A spicy family tree: TRPV1 and its thermoceptive and nociceptive lineage.

In the current issue, Mishra and colleagues demonstrate that mice lacking somatosensory neurons in the TRPV1 lineage are completely insensitive to thermal stimuli of any quality or modality, including both hot and cold temperatures. TRPV1 is a heat-gated ion channel expressed in most heat-sensitive nociceptive neurons and is the receptor for capsaicin, the pungent ingredient in ‘hot’ chili peppers (Caterina et al, 1997). In the adult mouse, TRPV1 neurons are molecularly heterogeneous, but channel expression is absent in the majority of coldsensitive neurons labelled with the menthol receptor TRPM8 and all presumptive mechanosensory neurons expressing the Mas-related G protein-coupled receptor D (Mrgprd). However, using a molecular genetic approach to label TRPV1 neurons from the inception of channel expression, the authors find that TRPV1 is a broad developmental marker for the majority of somatosensory neurons, including those expressing Mrgprd and TRPM8. Moreover, genetically targeted ablation of neurons within the TRPV1 lineage eliminates a broad range of mouse behaviours including thermosensation, thermoregulation, nociception, and pruriception, yet these animals retain normal mechanosensation. These results demonstrate that TRPV1 expression predominates embryonically, but is refined over postnatal development. Moreover, other thermosensitive and nociceptive molecules, such as TRPM8, are derived from the TRPV1 lineage even though they are not entirely co-expressed in adults. These findings expand the role of TRPV1 and show the channel has a patriarchal role as a molecular indicator of thermal and nociceptive afferent circuits. We detect changes in our environment with specialized sensory nerve endings in the skin, many of which are activated by multiple modes of somatosensory stimuli, such as thermal and mechanical. This polymodality suggests that decoding of a specific sensory modality does not occur in the afferent, but is deciphered in higher centres such as the spinal cord or brain. However, this hypothesis has come under considerable debate with several elegant reports showing that ablation of specific afferent subtypes abrogates only a single sensory modality (Cavanaugh et al, 2009; Mishra and Hoon, 2010). For example, chemical ablation of neurons expressing TRPV1 nullifies heat pain, but not cold or mechanical sensitivity (Cavanaugh et al, 2009; Mishra and Hoon, 2010). Similarly, ablation of non-peptidergic Mrgprd neurons attenuates mechanosensation, but not thermosensation (Cavanaugh et al, 2009), suggesting that processing of heat and mechanical stimuli is separated within distinct and largely non-overlapping afferent circuits. However, ablation of neurons expressing the nociceptor-specific Na channel Nav1.8 attenuates mechanical pain with little effect on heat, the latter surprising as these mice are severely deficient in TRPV1 (Abrahamsen et al, 2008). These studies highlight the complexity in defining a particular neuron type and reveal the importance of cell-type specificity when considering the link between polymodality and molecular expression. Nonetheless, the presence of these ‘labelled lines’ suggests that a significant component of modality decoding resides within the afferent itself. Mishra et al (2011) add to these results by generating novel transgenic mice expressing Cre recombinase via the trpv1 promoter (TRPV1-Cre), animals that were initially bred with a reporter line such that neurons within the TRPV1 lineage are genetically labelled regardless of whether TRPV1 channel expression is maintained in these cells into adulthood (Figure 1). TRPV1 transcript expression has been detected as early as embryonic day 12.5 (E12.5) in mice, with 460% of DRG neurons capsaicin sensitive by E14.5 (Hjerling-Leffler et al, 2007). However in adults, channel expression and capsaicin sensitivity is restricted to B30–40% of neurons, results suggesting that TRPV1 is either developmentally downregulated or that a large number of these cells undergo programmed cell death. The current study supports the former hypothesis as the genetically labelled TRPV1 lineage accounts for greater than one-half of all DRG neurons in adult mice. The intriguing question is what are these additional cell types? As expected, transgene expression co-labels with a number of TRPV1-specific markers, including the irritant receptor TRPA1, the purinergic receptor P2X3, and the neuropeptides CGRP and substance P. While neither the neurotrophic receptor TrkA nor the transcription factor Runx1 were examined, two determinants of TRPV1 expression, the transgene was limited to presumptive thermoreceptors and nociceptors as large diameter low-threshold mechanoreceptors and proprioceptors expressing TrkB and TrkC were unlabelled. However, all neurons expressing the cold-gated channel TRPM8 were, in addition to a large percentage of non-peptidergic Mrgprd neurons (Zylka et al, 2005). In the adult, TRPV1 and Mrgprd express in non-overlapping populations, whereas only B25% of TRPM8 neurons express TRPV1 (Zylka et al, 2005; Takashima et al, 2007). Thus, these two molecularly and functionally distinct sensory The EMBO Journal (2011) 30, 453–455 | & 2011 European Molecular Biology Organization | All Rights Reserved 0261-4189/11 www.embojournal.org