REVIEW URRENT C OPINION

Emerging potassium channel targets for the treatment of pain Christoforos Tsantoulas

Purpose of review Poor management of chronic pain remains a significant cause of misery with huge socioeconomic costs. Accumulating research in potassium (Kþ) channel physiology has uncovered several promising leads for the development of novel analgesics. Recent findings We now recognize that certain Kþ channel subunits are directly gated to pain-relevant stimuli (Kv1.1, K2P) whereas others are specifically modulated by inflammatory processes (Kv7, BKCA, K2P). Genetic analyses illustrate that Kþ channel gene variation can predict pain sensitivity (KCNS1, GIRKs), risk for persistent pain (KCNS1, GIRKs, TRESK) and analgesic effectiveness (GIRK2). Importantly, preclinical studies confirm that Kþ channel dysfunction can be a pain trigger in traumatic neuropathies (Kv9.1/Kv2.1, Kv7, Kv1.2) and migraine (TRESK). Finally, emerging data suggest that even pain in diabetes, bone cancer and autoimmune neuropathies may have Kþ channel dysfunction constituents. Summary There is a long-sought need for superior pharmacotherapy of pain syndromes. Although universal enhancement of Kþ channel function in the periphery can decrease nociceptive excitability irrespective of the underlying cause, a more refined targeting of subunits with dominant nociceptive roles could yield highly efficacious treatments with fewer side-effects. The ongoing characterization of molecular interactions linking Kþ channel dysfunction to pain is instrumental for identifying candidates with the most therapeutic potential. Keywords analgesic, inflammation, pain, potassium channel, voltage-gated potassium channel

INTRODUCTION The ability to sense painful stimuli constitutes a warning mechanism against ongoing tissue damage or imminent danger of such. Although this process has paramount survival value via facilitating protective and/or healing behaviours, there are scenarios of maladaptive pain in which clinical modulation is sought, such as those associated with persistent pain phenotypes due to nerve trauma, inflammation, diabetes, cancer, infection and autoimmunity. In the clinic, decades have passed with no major breakthrough and chronic pain is intractable in up to two-thirds of patients with current treatments [1]. This pharmacological inadequacy combined with the fact that many diseases that cause chronic pain are on the rise underscore the necessity for novel analgesic tactics. Pain processing relies on the activity of nociceptive neurons that transduce stimuli from the periphery to the central nervous system (CNS) [2]. The function of these neurons is shaped by the identity,

organization and activity of specialized ion channels and receptors they contain on their cell membrane [3–5]. For instance, membrane depolarization and action potential generation during pain signalling is critically dependent on sodium channels (Nav), and for this reason, Nav have dominated pain research for many years. Unfortunately, this approach has not been particularly fruitful, whereas the jury is still out for Nav1.7 inhibitors in clinical trials. Another group of proteins that hold great promise is Kþ channels that also influence action potential threshold, duration and firing rate (Fig. 1). In contrast to Nav channels, however, their activity Wolfson Centre for Age-Related Diseases, King’s College London, London, UK Correspondence to Christoforos Tsantoulas, PhD, Wolfson Centre for Age-Related Diseases, King’s College London, London SE1 1UL, UK. Tel: +44 020 7848 6568; e-mail: [email protected] Curr Opin Support Palliat Care 2015, 9:147–154 DOI:10.1097/SPC.0000000000000131

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Pain: non-malignant disease

KEY POINTS  Kþ channels are the most populous family of ion channels in mammals, enlisting approximately 80 members. Kþ channel function is fundamental for sensory neuron activity during pain signalling. Opening of these channels allows a hyperpolarizing Kþ efflux across the cell membrane, which counteracts neuronal depolarization and therefore typically inhibits neuronal excitability.  As increased neuronal excitability is a hallmark of pathological pain, enhancement of Kþ channel conduction with activating compounds can shape novel analgesic opportunities. An accumulating body of research has now implicated various Kþ channel subunits in diverse chronic pain conditions, including those associated with nerve trauma, diabetic neuropathy, bone cancer, migraine and autoimmune disease.  The traditional view of Kþ channels being ‘passive players’ that mainly become engaged following action potential generation has been critically expanded with the identification of subunits conducting at subthreshold levels (Kv7, Kv1.2) or even directly gated by painrelated stimuli (K2P, Kv1.1). Concurrently, our understanding of the impact of Kþ channel activity on spike propagation (Kv2.1) and transmission (BKCA) has been substantially improved.  The clinical relevance of Kþ channel function is reflected in genetic screens demonstrating that Kþ channel genotype is useful in predicting acute pain thresholds (KCNS1, GIRKs), risk of developing persistent pain (KCNS1, GIRKs, TRESK) as well as analgesic effectiveness (GIRK2).  The most advanced Kþ channel enhancers in development are Kv7 activators such as retigabine, and these hold considerable potential for the treatment of both inflammatory and neuropathic pain. Restoring Kv9.1/Kv2 signalling may be beneficial in traumatic neuropathies, whereas regulating TRESK activity in trigeminal neurons could have therapeutic value for migraine. Compounds against BKCA can provide alternative anti-inflammatories whereas K2P and GIRK modulators may recapitulate opioid analgesia without dose-limiting side-effects. Synergistic effects among Kþ channel modulators or with other analgesics is also a possibility for superior pain management.

