A cold- and menthol-activated current in rat dorsal root ganglion neurones: properties and role in cold transduction

J Physiol. 2002 Dec 1;545(2):595-614. doi: 10.1113/jphysiol.2002.024331.


Skin temperature is sensed by peripheral thermoreceptors. Using the neuronal soma in primary culture as a model of the receptor terminal, we have investigated the mechanisms of cold transduction in thermoreceptive neurones from rat dorsal root ganglia. Cold-sensitive neurones were pre-selected by screening for an increase in [Ca(2+)](i) on cooling; 49 % of them were also excited by 0.5 microM capsaicin. Action potentials and voltage-gated currents of cold-sensitive neurones were clearly distinct from those of cold-insensitive neurones. All cold-sensitive neurones expressed an inward current activated by cold and sensitised by (-)-menthol, which was absent from cold-insensitive neurones. This current was carried mainly by Na(+) ions and caused a depolarisation on cooling accompanied by action potentials, inducing voltage-gated Ca(2+) entry; a minor fraction of Ca(2+) entry was voltage-independent. Application of (-)-menthol shifted the threshold temperatures of the cold-induced depolarisation and the inward current to the same extent, indicating that the cold- and menthol-activated current normally sets the threshold temperature for depolarisation during cooling. The action of menthol was stereospecific, with the (+)-isomer being a less effective agonist than the (-)-isomer. Extracellular Ca(2+) modulated the cold- and menthol-activated current in a similar way to its action on intact cold receptors: lowered [Ca(2+)](o) sensitised the current, while raised [Ca(2+)](o) antagonised the menthol-induced sensitisation. During long cooling pulses the current showed adaptation, which depended on extracellular Ca(2+) and was mediated by a rise in [Ca(2+)](i). This adaptation consisted of a shift in the temperature sensitivity of the channel. In capsaicin-sensitive neurones, capsaicin application caused a profound depression of the cold-activated current. Inclusion of nerve growth factor in the culture medium shifted the threshold of the cold-activated current towards warmer temperatures. The current was blocked by 50 microM capsazepine and 100 microM SKF 96365. We conclude that the cold- and menthol-activated current is the major mechanism responsible for cold-induced depolarisation in DRG neurones, and largely accounts for the known transduction properties of intact cold receptors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Animals
  • Calcium / pharmacology
  • Calcium / physiology
  • Calcium Signaling / drug effects
  • Calcium Signaling / physiology*
  • Capsaicin / pharmacology
  • Cold Temperature*
  • Electrophysiology
  • Fluorescent Dyes
  • Ganglia, Spinal / drug effects
  • Ganglia, Spinal / physiology*
  • Imidazoles / pharmacology
  • In Vitro Techniques
  • Ion Channel Gating / drug effects
  • Ion Channel Gating / physiology
  • Ion Channels / drug effects
  • Ion Channels / physiology
  • Male
  • Membrane Potentials / physiology
  • Menthol / chemistry
  • Menthol / pharmacology*
  • Nerve Growth Factor / pharmacology
  • Organic Chemicals
  • Patch-Clamp Techniques
  • Rats
  • Rats, Wistar
  • Sodium / physiology
  • Stereoisomerism
  • Thermoreceptors / drug effects
  • Thermoreceptors / physiology*


  • Fluorescent Dyes
  • Imidazoles
  • Ion Channels
  • Organic Chemicals
  • calcium green
  • Menthol
  • Nerve Growth Factor
  • Sodium
  • 1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole
  • Capsaicin
  • Calcium