Pain is a somatic sensation that alerts the organism about the body damage. As such, pain is crucial for avoiding injury (and ultimately – for survival). However, in some disease states (e.g. arthritis, migraine, neuropathic pains etc.) the transmission within the pain pathways of peripheral and/or central nervous system can become partially or totally disconnected from the external stimuli causing pain which is no longer beneficial but may bring severe suffering and distress. These pains often are very difficult to treat. Electrical excitation of the peripheral damage-sensing (nociceptive) neurones constitutes an initial phase of nociceptive transmission to the CNS, therefore, ion channels that define and control the excitability of nociceptive neurons are curtail determinants of pain signaling. One of the major mechanisms controlling tonic excitability of mammalian neurones is M current, a slow-kinetics K+ current conducted by Kv7 channels (coded for by the KCNQ1-5 genes). Most M channels in neurones are homo- or heteromultimers of Kv7.2, 7.3 and Kv7.5. Due to their distinctive biophysical properties, M channel activity maintains a strong control over neuronal excitability. Accordingly, loss-of-function mutations within KCNQ genes often result in epilepsy (reviewed in (1)). Recently we and others identified functional M channels in sensory neurones (2-6). We demonstrated that pharmacological inhibition of M channels in peripheral nociceptive terminals produces excitation and causes pain. Thus, hind paw injection of a specific M channel blocker, XE991 induced nocifensive behaviour (3, 4, 6) while in cultured DRG neurones XE991 induced marked depolarisation and increased action potential (AP) firing (2-4). We have also demonstrated that inflammatory mediators such as proteases (3) and bradykinin (4) can cause acute nociception by inhibiting M channels in sensory fibres via the G protein coupled receptor signalling cascade utilising depletion of the plasma membrane phosphatidylinositol 4,5-bisphosphate and release of Ca2+ from intracellular stores as M channel inhibiting signals (2-4). On the contrast, a neuropeptide substance P, acting via a novel signalling cascade utilising mitochondrially-generated reactive oxygen species (ROS) as intermediates, augments peripheral M channel activity thus reducing peripheral fibre excitability (unpublished). We have also demonstrated that pharmacological augmentation of M current in sensory fibres has an antiexcitatory and antinociceptive effect (2, 4, 6). In another recent study we identified a functional binding site (RE1) for the repressor Element 1-Silencing Transcription factor (REST, NRSF) within the KCNQ2, KCNQ3 and KCNQ5 genes (7). We demonstrated that REST can bind to KCNQ genes and repress their transcription. Overexpression of REST in cultured DRG neurones robustly suppressed M current density and increased tonic excitability of these neurones. Baseline REST expression in neurones is low but it increases greatly after the neuropathic injury (6). Accordingly, quantitative RT-PCR and immunostaining demonstrated that after the neuropathic injury produced by the partial sciatic nerve ligation (PSNL), the expression of KCNQ2 in rat dorsal root ganglion (DRG) was dramatically downregulated, an effect that was paralleled by the reciprocal upregulation of REST expression in DRG. In sum, our data put forward a strong case for the M current as a key determinant of peripheral sensory fibre excitability and a peripheral target for pain therapeutics.