elegans. MeT channels are formed by DEG/ENaC proteins in PLMs and TRP proteins in CEPs. The ion channel proteins that form MeT channels that detect mechanical cues in nociceptors have yet to be determined. Many nociceptors, including those forming mammalian

C fibers, express both DEG/ENaC and TRP channels proteins (Lumpkin and Caterina, 2007 and Woolf and Ma, 2007). Notable examples include multidendritic neurons in Drosophila larvae ( Tracey et al., 2003 and Zhong et al., 2010) and in C. elegans ( Chatzigeorgiou and Schafer, 2011 and Chatzigeorgiou et al., 2010). Some studies suggest that both channel types are needed for responses to mechanical cues, while others have demonstrated that only one of these channel types has a role. In Drosophila CP-690550 purchase larvae, both the Pickpocket DEG/ENaC channel and the Painless TRP channel are required in multidendritic neurons for behavioral responses to noxious Selisistat cell line mechanical stimuli ( Tracey et al., 2003 and Zhong et al., 2010). Because optogenetic stimulation of these neurons evokes aversive behaviors in larvae lacking Pickpocket, Zhong et al. (2010) proposed that Pickpocket is upstream of Painless in the mechanosensory signaling pathway. In C. elegans, by contrast, only DEG/ENaC channels are required for noxious mechanical stimulus-evoked calcium transients in the PVD and FLP multidendritic neurons ( Chatzigeorgiou and Schafer, 2011 and Chatzigeorgiou

et al., 2010). Indeed, mechanoreceptor currents (MRCs) in PVD have properties expected of currents carried by DEG/ENaC channels ( Li et al., 2011). Like the multidendritic neurons, the amphid ASH neurons in C. elegans also coexpress DEG/ENaC and TRP channels.

For several reasons, these neurons are an excellent model nociceptor. First, they are polymodal: chemical, osmotic, and mechanical stimuli evoke transient increases in cytoplasmic calcium and an ASH-dependent withdrawal behavior ( Chronis et al., 2007, Hilliard et al., 2005 and Kindt et al., 2007). An intact ASH is required for full sensitivity to multiple aversive stimuli ( Hart et al., 1995 and Kaplan and Horvitz, 1993). Second, artificial activation of the ASH Cediranib (AZD2171) neurons is sufficient to induce defensive avoidance behavior ( Guo et al., 2009 and Tobin et al., 2002). Thus, ASH neurons perform all of the functions expected of a polymodal nociceptor. The ASH neurons express at least two deg/ENaC and two trp genes ( Colbert et al., 1997, Hall et al., 1997, Tavernarakis et al., 1997 and Tobin et al., 2002): the deg/ENaC genes are deg-1 and unc-8 which encode proteins related to the MEC-4 and MEC-10 proteins that form force-gated ion channels in C. elegans touch receptor neurons, while the trp channel genes are osm-9 and ocr-2 both of which encode TRPV proteins. Until now, the lack of deletion alleles in deg-1 and unc-8 has limited understanding of their role in ASH. In contrast, a great deal is known about the TRPV channel genes osm-9 and ocr-2.