Different of L4 DRG neurons triggers theDifferent of L4 DRG neurons triggers the

Different sets of modality-specific sets of sensory neurons seem to be activated in response to noxious heat or noxious cold (see Fig. 2). As can be seen from the study of Emery et al. (2016), mechanical stimulation of L4 DRG neurons triggers the activation of polymodal sensory neurons and, throughout this review, it appeared that noxious heat- or cold-specific pain pathways overlapped with those for the transmission of noxious mechanical stimuli. It is thus unlikely that there is a distinct neural pathway for the selective propagation of noxious mechanosensory signals. Voltage-gated Na+ channels seem to be playing a critical role in the segregation of noxious cold and noxious heat modality-specific pathways (see Fig. 2). It is yet unclear whether Nav1.7 and Nav1.8 channels are selectively expressed in noxious heat- and noxious cold-specific pain pathways, respectively. As was previously mentioned, withdrawal responses to noxious heat were eliminated in Nav1.7Advill mice, but were maintained in Nav1.7Nav1.8 mice (Minett et al., 2012). Whilst it is likely that Nav1.7 channels in Nav1.8-negative nociceptors are essential for the transmission of noxious heat stimuli (Minett et al., 2012), the possibility that Nav1.7 channels in Nav1.8-expressing neurons contribute to noxious thermal sensation should not be rejected. It is possible that all Nav1.7-expressing DRG nociceptors are involved in the propagation of noxious heat stimuli and that noxious thermal reflexes in Nav1.7Advill mice were abolished due to a complete knockout of Nav1.7 channels from all DRG nociceptors, whereas in Nav1.7Nav1.8 mice, the activity of Nav1.7 channels in Nav1.8-negative DRG nociceptors could have been sufficient to maintain the behavioural response in the absence of Nav1.7 channels in Nav1.8-expressing neurons. It is, therefore, also probable that Nav1.7 channels in both Nav1.8-negative and Nav1.8-positive DRG nociceptors are involved in thermal pain sensation. A direct comparison in thermal pain reflexes between mice that lack Nav1.7 channels in Nav1.8-negative sensory neurons only and mice lacking Nav1.7 channels solely in Nav1.8-positive neurons (Nav1.7Nav1.8) could have offered greater insight into the involvement of specific Nav1.8-expressing DRG nociceptors in thermal pain and the expression pattern of Nav1.7 channels in noxious heat-specific pain pathways. Our understanding of the expression pattern of Nav1.8 channels in noxious cold-pain pathways is also limited, as studies have made wide use of global Nav1.8 knockout mouse lines, e.g. Nav1.8DTA (Abrahamsen et al., 2008), and not of conditional Nav1.8 knockout mice.