Chemical and Cold Sensitivity of Two Distinct Populations of TRPM8-Expressing Somatosensory Neurons

Abstract

The cold- and menthol-sensing TRPM8 receptor has been proposed to have both nonnociceptive and nociceptive functions. However, one puzzle is how this single type of receptor may be used by somatosensory neurons to code for two distinct sensory modalities. Using acutely dissociated rat dorsal root ganglion (DRG) neurons without culture, we show that TRPM8 receptors are expressed on two distinct classes of somatosensory neurons. One class is sensitive to menthol and features nonnociceptive neuron properties, including capsaicin-insensitive, ATP-insensitive, transient acid response, and expression of TTX-sensitive sodium channels only. This class is termed the menthol-sensitive/capsaicin-insensitive neuron class (MS/CIS). The other class is also sensitive to menthol but has characteristics of nociceptive neurons including capsaicin-sensitive, ATP-sensitive, prolonged acid response, and expression of both TTX-sensitive and TTX-resistant sodium channels. This class is termed the menthol-sensitive/capsaicin-sensitive neuron class (MS/CS). The presence of these two neuron classes in acutely dissociated DRG neurons support the idea that TRPM8 receptors can have both nonnociceptive and nociceptive functions. While both neuron classes respond to menthol and cold, the overall responses induced by menthol and cold are significantly larger in MS/CIS than in MS/CS neurons. Furthermore, low concentrations of menthol produce strong selection of the MS/CIS neuron population over the MS/CS neuron population. On the other hand, the population selection becomes weaker with higher concentrations of menthol. TRPM8 current density shows significant higher in MS/CIS neurons than in MS/CS neurons, suggesting different expression levels of TRPM8 receptors between the two neuron populations, and this difference may provide a mean of selective activation of MS/CIS neurons at low stimulation intensity.

Variable Threshold of Trigeminal Cold-Thermosensitive Neurons Is Determined by a Balance between TRPM8 and Kv1 Potassium Channels

“…This finding and the higher density of menthol-sensitive currents in LT-CS neurons strongly suggest that they express higher levels of TRPM8. A similar conclusion was reached previously in rat trigeminal and dorsal root ganglion (DRG) (Xing et al, 2006) neurons.…”

“…In its absence, nociceptor sensory terminals become unexcitable at low temperatures, and it is attractive to speculate that this channel is also expressed by highthreshold cold thermoreceptors. A significant fraction of menthol-and cold-sensitive neurons in DRGs were found to express TTX-resistant sodium channels (Xing et al, 2006). A schematic representation of our proposal is illustrated in supplemental Figure 4, available at www.jneurosci.org as supplemental material.…”

Nociceptive sensations evoked from ‘spots’ in the skin by mild cooling and heating

“…In addition, TRPV3 continues to respond to painfully hot temperatures (Peier et al 2002b) knockout mice that lack TRPV3 show deficits in response to both noxious and innocuous heat (Moqrich et al 2005). Similarly, the menthol and cold receptor TRPM8 (McKemy et al 2002;Peier et al 2002a), which was recently shown in mice to be the principal receptor for cold below 30°C (Bautista et al 2007;Colburn et al 2007;Dhaka et al 2007;see however Munns et al 2007), has been reported in some DRG and trigeminal ganglion neurons that are capsaicin-sensitive and/or were shown to express TRPV1 (McKemy et al 2002;Okazawa et al 2004;Abe et al 2005;Xing et al 2006;Hjerling-Leffler et al 2007). (See, however, Kobayashi et al 2005.…”

Diversity in the Neural Circuitry of Cold Sensing Revealed by Genetic Axonal Labeling of Transient Receptor Potential Melastatin 8 Neurons

“…Moreover, functional data from cultured sensory neurons show that approximately one-half of menthol-sensitive neurons are also capsaicinsensitive, suggesting coexpression of both TRPM8 and TRPV1 in this subset of cold-and menthol-sensitive neurons (McKemy et al, 2002;Viana et al, 2002;Hjerling-Leffler et al, 2007). Last, in primary culture, a subset of menthol-sensitive DRG neurons has been shown to have nociceptive properties (Xing et al, 2006). Thus, we examined coexpression of GFP and TRPV1 immunoreactivity in TG and DRG and, consistent with functional data, found that 38.8 Ϯ 2.2% (n ϭ 719) and 23.7 Ϯ 4.6% (n ϭ 221) of GFP ϩ TG and DRG soma also express TRPV1, respectively (Fig.…”