creates a hyperpolarizing Kþ efflux across the cell membrane, and therefore Kþ channels generally inhibit neuronal excitability. On the basis of structural and physiological attributes, members of the Kþ superfamily are classified into voltage gated potassium channel (Kv), which are activated by changes in voltage; two pore potassium channel (K2P), which generate leak currents that influence resting membrane potential 148

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Subthreshold

Suprathreshold

Nav1.8 Nav1.7 Nav1.9

Kv1.1/1.2 Kv7.2/7.3 K2P

Kv2.1/Kv9.1 Kv3.4 BKCA

HCN

FIGURE 1. Schematic of Kþ channel recruitment during action potential firing in a sensory neuron. Subthreshold Kþ channels can oppose the depolarizing influence of Nav channels by conducting persistent background currents that do not inactivate (Kv7) or via engagement by small depolarizations due to mechanical or heat stimuli (Kv1, K2P). Following a sufficiently large stimulus and recruitment of enough Nav channels (mainly, Nav1.7 and Nav1.9), the neuronal membrane reaches firing threshold (dotted line) and an action potential is generated. The robust depolarization during action potential firing (mostly carried by Nav1.8) results in opening of previously inactive high-threshold Kþ channels such as Kv2.1 and Kv3.4 that facilitate repolarization, hyperpolarization and/or afterhyperpolarization, depending on their voltage dependence and kinetics. For instance, Kv2.1 is found to mainly influence interspike hyperpolarization of sensory neurons, presumably because of its very slow rate of activation. BKCA are also recruited slowly because of their dependence on firing-mediated Ca2þ accumulation whereas return to RMP is further facilitated by the activity of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. Only channels with prominent functions are illustrated; however, many more Kþ (or other ion) channels participate in regulation of action potential under physiological conditions.

(RMP); calcium activated potassium channel (KCA), which are sensitive to Ca2þ and regulate ongoing activity at synapses; and inward rectifying (Kir), which conduct atypical inward currents assisting extracellular Kþ homeostasis. This review covers recent insights on the role of specific subunits in nociceptive processing, with a focus on peripheral mechanisms that involve representative members from all families.

KR CHANNELS IN NOCICEPTIVE SIGNALLING The influence of Kþ channels on neuronal excitability starts at nociceptive terminals in the periphery (Fig. 2). It is certainly true that Kþ channels provide Volume 9  Number 2  June 2015

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Emerging potassium channel targets for the treatment of pain Tsantoulas

Transmission

Propagation

Initiation

Kv3.4

Kv1 (Kv1.1/Kv1.2)

Kv1 (Kv1.1/Kv1.2)

BKCA

Kv2 (Kv2.1/Kv9.1)

Kv7 (Kv7.2/Kv7.3)

Kv7 (Kv7.2/7.3)

