), sodium currents are classified into TTX-sensitive (TTX-S) and TTXresistant (TTX-R) components. Na V 1.8 is the TTX-R sodium channels while Na V 1.7 mediates TTX-sensitive sodium currents.…”

Drug Management of Visceral Pain: Concepts from Basic Research

“…Tetrodotoxin-resistant channels and Na 1.7 are mainly expressed on nociceptor sensory afferents [ 79 ]. These membrane glycoproteins have large alpha subunits and smaller beta subunits which form 9 recognizable subsets [ 80 ]. These channels have 4 domains made up of individual 6 transmembrane segments (S1-6).…”