Specificity of cold thermotransduction is determined by differential ionic channel expression

Abstract

Sensations of cold are mediated by specific thermoreceptor nerve endings excited by low temperature and menthol. Here we identify a population of cold-sensitive cultured mouse trigeminal ganglion neurons with a unique set of biophysical properties. Their impulse activity during cooling and menthol application was similar to that of cold thermoreceptor fibers in vivo. We show that cooling closes a background K+ channel, causing depolarization and firing that is limited by the slower reduction of a cationic inward current (Ih). In cold-insensitive neurons, firing is prevented by a slow, transient, 4-AP-sensitive K+ current (IKD) that acts as an excitability brake. In addition, pharmacological blockade of IKD induced thermosensitivity in cold-insensitive neurons, a finding that may explain cold allodynia in neuropathic pain. These results suggest that cold sensitivity is not associated to a specific transduction molecule but instead results from a favorable blend of ionic channels expressed in a small subset of sensory neurons.

Temperature sensing across species

“…However, a number of laboratories interested in cold transduction began to use primary cultures of either DRG or TG neurons as in vitro models of sensory afferents. Approximately 10% respond to cold temperatures, with thresholds for activation below 30°C, and almost all of these sensory neurons are menthol-sensitive as well [47,71,78,79]. Thus, these in vitro data support the hypotheses of Hensel and Zotterman in that it seemed likely that cold and menthol work through a similar mechanism, leading to the search for their common molecular site of action.…”

“…It is a biochemical axiom that cold temperatures hamper protein function, and this inhibitory property of cold has been suggested to be a mechanism for neuronal depolarization. A number of studies have suggested that cold inhibition of background K + conductances or the Na + /K + -ATPase leads to membrane depolarization of cold-sensitive afferents [78,[108][109][110]. In the former example, the K + -channel TREK-1 is strongly inhibited by cooling in vitro and expressed very highly in sensory neurons [111].…”

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

“…However, behavioral studies with TRPM8-null mice show that TRPM8 does serve a role in noxious cold sensing, but that it is likely not the sole determinant (Bautista et al, 2007;Colburn et al, 2007;Dhaka et al, 2007). 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).…”

TRPM8 mRNA Is Expressed in a Subset of Cold-Responsive Trigeminal Neurons From Rat

“…While there has been significant recent progress in defining the means by which peripheral neurons detect heat stimuli (Caterina and Julius 2001;Peier et al 2002b;Smith et al 2002;Souslova et al 2000;Xu et al 2002), the molecular mechanisms underlying the detection of cool and painfully cold stimuli remain less well understood. Cooling-evoked changes in membrane potential, ionic conductance, or intracellular calcium can be recapitulated in sensory neurons cultured from dorsal root (DRG) and trigeminal ganglia (TG) (McKemy et al 2002;Okazawa et al 2002;Flonta 2001a,b, 2002;Suto and Gotoh 1999;Thut et al 2003;Viana et al 2002). Data from several recent electrophysiological studies have revealed two general mechanisms that appear to underlie cold transduction in these neurons.…”

“…One mechanism involves the cooling-induced activation of a nonselective cationic current that is present in approximately 10% of cultured sensory neurons (Okazawa et al 2002;Flonta 2001a, 2002) and can be potentiated by the cooling agent menthol Flonta 2001a, 2002). A second mechanism entails the cooling-induced inhibition of certain potassium currents, which results in net membrane depolarization (Reid and Flonta 2001b;Viana et al 2002). In addition, a distinct potassium current has been reported to mask cooling-induced depolarization in a subset of apparently cold-insensitive sensory neurons (Viana et al 2002).…”