Opening paths to novel analgesics: the role of potassium channels in chronic pain
Authors: Christoforos Tsantoulas, Stephen B. McMahon
Journal: Trends in Neurosciences (2014)

•Potassium (K+) channels are crucial determinants of neuronal excitability.•Nerve injury or inflammation alters K+ channel activity in neurons of the pain pathway.•These changes can render neurons hyperexcitable and cause chronic pain.•Therapies targeting K+ channels may provide improved pain relief in these states. Chronic pain is associated with abnormal excitability of the somatosensory system and remains poorly treated in the clinic. Potassium (K+) channels are crucial determinants of neuronal activity throughout the nervous system. Opening of these channels facilitates a hyperpolarizing K+ efflux across the plasma membrane that counteracts inward ion conductance and therefore limits neuronal excitability. Accumulating research has highlighted a prominent involvement of K+ channels in nociceptive processing, particularly in determining peripheral hyperexcitability. We review salient findings from expression, pharmacological, and genetic studies that have untangled a hitherto undervalued contribution of K+ channels in maladaptive pain signaling. These emerging data provide a framework to explain enigmatic pain syndromes and to design novel pharmacological treatments for these debilitating states. Chronic pain is associated with abnormal excitability of the somatosensory system and remains poorly treated in the clinic. Potassium (K+) channels are crucial determinants of neuronal activity throughout the nervous system. Opening of these channels facilitates a hyperpolarizing K+ efflux across the plasma membrane that counteracts inward ion conductance and therefore limits neuronal excitability. Accumulating research has highlighted a prominent involvement of K+ channels in nociceptive processing, particularly in determining peripheral hyperexcitability. We review salient findings from expression, pharmacological, and genetic studies that have untangled a hitherto undervalued contribution of K+ channels in maladaptive pain signaling. These emerging data provide a framework to explain enigmatic pain syndromes and to design novel pharmacological treatments for these debilitating states. Chronic pain afflicts one in five adults in Europe and many diseases accompanied by pain are on the rise [1van Hecke O. et al.Chronic pain epidemiology and its clinical relevance.Br. J. Anaesth. 2013; 111: 13-18Crossref PubMed Scopus (64) Google Scholar]. The diverse etiology of chronic pain encompasses trauma, metabolic or autoimmune disorders, infection, anti-retroviral treatment, and chemotherapy. Affected individuals typically report a combination of incapacitating sensory abnormalities, including spontaneous pain, hypersensitivity to stimulation, dysesthesias, and paresthesias. Despite significant progress, chronic pain remains refractory to treatment, with only one-third to two-thirds of patients reporting adequate (>50%) pain relief [1van Hecke O. et al.Chronic pain epidemiology and its clinical relevance.Br. J. Anaesth. 2013; 111: 13-18Crossref PubMed Scopus (64) Google Scholar]. Moreover, our first-line drugs, non-steroidal anti-inflammatory agents (NSAIDS; e.g., aspirin) and opioids (e.g., morphine), are associated with adverse dose-limiting side-effects, dependence, and tolerance [2Labianca R. et al.Adverse effects associated with non-opioid and opioid treatment in patients with chronic pain.Clin. Drug Investig. 