Role of Voltage-gated Sodium Channel Isoforms in Electrophysiological Properties of Neurons Innervating the Viscera in Mice

Chronic visceral pain is a poorly managed symptom of functional and inflammatory gastrointestinal disorders and there is a lack of suitable analgesics that are efficacious without gastrointestinal side effects. Voltage-gated sodium (Nav) channels regulate action potential generation and cell membrane excitability in sensory neurons and are implicated in several enhanced pain and loss-of-pain phenotypes in humans. Pharmacological modulation of Nav channels has been investigated as a therapeutic strategy for the past two decades in a range of pain modalities, including somatic, neuropathic, and more recently - visceral pain. In this thesis, gene transcripts for the nine Nav channel isoforms (Nav1.1-Nav1.9) were detected in dorsal root ganglia (DRG) neurons retrogradely labeled from the colon and bladder in mice, and the contribution of different isoforms to active electrophysiological properties in these neurons was evaluated using Nav-selective modulators. An evaluation of electrophysiological properties of colon-innervating DRG neurons from healthy and chronic visceral hypersensitivity (CVH) mice was also conducted and did not provide sufficient support for a model-related phenotype in vitro. In the pharmacological part of this thesis, it was found that inhibition of tetrodotoxin-sensitive Nav channels (Nav1.1-Nav1.4, Nav1.6 and Nav1.7) effectively altered electrophysiological responses in colon-innervating and bladder-innervating neurons, and furthermore reduced bladder afferent responses to distension and nociceptive signaling to the spinal cord. Electrophysiological responses in colon-innervating DRG neurons were also modulated by less selective Nav modulators, such as veratridine, which targets all Nav channel isoforms, and more selective Nav modulators, such as Hs1a, which targets Nav1.1, Nav1.2, Nav1.3, Nav1.6, and Nav1.7; OD1, which targets Nav1.4, Nav1.6, and Nav1.7; ICA-121341, which targets Nav1.1-Nav1.3; A-803467, which targets Nav1.8; and Compound B, which targets Nav1.1. inhibition of Nav1.1 using Compound B was furthermore shown to be effective in reducing pain responses to colorectal distension in CVH mice.Thesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 201