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The study by Minett et al. (2012) offers insight into the relationship between Nav1.7-expressing sensory neurons, reflex withdrawal responses to heat, and responses to the hotplate test. Nav1.7 channels were either only deleted from Nav1.8-expressing sensory neurons through Cre driven by Nav1.8 (Nav1.7Nav1.8) or they were deleted from all sensory neurons through Advillin promoter-driven Cre expression (Nav1.7Advill). Withdrawal responses to heat and mechanical pain were abolished when Nav1.7 channels were deleted from all sensory neurons, whereas withdrawal responses to heat were maintained when Nav1.7 channels were only deleted from Nav1.8-expressing sensory neurons. Responses to the hotplate test were only abolished when Nav1.7 channels were deleted both from DRG neurons and sympathetic neurons by Wnt1-Cre (Nav1.7Wnt1). At the same time, all conditional Nav1.7 knockout mouse lines (Nav1.7Nav1.8, Nav1.7Advill and Nav1.7Wnt1) responded normally to noxious cold stimuli. This indicates that Nav1.7 channels are not involved in the propagation of noxious cold stimuli. Overall, the study by Minett et al. (2012) offers support for the existence of different subsets of Nav1.7-expressing neurons for heat-evoked withdrawal responses and responses to the hotplate test.Several mechanisms have been suggested for the link between Nav1.7 and painful heat responses. Of note, mutations in the gene encoding Nav1.7 channels, SCN9A, conveys inherited erythromelalgia, a condition associated with burning pain (Dib-Hajj et al., 2006). These gain-of-function mutations result in the shift of the activation threshold of Nav1.7 channels towards hyperpolarizing membrane potentials, a shift of steady-state inactivation towards less negative potentials, lower rheobase currents and high-frequency DRG neuronal activity (Dib-Hajj et al., 2005). More specifically, the erythromelalgia mutation Q875E is suggested to form a disulphide bridge between the voltage sensor of domain I and the pore region of domain II, forcing the pore into opened position (Stadler, O’Reilly, Lampert, 2015). In conditions of health, Nav1.7 channels are thought to amplify the transducer currents of heat-sensing channels, e.g. TRPV1 (Shields et al., 2012). Additionally, it has been suggested that burn injury-induced lowering of the Nav1.7 channel activation threshold could be brought about by ERK1/2-mediated modulatory phosphorylation of T531, S535, S608 and S712 in the first intracellular loop (Stamboulian et al., 2010; Shields et al., 2012). Furthermore, Mazarío and Basbaum (2007) supported that deletion of preprotachykinin-A (PPT-A), the gene that encodes Substance P and Neurokinin A, in mice, decreased the responses of lamina I and V neurons to noxious thermal stimuli, whereas the responses of the laminal neurons to noxious mechanical stimulation did not differ between WT and PPT-A knockout mice. In their study, Minett et al. (2012) also observed that deletion of Nav1.7 in mouse DRG neurons abolished substance P release into the dorsal horn of the DRG neurons and did not result in wind-up upon electrical stimulation of the spinal lamina V wide dynamic range neurons. Therefore, Nav1.7 channel activity could be critical for the release of substance P and wind-up in spinal pain pathways specific for heat-evoked pain, but not for noxious mechanical stimuli.Nav1.9 channels are also thought to play a role in heat-evoked pain. Lolignier et al. (2011) supported that Nav1.9 channels are involved in noxious thermal and mechanical hypersensitivity associated with subacute paw inflammation and chronic ankle inflammation in mice and rats, without any alterations in basal pain thresholds. They also observed increased Nav1.9 immunoreactivity in ipsilateral DRG neurons and increased Nav1.9 immunolabeling in nerve fibres that surrounded inflamed areas, without any changes in Nav1.9 mRNA levels, 24 h after carrageenan (thermal pain-inducing chemical) application, which they attributed to increased transport of Nav1.9 channels from the soma towards the nerve terminals. Thus, it may be that, in response to inflammatory thermal and inflammatory mechanical pain, Nav1.9 channels are transported to nerve terminals and sensitize nociceptors to noxious heat and mechanical stimuli.