2012; 32: 53-63Crossref Scopus (0) Google Scholar]. The lack of improved treatment reflects our incomplete understanding of the molecular pathophysiology underlying these pain states. Pain is usually triggered by the activity of specialized damage-sensing neurons innervating the limbs and torso, whose cell somata cluster paraspinally in the dorsal root ganglion (DRG). These pseudo-unipolar cells project axons that bifurcate into peripheral fibers innervating the skin, muscle, or other organs, and central fibers that synapse with second-order spinal cord neurons. A similar architecture is encountered in trigeminal ganglion neurons located on each side of the cranium, which transduce sensory information from the face. Based on anatomical, neurochemical, and functional attributes, sensory neurons are distinguished into small-diameter with unmyelinated C-fibers, medium-diameter with thinly myelinated Aδ-fibers, and large-diameter that principally give rise to heavily myelinated Aβ-fibers. Because of their ability to encode noxious mechanical, thermal, or chemical stimuli, C- and Aδ-fibers are considered the main nociceptive afferents signaling pain. Aβ-fibers innervating the skin or muscles are predominantly low-threshold mechanoreceptive afferents responding to light touch or pressure, although a proportion are also activated by high-threshold stimuli. Signals initiated at sensory endings are relayed to the dorsal horn of the spinal cord and subsequently the brain via spinal projection systems including the spinothalamic tract, where the information is evaluated and an appropriate response generated. Spinal transmission is not a passive process but rather involves regulatory spinal processing, such as facilitatory or inhibitory modulation by interneurons, astroglia, and descending pathways, which can robustly increase or decrease the output [3D’Mello R. Dickenson A.H. Spinal cord mechanisms of pain.Br. J. Anaesth. 2008; 101: 8-16Crossref PubMed Scopus (163) Google Scholar]. Under normal conditions, generation of action potentials (APs) in sensory nerves typically originates at their peripheral nerve endings in the presence of a suprathreshold stimulus activating specialized receptors. However, following nerve trauma, electrogenesis can occur spontaneously at the site of injury (neuroma), DRG cell body, or even mid-nerve [4Kajander K.C. et al.Spontaneous discharge originates in the dorsal root ganglion at the onset of a painful peripheral neuropathy in the rat.Neurosci. Lett. 1992; 138: 225-228Crossref PubMed Scopus (0) Google Scholar]. Furthermore, inflammation and neuropathic lesions are linked to enhanced responsiveness to supra- or even subthreshold stimulation [5Kajander K.C. Bennett G.J. Onset of a painful peripheral neuropathy in rat: a partial and differential deafferentation and spontaneous discharge in Abeta and Adelta primary afferent neurons.J. 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These maladaptive changes also have downstream effects at the spinal level; C-fiber activity can induce central sensitization, a state of heightened responsiveness of spinal cord neurons, such that innocuous input can now result in abnormally painful responses (e.g., tactile allodynia after Aβ-fiber stimulation) [8Costigan M. et al.Neuropathic pain: a maladaptive response of the nervous system to damage.Annu. Rev. Neurosci. 2009; 32: 1-32Crossref PubMed Scopus (608) Google Scholar]. In addition, lesioned Aβ-fibers can acquire de novo nociceptive qualities that may also contribute to central sensitization [9Devor M. Ectopic discharge in Abeta afferents as a source of neuropathic pain.Exp. Brain Res. 2009; 196: 115-128Crossref PubMed Scopus (0) Google Scholar]. Until recently the search for ion channel correlates of pathological excitability primarily focused on sodium and calcium channels. Unfortunately, despite significant discoveries in acute and inflammatory pain, no decisive involvement has been definitely established yet, particularly in neuropathic pain [10Liu M. Wood J.N. The roles of sodium channels in nociception: implications for mechanisms of neuropathic pain.Pain Med. 2011; 12: S93-S99Crossref PubMed Scopus (0) Google Scholar]. New evidence however suggests a previously unappreciated contribution of K+ channels in chronic pain processing, which we review here. K+ channels are the most populous, widely distributed, and diverse class of ion channels in neurons, governed by some 78 genes in humans [11Ocana M. et al.Potassium channels and pain: present realities and future opportunities.Eur. J. Pharmacol. 