The role of voltage-gated sodium channels in modality-specific pain pathways

Georgios Louloudis


21 May 2017


18 Jul 2017


2 Nov 2017






pain pathways, modality, sodium channels, Nav1.7, Nav1.8, Nav1.9


Pain is a distressing physical and emotional experience associated with actual or potential tissue injury, or an experience described in terms of such injury. The primary function of nociceptors, such as some dorsal root ganglion (DRG) neurons, is to transduce noxious sensory modalities, e.g. mechanical pressure, cold and heat, into electrical impulses and to transmit these to processing centres in the central nervous system (CNS). Modality-specific pain pathways have been identified through in vivo deletion of voltage-gated Na+ channels in mouse DRG neurons. Deletion of Nav1.8 channels has been shown to result in loss of mechanosensory and cold-induced pain, but not-heat induced pain, whereas deletion of Nav1.7 channels has been seen to abolish responses to noxious heat and mechanical stimuli. The present review constitutes an attempt to elucidate the mechanisms through which voltage-gated Na+ channels are involved in modality-specific pain pathways. It has been found that Nav1.8 and Nav1.9 channels are resistant to slow inactivation upon cooling, maintaining activity even though channels on other sensory afferents may be inactivated. Nav1.7 channel activity is reported to be coupled to substance P release into the dorsal horn of dorsal root ganglion (DRG) neurons in heat-specific pain pathways. Recent research has also offered insight into the role of Nav1.7 and Nav1.9 mutations in pain-related conditions, e.g. inherited erythromelalgia and cold-aggravated pain, respectively, as these influence kinetic parameters, such as open state probability. Therefore, voltage-gated Na+ channels appear to be playing an important role in segregating modality-specific pain pathways. The identification of markers for mechanisms implicated in the activation of these pathways could potentially pave the way towards the development of more effective analgesics.

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