The sensation of cold or heat depends on the activation of specific nerve endings in the skin. This involves heat‐ and cold‐sensitive excitatory transient receptor potential (TRP) channels. However, we show here that the mechano‐gated and highly temperature‐sensitive potassium channels of the TREK/TRAAK family, which normally work as silencers of the excitatory channels, are also implicated. They are important for the definition of temperature thresholds and temperature ranges in which excitation of nociceptor takes place and for the intensity of excitation when it occurs. They are expressed with thermo‐TRP channels in sensory neurons. TRAAK and TREK‐1 channels control pain produced by mechanical stimulation and both heat and cold pain perception in mice. Expression of TRAAK alone or in association with TREK‐1 controls heat responses of both capsaicin‐sensitive and capsaicin‐insensitive sensory neurons. Together TREK‐1 and TRAAK channels are important regulators of nociceptor activation by cold, particularly in the nociceptor population that is not activated by menthol. There is a [Have you seen ...?][1] (May 2009) associated with this Article. [1]: http://dx.doi.org/10.1038/emboj.2009.107

Cold hypersensitivity is the hallmark of oxaliplatin‐induced neuropathy, which develops in nearly all patients under this chemotherapy. To date, pain management strategies have failed to alleviate these symptoms, hence development of adapted analgesics is needed. Here, we report that oxaliplatin exaggerates cold perception in mice as well as in patients. These symptoms are mediated by primary afferent sensory neurons expressing the thermoreceptor TRPM8. Mechanistically, oxaliplatin promotes over‐excitability by drastically lowering the expression of distinct potassium channels (TREK1, TRAAK) and by increasing the expression of pro‐excitatory channels such as the hyperpolarization‐activated channels (HCNs). These findings are corroborated by the analysis of TREK1‐TRAAK null mice and use of the specific HCN inhibitor ivabradine, which abolishes the oxaliplatin‐induced cold hypersensibility. These results suggest that oxaliplatin exacerbates cold perception by modulating the transcription of distinct ionic conductances that together shape sensory neuron responses to cold. The translational and clinical implication of these findings would be that ivabradine may represent a tailored treatment for oxaliplatin‐induced neuropathy.

Two-pore domain background K(+) channels (K2p or KCNK) produce hyperpolarizing currents that control cell membrane polarity and neuronal excitability throughout the nervous system. The TREK2 channel as well as the related TREK1 and TRAAK channels are mechanical-, thermal- and lipid-gated channels that share many regulatory properties. TREK2 is one of the major background channels expressed in rodent nociceptive neurons of the dorsal root ganglia that innervate the skin and deep body tissues, but its role in somatosensory perception and nociception has remained poorly understood. We now report that TREK2 is a regulatory channel that controls the perception of non aversive warm, between 40°C and 46°C, and moderate ambient cool temperatures, between 20°C and 25°C, in mice. TREK2 controls the firing activity of peripheral sensory C-fibers in response to changes in temperature. The role of TREK2 in thermosensation is different from that of TREK1 and TRAAK channels; rather, TREK2, TREK1, and TRAAK channels appear to have complementary roles in thermosensation. TREK2 is also involved in mechanical pain perception and in osmotic pain after sensitization by prostaglandin E2. TREK2 is involved in the cold allodynia that characterizes the neuropathy commonly associated with treatments with the anticancer drug oxaliplatin. These results suggest that positive modulation of the TREK2 channel may have beneficial analgesic effects in these neuropathic conditions.

Recent findings indicate that in addition to its hyperlipemic effect, a high fructose diet has a pro-oxidant effect in rats compared with a starch-based diet. Oligofructose (OFS) has already been shown to decrease plasma lipids in rats. We assessed the impact of fructose on oxidative stress by supplementing a high fructose diet with OFS. Rats were fed either a high fructose diet or a starch-based diet, with or without supplementation of 10 g/100 g oligofructose for 4 wk. Regardless of the type of carbohydrate, OFS in the diet produced an enlargement of the cecum and led to a significant increase in the SCFA cecum pool. Fructose feeding was associated with significantly higher insulin plasma concentrations (+63%) in the control groups, whereas insulin plasma concentrations did not differ in rats fed the fructose diet supplemented with OFS. Plasma leptin concentration was significantly lower (≈50%) in the OFS-supplemented fructose group compared with the other three groups. Fructose feeding in rats also significantly increased plasma (P < 0.001) and liver (P < 0.001) triglyceride (TG) concentrations and the addition of OFS prevented the TG accumulation induced by fructose in the liver (P < 0.05) and hyperlipemia (P < 0.05). OFS consumption prevented (P < 0.05) the lower plasma vitamin E/TG ratio in rats fed the fructose diet. Control rats fed the fructose diet had high plasma TBARS values compared with rats fed the starch diet, whereas TBARS values remained unchanged when rats were supplemented with OFS. Control rats fed the fructose diet had higher TBARS urine values and higher heart tissue susceptibility to peroxidation compared with rats fed the starch diet, and this effect was significantly reduced by OFS consumption. Further studies are required to identify the mechanisms underlying the protective effect of OFS against the pro-oxidant effect of fructose. However, the potential nutritional benefits of OFS supplementation in fructose-rich diets are suggested.

A workshop of the 2015 International Neuropathic Pain Congress was focused on potassium channels to propose emerging ideas on the role of these channels on pain modulation and to determine whether they can become relevant targets for designing novel analgesic compounds. Two kinds of potassium channels were particularly evoked: selected subunits of the voltage-gated potassium (Kv) and of the K2P channel families. In this review, the role of the former is described with a focus first on silent subunits as modulators of Kv and second on the Kv7 subunits. The physiological, pathophysiological, and pharmacological involvement of the K2P in pain modulation is then described. Throughout this review, the role of potassium channels in pain is obvious, which renders them potential targets for innovative analgesics with peripheral and/or central action depending on the channel. Clearly, some preliminary results obtained with known or novel potassium channel openers suggest that they might represent a novel class of analgesics in neuropathic pain or other pathological contexts.