2004; 500: 203-219Crossref PubMed Scopus (0) Google Scholar]. Upon activation, K+ channels facilitate an extremely rapid transmembrane K+ efflux that can influence AP threshold, waveform and frequency. Because K+ channel opening repolarizes (or even hyperpolarizes) the neuronal membrane, this function can limit AP generation and firing rate. Depending on the biophysical profile and precise subcellular localization in sensory neurons, K+ channel conduction is postulated to inhibit peripheral excitability by counteracting AP initiation at peripheral nerve terminals, reducing conduction fidelity across the axon, or limiting neurotransmitter release at central terminals (Figure 1). In addition, although normal sensory transduction does not rely on cell soma spiking, in chronic pain states K+ channels could provide a brake to the spontaneous activity developing in the DRG soma or other ectopic loci (e.g., the neuroma). Indeed, peripheral application of K+ channel openers on the cell body or terminals invariably decreases DRG excitability, whereas K+ channel blockers augment firing [5Kajander K.C. Bennett G.J. Onset of a painful peripheral neuropathy in rat: a partial and differential deafferentation and spontaneous discharge in Abeta and Adelta primary afferent neurons.J. Neurophysiol. 1992; 68: 734-744PubMed Google Scholar, 11Ocana M. et al.Potassium channels and pain: present realities and future opportunities.Eur. J. Pharmacol. 2004; 500: 203-219Crossref PubMed Scopus (0) Google Scholar, 12Passmore G.M. et al.KCNQ/M currents in sensory neurons: significance for pain therapy.J. Neurosci. 2003; 23: 7227-7236Crossref PubMed Google Scholar, 13Kirchhoff C. et al.Excitation of cutaneous sensory nerve endings in the rat by 4-aminopyridine and tetraethylammonium.J. Neurophysiol. 1992; 67: 125-131Crossref PubMed Scopus (0) Google Scholar]. In the CNS, K+ channel opening could conceptually lead to enhanced nociception, for instance if the affected neuron participates in an inhibitory circuit. Nevertheless, the available data so far indicate that a variety of antinociceptive drugs mediate their action by directly opening spinal K+ channels [11Ocana M. et al.Potassium channels and pain: present realities and future opportunities.Eur. J. Pharmacol. 2004; 500: 203-219Crossref PubMed Scopus (0) Google Scholar]. Based on structural and physiological characteristics, K+ channels are organized into four distinct groups: voltage-gated, two-pore, calcium-activated, and inward rectifying, which we discuss in turn below. The Kv superfamily is the most numerous among K+ channels, comprising of 40 genes in humans [14MacKinnon R. Potassium channels.FEBS Lett. 2003; 555: 62-65Abstract Full Text Full Text PDF PubMed Scopus (273) Google Scholar, 15Johnston J. et al.Going native: voltage-gated potassium channels controlling neuronal excitability.J. Physiol. 2010; 588: 3187-3200Crossref PubMed Scopus (0) Google Scholar, 16Gutman G.A. et al.International Union of Pharmacology. LIII. Nomenclature and molecular relationships of voltage-gated potassium channels.Pharmacol. Rev. 2005; 57: 473-508Crossref PubMed Scopus (431) Google Scholar]. They are further classified in 12 families of α subunits that can interact to form functional homo- or hetero-tetrameric channels. Members of Kv1-Kv4, Kv7 and Kv10-Kv12 are pore-forming subunits, whereas Kv5, Kv6, Kv8, and Kv9 members do not form conducting channels unless associated with pore-forming subunits (Box 1). Channel tetramerization leads to tremendous functional diversity, further elevated by association with auxiliary β subunits, splice variants, and post-translational modifications. The largely overlapping pharmacology in neurons suggests a spectrum of Kv currents rather than fixed groups, reflecting the variant heterotetrameric composition, functional redundancy within families, and complex regulation. The majority of Kv channels are delayed rectifiers, because they are activated slowly to counteract (rectify) depolarization. On the basis