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

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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.