K2P (TREK1, TREK2, TRAAK) BKCA

CNS

Periphery

FIGURE 2. Representation of the key involvement of several Kþ channel subunits during nociceptive signalling in a sensory neuron. The activity of Kþ channels regulates all phases of an excitatory event, from generation of an action potential in the periphery to propagation of the signal along the axon and transmission to second-order neurons in the spinal cord. In peripheral nerve terminals, Kþ channels that conduct subthreshold (Kv7) or leak currents (K2P) modulate firing by influencing RMP and action potential threshold. Some channels, however, can directly respond to mechanical (e.g. Kv1.1, TREK1, TREK2 and TRAAK) and heat (TREK1 and presumably BKCA through functional complexes with TRPV1) stimuli. The fidelity of action potential propagation along the axon is also critically dependent on the function of several channels such as Kv2.1 (most likely in association with Kv9.1), Kv7 channels (e.g. influencing saltatory conduction at nodes of myelinated neurons) and Kv1 channels (as evident by painful neuropathies associated with autoimmunity to juxtaparanodal Kv1 complexes). At the central synapses, accumulation of Ca2þ during neurotransmission can activate a negative feedback loop by recruitment of BKCA channels. This results in shortening of action potential and thus limiting of neurotransmitter release, an effect that may also be assisted by the high-threshold-activated Kv3.4 subunit. The summation of signal regulation by different Kþ channels along this pathway will determine the waveform and frequency of action potentials arriving in the spinal cord, and thus pain sensation. Because nerve damage or inflammation typically reduces the function of peripheral Kþ channels resulting in augmented pain processing, Kþ channel activators hold potential as new analgesic drugs. It is noted that many channels have parallel roles across different neuronal compartments; only key functions are depicted here. CNS, central nervous system.

a general nociceptive brake by opposing action potential initiation through subthreshold activity around RMP (e.g. Kv1, Kv7 and K2P) or limiting spike duration and frequency after action potential generation. Recent evidence, however, reveals a more intricate operation, wherein certain channels can be directly gated from pain-relevant stimuli. For instance, the K2P members TWIK-related potassium channel 1 (TREK1), TREK2 and TWIK-related arachidonic acid activated Kþ channel (TRAAK) can be engaged by mechanical and thermal stimuli at nerve endings, suggesting that under normal conditions, K2P function directly antagonizes pro-nociceptive mechanoreceptors and thermoreceptors [6,7,8 ]. Supporting this notion, TREK1 is localized in transient receptor potential cation channel subfamily V member 1 (TRPV1)-positive nociceptors and its deletion leads to reduced thermal (as well as mechanical) pain thresholds [9]. Intriguingly, Kv1.1, a subunit previously designated as voltage sensitive, &

was also recently demonstrated to underlie a hyperpolarizing mechanosensitive current relevant in pain perception [10 ]. The fidelity of action potential conduction across the neuronal axon and T-junction is also subject to regulation by numerous Kv channels (e.g. Kv2 [11 ] and Kv7 [12]), whereas activity in central terminals [e.g. Kv3.4 and largeconductance KCA (BKCA)] reduces action potential duration and thus neurotransmitter release and synaptic strength. Given this multidimensional involvement in excitability, it is no surprise that nonspecific Kþ channel blockers enhance neuronal excitability and promote pain signalling, whereas Kþ channel openers have the opposite effect. Nevertheless, the ability to decipher subunits with dominant roles is paramount for the development of selective analgesic compounds with fewer side-effects. One method of acquiring such information is through genetic screening. Thus, a potassium voltage-gated channel,

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modifier subfamily S, member 1 (KCNS1) allele (encoding Kv9.1) is associated with enhanced sensitivity to painful stimuli in both healthy and chronic pain individuals [13,14]. The G proteincoupled inwardly-rectifying potassium channels (GIRK)2 subunit encoded by KCNJ6 is linked to pain sensitivity and tolerance, as well as analgesic effectiveness [15,16 ]. Genetic interrogation of a breast cancer cohort by Langford et al. [17] indicated that breast pain correlates with genetic variation in KCNS1, KCNJ3 (encoding GIRK1), KCNJ6 and KCNK9 (encoding TASK3). This knowledge is important because acute pain sensitivity often overlaps with propensity for persistent pain and ideal pharmacotherapy for chronic pain should normalize pathological excitability without compromising acute sensation. &