of biophysical properties and sensitivity to tetraethylammonium (TEA), α-dendrotoxin, 4-aminopyridine, and muscarinic agonists, Kv currents are broadly distinguished into sustained delayed rectifying (IK), transient slowly inactivating (ID), transient fast-inactivating (IA) and non-inactivating (IM) that, as their names suggest, exhibit different kinetics. Although this classification is an oversimplification, it has value as a starting point to examine the different Kv components in physiological systems. These typical currents are also present in dorsal root and trigeminal ganglia neurons, whereas Gold and colleagues described six distinct K+ currents, three of which in small nociceptors [17Gold M.S. et al.Characterization of six voltage-gated K+ currents in adult rat sensory neurons.J. 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Reduction in potassium currents in identified cutaneous afferent dorsal root ganglion neurons after axotomy.J. Neurophysiol. 1999; 82: 700-708Crossref PubMed Scopus (166) Google Scholar]. Kv1.1 and Kv1.2 are delayed rectifiers activated by modest membrane depolarizations, and mainly contribute to the ID current. In many CNS neurons, these channels are preferentially localized at the axon initial segment (AIS, the site of AP initiation in CNS neurons) where they regulate AP threshold and firing rates, as well as nerve terminals where they modulate neurotransmitter release by controlling AP invasion in axonal branches [22Dodson P.D. et al.Presynaptic rat Kv1.2 channels suppress synaptic terminal hyperexcitability following action potential invasion.J. Physiol. 2003; 550: 27-33Crossref PubMed Scopus (0) Google Scholar, 23Wang H. et al.Localization of Kv1.1 and Kv1.2, two K channel proteins, to synaptic terminals, somata, and dendrites in the mouse brain.J. Neurosci. 1994; 14: 4588-4599Crossref PubMed Google Scholar]. The dominant role of Kv1 becomes apparent in type 1 episodic ataxia, where Kv1.1 mutations drive excitability changes in the cerebellum that cause severe seizures and premature death [24Browne D.L. et al.Episodic ataxia/myokymia syndrome is associated with point mutations in the human potassium channel gene, KCNA1.Nat. Genet. 1994; 8: 136-140Crossref PubMed Scopus (0) Google Scholar]. In the peripheral nervous system (PNS), Kv1.1 and Kv1.2 are predominantly found in the soma and juxtaparanodes of medium-large DRG neurons, often in heterotetramers [25Rasband M.N. et al.Distinct potassium channels on pain-sensing neurons.Proc. Natl. Acad. Sci. U.S.A. 2001; 98: 13373-13378Crossref PubMed Scopus (0) Google Scholar], and are largely decreased after axotomy [26Ishikawa K. et al.Changes in expression of voltage-gated potassium channels in dorsal root ganglion neurons following axotomy.Muscle Nerve. 1999; 22: 502-507Crossref PubMed Scopus (0) Google Scholar, 27Kim D.S. et al.Downregulation of voltage-gated potassium channel alpha gene expression in dorsal root ganglia following chronic constriction injury of the rat sciatic nerve.Brain Res. Mol. Brain Res. 2002; 105: 146-152Crossref PubMed Scopus (0) Google Scholar]; this may contribute to the hyperexcitable phenotype. Indeed, Kv1.1 loss-of-function results in reduced firing thresholds, attenuated mechanical and heat pain, and increased sensitivity in both phases of the formalin test [28Clark J.D. Tempel B.L. Hyperalgesia in mice lacking the Kv1.1 potassium channel gene.Neurosci. Lett. 1998; 251: 121-124Crossref PubMed Scopus (0) Google Scholar, 29Chi X.X. Nicol G.D. Manipulation of the potassium channel Kv1.1 and its effect on neuronal excitability in rat sensory neurons.J. Neurophysiol. 2007; 98: 2683-2692Crossref PubMed Scopus (0) Google Scholar]. By contrast, diminished Kv1.2 activity contributes to mechanical and cold neuropathic pain by depolarizing the resting membrane potential (RMP), reducing threshold current, and augmenting firing rates in myelinated neurons [30Zhao X. et al.A long noncoding RNA contributes to neuropathic pain by silencing Kcna2 in primary afferent neurons.Nat. Neurosci. 