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.

Morphine is the gold-standard pain reliever for severe acute or chronic pain but it also produces adverse side effects that can alter the quality of life of patients and, in some rare cases, jeopardize the vital prognosis. Morphine elicits both therapeutic and adverse effects primarily through the same m opioid receptor subtype, which makes it difficult to separate the two types of effects. Here we show that beneficial and deleterious effects of morphine are mediated through different signalling pathways downstream from m opioid receptor. We demonstrate that the TREK-1 K þ channel is a crucial contributor of morphine-induced analgesia in mice, while it is not involved in morphine-induced constipation, respiratory depression and dependence-three main adverse effects of opioid analgesic therapy. These observations suggest that direct activation of the TREK-1 K þ channel, acting downstream from the m opioid receptor, might have strong analgesic effects without opioid-like adverse effects.