[19,22,23]. Importantly, retigabine can also reverse pain behaviour in inflammatory pain models and this effect was attributed to activation of peripheral Kv7 channels [24]. A structurally similar compound, flupirtine, has been used in Europe for over 30 years to treat pain of diverse causes [25], whereas the popular anti-inflammatory diclofenac can also engage Kv7 channels, amongst other targets [26]. A connection between KCA activity and inflammatory hyperexcitability has been suspected since the discovery that KCA currents in nociceptors are inhibited by prostaglandin E2 and other archetypal inflammatory mediators [27], the enticing finding that KCA are functionally coupled to TRPV1, one of the main receptors implicated in inflammation [28 ], and hints of interactions with transient receptor potential cation channel, subfamily A, member 1 (TRPA1) [29 ]. Recent work by Lu et al. [29 ] provided more direct evidence; thus deleting the main contributor of KCA current, the large-conductance KCA subfamily (BKCA) from mouse nociceptors modestly augmented pain in persistent inflammatory pain paradigms, with no effect on acute nociception or neuropathic pain behaviours [29 ]. The pathological phenotype could be offset by systemic administration of the BKCA opener N1619, an effect attributed to inhibition of peripheral hyperexcitability via activation of residual KCA [29 ]. It will be important to test the analgesic effectiveness of BKCA openers in humans; andolast is currently being evaluated in phase III trials as an anti-inflammatory for chronic obstructive pulmonary disease. Finally, the K2P family also make good candidates because they are known to be inhibited by molecular events characteristic of inflammation such as prostaglandin E2 secretion, tissue acidification and activation of G-protein coupled receptors [30]. It is probably the loss of this inhibitory pathway that reduces inflammatory pain in TREK1 knockout mice [9]. In addition, attenuation of K2P expression during chronic inflammation may also promote a hyperexcitable phenotype [31,32]. &

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KR CHANNELS IN INFLAMMATION Pain can be a result of inflammation, a complex homeostatic reaction orchestrated by numerous inflammatory mediators secreted in the vicinity of injury by immune cells and neurons. Although typically acute, under certain circumstances, inflammation can persist and the accompanying pain is also manifested chronically. Inflammatory agents, for example cytokines and chemokines, bradykinin, substance P, ATP, tumour necrosis factor-a, Hþ and nitric oxide, are known to promote pain by sensitizing or directly activating nociceptors. One way of achieving this is via direct inhibition of Kþ conductance, effectively mimicking the effect of inflammatory sensitization on pro-algesic channels [e.g. TRPV1, Nav and acid-sensing ion channels (ASICs)]. A subfamily that fits this description is Kv7, members of which conduct a low-threshold noninactivating current with a dominant role in stabilizing RMP, setting firing threshold and firing rate in sensory neurons. Kv7 channels are inhibited by inflammation-induced G-protein coupled receptors such as bradykinin receptor B2, protease-activated receptor-2, histamine receptor H1 and prostaglandin E receptor 1 (EP1) [18]. This signalling pathway involves recruitment of phospholipase C, which causes phosphatidylinositol 4,5-biphosphate depletion and 1,4,5-triphosphate-mediated Ca2þ release from intracellular stores, both of which directly inhibit Kv7 conductance [19,20]. In addition, a nitric oxideinduced inhibitory cascade was recently identified in trigeminal ganglion neurons and may be implicated in headache and migraine [21]. The inflammation-mediated decrease of Kv7 activity correlates with increased nociceptor excitability, can be recapitulated using specific blockers (e.g. XE-991) and antagonized by enhancers such as retigabine 150

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KR CHANNELS IN NEUROPATHIC PAIN The prolonged neuronal excitability encountered in neuropathic pain can be mechanistically explained by persistent reductions on ion channel expression/ function. Indeed, a large body of evidence has now documented downregulation of many Kþ channels and associated currents in sensory neurons under chronic pain states, and this is often a trigger of hyperexcitability [4]. It is beyond the scope of this review to provide a detailed account of these observations; instead, a selection of emerging key players in divergent pain syndromes will be highlighted. Volume 9  Number 2  June 2015

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Emerging potassium channel targets for the treatment of pain Tsantoulas