2013; 16: 1024-1031Crossref PubMed Scopus (0) Google Scholar]. Moreover, Hao et al. recently reported that Kv1.1 tetramers form a bona fide mechanosensor that acts as an excitability brake in Aβ-mechanoreceptors of mouse DRG, with a minor contribution of Kv1.2 [31Hao J. et al.Kv1.1 channels act as mechanical brake in the senses of touch and pain.Neuron. 2013; 77: 899-914Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. Interestingly, this mechanosensitive current was also detected in some high-threshold C-mechano-nociceptors (C-HTMRs). Although the literature highlights predominant Kv1.1 expression in myelinated neurons, the authors confirmed the presence of Kv1.1 subunits in a subpopulation of capsaicin-insensitive small neurons and C-fiber terminals in the skin using a monoclonal antibody [30Zhao X. et al.A long noncoding RNA contributes to neuropathic pain by silencing Kcna2 in primary afferent neurons.Nat. Neurosci. 2013; 16: 1024-1031Crossref PubMed Scopus (0) Google Scholar]. This pattern may correspond to the occasional expression Rasband et al. documented in small DRG neurons from rat [25Rasband M.N. et al.Distinct potassium channels on pain-sensing neurons.Proc. Natl. Acad. Sci. U.S.A. 2001; 98: 13373-13378Crossref PubMed Scopus (0) Google Scholar]. Although species differences may account for the discrepancy (and multiple species variations are recognized), other studies implementing molecular, immunohistological, and electrophysiological techniques have also indicated presence of Kv1.1 subunits in rat small sensory neurons [26Ishikawa K. et al.Changes in expression of voltage-gated potassium channels in dorsal root ganglion neurons following axotomy.Muscle Nerve. 1999; 22: 502-507Crossref PubMed Scopus (0) Google Scholar, 29Chi X.X. Nicol G.D. Manipulation of the potassium channel Kv1.1 and its effect on neuronal excitability in rat sensory neurons.J. Neurophysiol. 2007; 98: 2683-2692Crossref PubMed Scopus (0) Google Scholar, 32Glazebrook P.A. et al.Potassium channels Kv1.1, Kv1.2 and Kv1.6 influence excitability of rat visceral sensory neurons.J. Physiol. 2002; 541: 467-482Crossref PubMed Scopus (0) Google Scholar, 33Beekwilder J.P. et al.Kv1.1 channels of dorsal root ganglion neurons are inhibited by n-butyl-p-aminobenzoate, a promising anesthetic for the treatment of chronic pain.J. Pharmacol. Exp. Ther. 2003; 304: 531-538Crossref PubMed Scopus (0) Google Scholar]. Intriguingly, an accumulating body of research indicates that some human neuropathic pain syndromes are caused by production of autoimmune antibodies against Kv1 subunits that disrupt normal A- or C-fiber function (Box 1).Box 1Pain syndromes associated with autoimmune Kv antibodiesCompelling evidence suggests that several neurological disorders linked to peripheral hyperexcitability and pain of a neuropathic nature, such as neuromyotonia (NMT) or Morvan's and cramp fasciculation syndromes, may be caused by erroneous Kv function due to host production of autoantibodies. Kv antibodies are detected in approximately 40% of NMT patients [111Hart I.K. et al.Phenotypic variants of autoimmune peripheral nerve hyperexcitability.Brain. 2002; 125: 1887-1895Crossref PubMed Google Scholar], and when transferred to mouse cells they cause reduction of K+ currents, DRG hyperexcitability and other signs of the disease [112Shillito P. et al.Acquired neuromyotonia: evidence for autoantibodies directed against K+ channels of peripheral nerves.Ann. Neurol. 1995; 38: 714-722Crossref PubMed Scopus (0) Google Scholar]. In agreement with an autoimmune etiology, immunomodulatory therapy can improve function and symptoms [113Sinha S. et al.Autoimmune aetiology for acquired neuromyotonia (Isaacs syndrome).Lancet. 1991; 338: 75-77Abstract PubMed Scopus (0) Google Scholar]. Interestingly, these conditions can also arise owing to autoantibodies against proteins of the functional Kv complexes, such as Caspr2 or LGI1 [114Irani S.R. et al.Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan's syndrome and acquired neuromyotonia.Brain. 