In living animals, the transduction of thermal stimuli into an electrical response takes place at specific free nerve endings harbouring different classes of transduction and voltage-gated ion channels. Mammalian cold thermoreceptors have variable sensitivities to temperature, and can be separated into low threshold (LT) and high threshold (HT) types. The cellular and molecular determinants of these different thresholds are currently unsettled. TRPM8 and TRPA1 have been postulated as low and high-threshold cold thermosensitive channels. In culture, cold-sensitive (CS) neurons also present very different temperature thresholds (range 34-20ordm;C). We investigated the influence of TRPM8, a cold- and menthol-activated TRP channel, and IKD, a slowly-inactivating, 4-AP-sensitive transient potassium current on temperature-evoked responses in cold thermoreceptors. To this end, we performed calcium imaging and patch-clamp recordings from neonatal mice cultured trigeminal neurons. Temperature response threshold was measured on the cold-evoked intracellular calcium elevation. Expression of TRPM8 was quantified by the amplitude of the menthol-evoked current at 20ordm;C (Imenthol). The amplitude of IKD was measured at subthreshold membrane potential levels. We found that Imenthol was significantly larger in LT-CS neurons while the opposite was true for IKD. Many CS trigeminal neurons express both, ITRPM8 and IKD. Using pharmacological tools (i.e. specific agonists and antagonists), we demonstrate that these two conductances exert opposite influences on temperature-dependent excitability in trigeminal thermoreceptors: one current, IKD, acts as a brake while the other, TRPM8, promotes cold-induced activity.Alterations in the balance between ITRPM8 and IKD may be an important factor in the development of cold allodynia symptoms, characteristic of many neuropathic pain conditions. Supported by MEC projects SAF2004-01011 and BFU2005-08741.