Merkel Cells Sense Cooling with TRPM8 Channels.

In the skin, Merkel cells connect with keratinocytes and Aß nerve fibers to form a touch receptor that functions as a slow adapting mechanoreceptor (slow adapting type 1). In human and mouse Merkel cells, we observed an increased concentration of intracellular Ca2+ ions in response to cold temperature and transient receptor potential melastatine 8 (TRPM8) ion channel agonists. A reduction in the response to cooling and TRPM8 agonists occurred after the addition of TRPM8 antagonists, as well as in TRPM8 knockout mice. Cold temperature and TRPM8 agonists also induced a current that was inhibited by a TRPM8 antagonist. Our results indicate that Merkel cells sense cooling through TRPM8 channels. We hypothesized that cooling modulates the slow adapting type 1 receptor response. Cooling mouse skin to 22°C reduced the slow adapting type 1 receptor discharge frequency. Interestingly, we observed no such reduction in TRPM8 knockout mice. Similarly, in human skin, a temperature of 22°C applied to the slow adapting type 1 receptive field reduced the spiking discharge. Altogether, our results indicate that Merkel cells are polymodal sensory cells that respond to mild cold stimuli through the activation of TRPM8 channels. Thermal activation of Merkel cells, and possibly other TRPM8-expressing non-neuronal cells, such as keratinocytes, potentially adapts the discharge of slow adapting type 1 receptors during cooling.

The Nav1.9 channel is a key determinant of cold pain sensation and cold allodynia.

Cold-triggered pain is essential to avoid prolonged exposure to harmfully low temperatures. However, the molecular basis of noxious cold sensing in mammals is still not completely understood. Here, we show that the voltage-gated Nav1.9 sodium channel is important for the perception of pain in response to noxious cold. Nav1.9 activity is upregulated in a subpopulation of damage-sensing sensory neurons responding to cooling, which allows the channel to amplify subthreshold depolarizations generated by the activation of cold transducers. Consequently, cold-triggered firing is impaired in Nav1.9(-/-) neurons, and Nav1.9 null mice and knockdown rats show increased cold pain thresholds. Disrupting Nav1.9 expression in rodents also alleviates cold pain hypersensitivity induced by the antineoplastic agent oxaliplatin. We conclude that Nav1.9 acts as a subthreshold amplifier in cold-sensitive nociceptive neurons and is required for the perception of cold pain under normal and pathological conditions.