2010; 133: 2734-2748Crossref PubMed Scopus (504) Google Scholar]. Thus Caspr2 dysfunction may affect Kv1 assembly at juxtaparanodes, whereas altered Kv1 association with LGI1 in presynaptic C-fiber complexes could explain symptoms such as heat hyperalgesia. Although still in its infancy, the concept of Kv complex autoimmunity is an exciting development that may explain idiosyncratic pain in the absence of injury (e.g., fibromyalgia) or other presently enigmatic congenital pain states. Compelling evidence suggests that several neurological disorders linked to peripheral hyperexcitability and pain of a neuropathic nature, such as neuromyotonia (NMT) or Morvan's and cramp fasciculation syndromes, may be caused by erroneous Kv function due to host production of autoantibodies. Kv antibodies are detected in approximately 40% of NMT patients [111Hart I.K. et al.Phenotypic variants of autoimmune peripheral nerve hyperexcitability.Brain. 2002; 125: 1887-1895Crossref PubMed Google Scholar], and when transferred to mouse cells they cause reduction of K+ currents, DRG hyperexcitability and other signs of the disease [112Shillito P. et al.Acquired neuromyotonia: evidence for autoantibodies directed against K+ channels of peripheral nerves.Ann. Neurol. 1995; 38: 714-722Crossref PubMed Scopus (0) Google Scholar]. In agreement with an autoimmune etiology, immunomodulatory therapy can improve function and symptoms [113Sinha S. et al.Autoimmune aetiology for acquired neuromyotonia (Isaacs syndrome).Lancet. 1991; 338: 75-77Abstract PubMed Scopus (0) Google Scholar]. Interestingly, these conditions can also arise owing to autoantibodies against proteins of the functional Kv complexes, such as Caspr2 or LGI1 [114Irani S.R. et al.Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan's syndrome and acquired neuromyotonia.Brain. 2010; 133: 2734-2748Crossref PubMed Scopus (504) Google Scholar]. Thus Caspr2 dysfunction may affect Kv1 assembly at juxtaparanodes, whereas altered Kv1 association with LGI1 in presynaptic C-fiber complexes could explain symptoms such as heat hyperalgesia. Although still in its infancy, the concept of Kv complex autoimmunity is an exciting development that may explain idiosyncratic pain in the absence of injury (e.g., fibromyalgia) or other presently enigmatic congenital pain states. Most of our knowledge on Kv2 comes from CNS studies, where Kv2.1 and Kv2.2 conduct the majority of delayed rectified IK current in several neuron subtypes [15Johnston J. et al.Going native: voltage-gated potassium channels controlling neuronal excitability.J. Physiol. 2010; 588: 3187-3200Crossref PubMed Scopus (0) Google Scholar, 34Bocksteins E. et al.Kv2.1 and silent Kv subunits underlie the delayed rectifier K+ current in cultured small mouse DRG neurons.Am. J. Physiol. Cell Physiol. 2009; 296: C1271-C1278Crossref PubMed Scopus (0) Google Scholar]. Kv2 channels are activated slowly after significant depolarization, therefore their opening primarily influences membrane repolarization and inter-spike hyperpolarization during AP firing [15Johnston J. et al.Going native: voltage-gated potassium channels controlling neuronal excitability.J. Physiol. 2010; 588: 3187-3200Crossref PubMed Scopus (0) Google Scholar]. Importantly, because Kv2 feature characteristically slow activation and inactivation, the progressive channel recruitment during sustained activity can have a cumulative limiting effect on firing rates. The prominent CNS function of Kv2 is substantiated by specific localization in dendrites and AIS where the channel can exert intricate control over somal AP invasion and back-propagation [35Sarmiere P.D. et al.The Kv2.1K+ channel targets to the axon initial segment of hippocampal and cortical neurons in culture and in situ.BMC Neurosci. 