The role of voltage-gated sodium channel 1.9 (Nav1.9) in visceral afferent signalling.

Abstract

Abdominal pain places a large burden on society and its current management is sub-optimal due to the lack of visceral-specific analgesics. Voltage-gated sodium channels (Nav) are crucial for action potential generation and Nav1.9 has the lowest activation threshold of all these channels. In addition, Nav1.9 expresses a unique, slow, persistent current and is peripherally expressed on small diameter dorsal root ganglion (DRG) neurons. Whereas, at the level of the DRG, the Nav1.9 current is enhanced in response to a number of inflammatory mediators, no data exist for the role of Nav1.9 in signalling at the nerve terminal. Behavioural studies in mice have established a role for Nav1.9 in the response of somatic afferents to inflammatory mediators where it has a role in the immediate response of the afferents as well as in the development of hyperalgesia. No studies have investigated the role of Nav1.9 in the response of visceral afferents to inflammatory and mechanical stimuli. This thesis investigated the role of Nav1.9 in the response of visceral afferents to a variety of chemical and mechanical stimuli. Electrophysiological recording of colonic and intestinal afferents from Nav1.9 wild type and knockout mice were made using a bespoke recording chamber. The tissue was superfused with a number of chemical mediators and the change in peak afferent activity compared between wild type and knockout mice. For some experiments, human inflammatory supernatant was generated from inflamed and control appendices. The effect of this supernatant on visceral afferents and the role of Nav1.9 in this response were studied. The response of visceral afferents to intraluminal distension was also studied in Nav1.9 wild type and knockout mice. The data presented in this thesis demonstrate a pivotal role for Nav1.9 in the activation of visceral afferents by chemical and mechanical stimuli as well as a human inflammatory supernatant. The response of colonic and intestinal afferents to bradykinin, capsaicin and intraluminal distension is significantly attenuated in Nav1.9 knockout mice. Although the peak response of afferents to acetic acid was not significantly different between the genotypes, there were significant differences in the profile of the responses. Additionally, the data show that cyclooxygenase blockade enhances the effect of elimination of Nav1.9 on the response of afferents to noxious stimuli. Finally, the activation of visceral afferents by human inflammatory supernatants was significantly decreased in Nav1.9 knockout mice suggesting that blockade of this channel in man could provide analgesic effects that, due to its restricted peripheral distribution, would not be expected to be associated with the side effect profile of the current non-specific sodium channel blockers.