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

Abstract

. TRPM8 mRNA is expressed in a subset of cold-responsive trigeminal neurons from rat. J Neurophysiol 90: 515-520, 2003. First published March 12, 2003 10.1152/jn.00843.2002. Recent electrophysiological studies of cultured dorsal root and trigeminal ganglion neurons have suggested that multiple ionic mechanisms underlie the peripheral detection of cold temperatures. Several candidate "cold receptors," all of them ion channel proteins, have been implicated in this process. One of the most promising candidates is TRPM8, a nonselective cationic channel expressed in a subpopulation of sensory neurons that is activated both by decreases in temperature and the cooling compound menthol. However, evidence for the expression of TRPM8 in functionally defined cold-sensitive neurons has been lacking. Here, we combine fluorometric calcium imaging of cultured rat trigeminal neurons with single-cell RT-PCR to demonstrate that there are distinct subpopulations of cold responsive neurons and that TRPM8 likely contributes to cold transduction in one of them. TRPM8 is preferentially expressed within a subset of rapidly responsive, low-threshold (approximately 30°C), cold-sensitive neurons. A distinct class of slowly responsive cold-sensitive neurons that is activated at lower temperatures (approximately 20°C) generally lacks detectable TRPM8 mRNA. Together with previous findings, our data support the notion that cold responsive neurons are functionally heterogeneous.

Bimodal Action of Menthol on the Transient Receptor Potential Channel TRPA1

“…However, activation of TRPM8 could not explain the algesic effects of menthol, given that the channel is not expressed in nociceptive primary sensory neurons. The presence of cold/menthol-sensitive neurons in vitro that do not have any detectable TRPM8 mRNA (Nealen et al, 2003) substantiate the hypothesis of various molecular receptors for menthol, and very recently, two independent groups could demonstrate that TRPM8-lacking mice still exhibit a considerable amount of menthol-sensing DRG and trigeminal neurons (Colburn et al, 2007;Dhaka et al, 2007). TRPA1 expression is restricted to a distinct subpopulation of nociceptive neurons from trigeminal and dorsal root ganglia that show very little or no expression of TRPM8 Kobayashi et al, 2005).…”

TRPM8-independent Menthol-induced Ca2+ Release from Endoplasmic Reticulum and Golgi

“…However, the molecular targets responsible for these menthol effects are only poorly understood. It is now generally believed that activation of TRPM8 in cold-sensitive neurons of trigeminal and dorsal root ganglia underlies the cooling effect of the menthol (3,4), although characterization of a TRPM8-deficient mouse would be needed to fully prove this point. Moreover, menthol has been shown to inhibit voltage-dependent Na ϩ and Ca 2ϩ channels, which may contribute to the antinociceptive and local anesthetic effects of menthol (21).…”

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

“…Indeed, the paucity of neurons that express TRPM8 has made the study of this thermosensor and these cells problematic at best. TRPM8 RNA transcripts are found in ϳ10% of either DRG or trigeminal ganglion (TG) soma (McKemy et al, 2002;Peier et al, 2002), and the current models for expression come largely from in situ hybridization analyses (Peier et al, 2002;Nealen et al, 2003;Kobayashi et al, 2005). Thus, to more readily identify TRPM8 neurons both in vivo and in vitro, we established a line of transgenic mice, using BAC clone transgenesis, in which cell-specific expression of enhanced GFP is driven by the Trpm8 transcriptional promoter.…”