2008; 9: 112Crossref PubMed Scopus (0) Google Scholar]. Other interesting features of Kv2 are the phosphorylation-dependent regulation by neuronal activity, which can fine-tune excitability of CNS neurons by altering the channel membrane distribution and biophysical properties [36O’Connell K.M. et al.Localization-dependent activity of the Kv2.1 delayed-rectifier K+ channel.Proc. Natl. Acad. Sci. U.S.A. 2010; 107: 12351-12356Crossref PubMed Scopus (0) Google Scholar], as well as their modulation by several silent Kv subunits [37Bocksteins E. Snyders D.J. Electrically silent Kv subunits: their molecular and functional characteristics.Physiology (Bethesda). 2012; 27: 73-84Crossref PubMed Scopus (0) Google Scholar]. Despite the pivotal Kv2 role in shaping CNS signaling, an involvement in chronic pain was only recently uncovered. Kv2 subunits are present in small nociceptors (where Kv2.1 conducts the majority of IK [34Bocksteins E. et al.Kv2.1 and silent Kv subunits underlie the delayed rectifier K+ current in cultured small mouse DRG neurons.Am. J. Physiol. Cell Physiol. 2009; 296: C1271-C1278Crossref PubMed Scopus (0) Google Scholar]) but are also abundantly expressed in myelinated DRG neurons [38Tsantoulas C. et al.Kv2 dysfunction after peripheral axotomy enhances sensory neuron responsiveness to sustained input.Exp. Neurol. 2013; 251C: 115-116Google Scholar]. Transcript and protein Kv2 levels are downregulated by traumatic nerve injury, and this could augment firing by limiting the Kv2 inhibitory effect on spike frequency [26Ishikawa K. et al.Changes in expression of voltage-gated potassium channels in dorsal root ganglion neurons following axotomy.Muscle Nerve. 1999; 22: 502-507Crossref PubMed Scopus (0) Google Scholar, 27Kim D.S. et al.Downregulation of voltage-gated potassium channel alpha gene expression in dorsal root ganglia following chronic constriction injury of the rat sciatic nerve.Brain Res. Mol. Brain Res. 2002; 105: 146-152Crossref PubMed Scopus (0) Google Scholar, 38Tsantoulas C. et al.Kv2 dysfunction after peripheral axotomy enhances sensory neuron responsiveness to sustained input.Exp. Neurol. 2013; 251C: 115-116Google Scholar]. Indeed, application of a Kv2 blocker on ex vivo DRG preparations promotes myelinated neuron hyperexcitability by increasing conduction fidelity to the cell soma during repetitive stimulation [38Tsantoulas C. et al.Kv2 dysfunction after peripheral axotomy enhances sensory neuron responsiveness to sustained input.Exp. Neurol. 2013; 251C: 115-116Google Scholar]. It is possible that particular subcellular Kv2 localization forms the basis of an important filtering capacity (for instance by controlling AP traffic through the T-junction [39Amir R. Devor M. Electrical excitability of the soma of sensory neurons is required for spike invasion of the soma, but not for through-conduction.Biophys. J. 2003; 84: 2181-2191Abstract Full Text Full Text PDF PubMed Google Scholar]), similarly to somatodendritic Kv2 filtering of somatic input in the CNS. Finally, a role in supraspinal pain pathways has also been demonstrated; cortical expression of Kv2.2 is reduced in oxaliplatin-induced neuropathy, and reproducing this in vivo results in marked cold and mechanical hypersensitivity [40Thibault K. et al.Cortical effect of oxaliplatin associated with sustained neuropathic pain: exacerbation of cortical activity and down-regulation of potassium channel expression in somatosensory cortex.Pain. 2012; 153: 1636-1647Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. All Kv3 channels are high-threshold and are typically encountered in fast-spiking neurons where they facilitate AP repolarization and hence dictate AP duration, but without affecting AP threshold or interspike interval [41Rudy B. McBain C.J. Kv3 channels: voltage-gated K+ channels designed for high-frequency repetitive firing.Trends Neurosci. 2001; 24: 517-526Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. Kv3.1 and Kv3.2 are delayed rectifiers contributing a small fraction (20%) of IK in small nociceptors, with a possible participation of Kv3.3 heterotetramers [42Bocksteins E. et al.Kv3 channels contribute to the delayed rectifier current in small cultured mouse dorsal root ganglion neurons.Am. J. Physiol. Cell Physiol. 2012; 303: