== Diagram depicting influence of various ion channels on the resting membrane potential of a nociceptive neuron. in peripheral pain pathways. The aim of the review is threefold. First, we will discuss current evidence for the expression and functional role of various K+ channels in peripheral nociceptive fibres. Second, we will consider a hypothesis suggesting that reduced functional activity of K+ channels within peripheral nociceptive pathways is a general feature of many types of pain. Third, we will evaluate the perspectives of pharmacological enhancement of K+ channels in nociceptive pathways as a strategy for new analgesic drug design. Keywords:K+ channel, M channel, two-pore K+ channel, KATP channel, Dorsal root ganglion, Pain, Nociception. == INTRODUCTION == Peripheral somatosensory systems in mammals are formed by mechano-, temperature- and damage-sensing (nociceptive) neurons whose cell bodies reside in the peripheral ganglia (e.g. dorsal root ganglia, DRG, Valdecoxib trigeminal ganglia, TG or nodose ganglia) while their long axons are spread throughout the body within sensory fibres. Distal ends of these axons form nerve endings in the skin, muscle, vasculature, viscera, etc. whereas proximal ends synapse in the spinal cord. Electrical excitation of peripheral terminals of sensory neurons is a primary event in somatosensation, including pain. Conversely, the origin of most pains is the excitation of peripheral sensory fibres. These peripheral nociceptive signals may be amplified centrally to reach pain-inducing intensity but, nevertheless, the peripheral signal is almost invariably necessary to trigger pain (excluding rare instances of pain of purely central origin). The excitation of peripheral nociceptive terminal or fibre is brought about by the concerted action of its plasmalemmal ion channels. Accordingly, channelopathies often underlie pathological pain states [1] and many current and prospective analgesics target ion channels [2]. Acute, physiological pain is initiated by opening of sensory ion channels within nociceptive terminals in response to damaging (or potentially damaging) stimuli of sufficient strength. Thus, damaging cold activates TRPM8 channel [3], Valdecoxib damaging heat activates TRPV1 [4] while strong mechanical stimulation activates mechanosensitive channels which can be Piezo2 [5]. Most of these sensory channels are non-selective cation channels which acutely depolarize nociceptive terminals causing action potential (AP) firing. These channels deactivate upon cessation of stimulation and many of them inactivate even in the presence of continuous stimulation. These mechanisms ensure that acute physiological pain is transient in nature. However, inflammation, nerve injury or degeneration often result in conditions where nociceptive signalling becomes persistent and pain chronic. These chronic pain conditions are often characterized by persistent overexcitability of peripheral nociceptors brought about by medium to long-term changes in ion channel activity (i.e. post-translational modifications, changes in trafficking, transcriptional and epigenetic regulation of ion channel gene expression) [1,2]. Treatment of chronic pain remains a challenge since most targets for current analgesics are within the CNS and, thus, are liable to various side-effects. Moreover, addiction, tolerance and limited efficacy further hinder successful chronic pain management. Therefore new ideas for analgesic drug design are urgently needed, especially given the number of recent high-profile failures with some prospective targets (i.e. the neurokinin receptor 1 antagonists [6]), which have caused many lead pharmaceutical companies to curb their R&D in this area. Let us consider plasma Mlst8 membrane of a mammalian nociceptive nerve ending at rest (Fig.1a; the figure is based on the data available for the cell body of a DRG neuron; while ionic gradients in the terminals can differ somewhat, we believe that the overall superposition is correct). The resting membrane potential (Em) of small-diameter dorsal root ganglion (DRG) neuron has been measured to be in the range of-55 -65 mV [7-9]. Since adult sensory neurons have high intracellular Cl-concentration withEClaround-40–30 mV [10-13] (and this value can get even higher in inflammation [14]), the only ion channels that can driveEmtowards 65 mV are K+channels. Therefore, depolarization of plasma membrane sufficient to trigger AP can be induced by eitheri)activation of any of the non-K+channels of the plasma membrane (Fig.1b) orii)inhibition of K+channels that are open atEm(Fig.1c). The overwhelming majority of known mechanisms of acute excitation of nociceptors belong to the groupi)of the above example (however a depolarization through a K+channel inhibition as a mechanism of burning sensation produced by the Szechuan pepper has been suggested [15], see below). Many ionic mechanisms underlying chronic pain conditions also belong to this group Valdecoxib (that is, these are mediated by the upregulation or enhancement of depolarizing ion channels; see [16,17] for review). This is why the majority of current research in the field is focused on these depolarizing.