Traumatic nerve injury Kv9.1 is one of the first subunits identified as a predictor of persistent pain after amputation (and also correlates with back pain risk and pain sensitivity in HIV-associated neuropathy) [13,14]. The significance of this subunit was validated in subsequent animal studies that illustrated a profound neuronal downregulation following nerve trauma [33]. This subunit is intriguing for a number of reasons. First, Kv9.1 is expressed in myelinated sensory neurons rather than small nociceptors, the usual suspects for peripheral sensitization. Second, Kv9.1 attenuation commenced within hours postinjury and was complete by 3 days, suggesting that it may precede development of neuropathic pain symptoms. Indeed, mimicking this reduction with intrathecal small interfering RNA in naive rats led to mechanical hypersensitivity, electrophysiologically traced back to increased spontaneous and evoked excitability of myelinated fibres. Third, Kv9.1 is atypical in that it belongs to a family of so-called ‘silent subunits’ that can only conduct currents in association with other pore-forming subunits such as Kv2.1. The effect of Kv9.1 dysfunction on neuronal excitability is somewhat unexpected, because in vitro Kv9.1 can reduce Kv2.1 conductance and promote inactivation [34]. Nevertheless, recent ex vivo experiments demonstrate that the main effect of Kv2 antagonism is facilitation of higher firing frequencies due to quicker afterhyperpolarization [11 ]. This result suggests that Kv9.1 is a promotor of Kv2.1 function in vivo, which raises intriguing questions about the elusive role of silent subunits in pain signalling. Another subunit with an emerging role in myelinated fibres is Kv1.2, injury-induced reduction of which drives hyperexcitability and pain that can be rescued by experimental overexpression [35]. What is more remarkable about Kv1.2 is its unique regulation by a specific long noncoding RNA that acts as an antisense molecule. Thus, nerve damage induces Kv1.2 antisense and blocking this signal with a complementary RNA retains Kv1.2 expression and precludes neuropathic pain development [36 ]. It is currently unknown whether other Kþ channel subunits are analogously modulated at the transcriptional level, but if true this could circumvent the fundamental difficulty of designing selective modulators to discriminate members of the highly conserved Kv family. Multiple lines of evidence suggest that enhancing Kv7.2/Kv7.3 function is antinociceptive in neuropathic models, a claim further substantiated by the effectiveness of the Kv7 opener flupirtine in human pain [19,23,37,38]. At odds with this, a phase II trial of systemic retigabine (a structural &

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analog of flupirtine) in postherpetic neuralgia was deemed inconclusive. One confounding factor may be the inappropriateness of pain condition assessed – there is no established link between Kv7 function and virus-associated neuropathies such as postherpetic neuralgia and flupirtine has not been systematically tested in this disease. Moreover, although similar doses of retigabine are effective in epilepsy, experience with flupirtine indicates that Kv7-conferred analgesia requires higher doses compared with anticonvulsant activity. Owing to the fact that retigabine is not as well tolerated as flupirtine, it is possible that CNS-mediated sideeffects kept doses below the threshold required for observation of analgesia. Given the effectiveness of peripheral Kv7 enhancement in many experimental paradigms, developing peripherally restricted Kv7activating compounds could bypass these difficulties and provide improved pain relief, particularly in traumatic neuropathies. For an excellent review of the latest advances in pharmacological Kv7 modulation in pain, see [39].

Migraine A rare mutation in TWIK-related spinal cord potassium channel (TRESK), a K2P channel found in nociceptors of the trigeminal ganglion, has been identified as a genetic switch for neurogenic dysfunction linked to migraine. In accordance with the general theme outlined in this review, the mutant allele encodes a truncated subunit that completely suppresses conduction of the functional dimer through a dominant-negative interaction, and this inhibition may promote trigeminal ganglion hyperexcitability and pain [40]. Consistently, TRESK provision inhibits nociceptor excitability and capsaicin-induced substance P release and can even reverse neuropathic pain symptoms [41–43]. Unfortunately, the only compounds known to activate TRESK do so via nonselective potentiation of protein kinase C and Ca2þ signalling rather than a direct interaction [44,45]. It is entirely plausible that with the constant refinement of DNA screening techniques, we can soon link more Kþ channelopathies to idiopathic pain. As a precautionary tale, however, a recent study showed no association between three common TRESK single-nucleotide polymorphisms and migraine, suggesting that genetic changes with dramatic effects on pain phenotypes may be relatively rare occurrences [46].

Painful diabetic neuropathy Painful neuropathy associated with diabetes mellitus is the leading cause of chronic pain in humans,

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with about a quarter of diabetic patients affected. Despite the clinical prevalence of this pain, we know desperately little information on its pathophysiology and the mechanisms governing disease progression. Kþ channels are putative key convergence points in diabetic neuropathy because Kþ conductance can regulate both insulin release and neuronal excitability, for example Kv2 [47,48]. Indeed, certain subunits and associated currents are decreased in diabetic models, namely Kv1.4, Kv3.4, Kv4.2 and Kv4.3, and this change was dependent on neurotrophin availability, imbalances in which have previously been associated with diabetes and inflammation [49–51]. Although the aforementioned subunits are predominantly detected in myelinated neurons, a recent report suggests that diabetes-mediated Kþ channel dysfunction may also be implicated in hyperresponsiveness of small nociceptors [52]. This may explain the analgesic effect of flupirtine in diabetic neuropathy, which interestingly can also potentiate morphine antinociception [53].

Cancer pain Management of pain induced by malignancies such as bone cancer is another unmet clinical need. Although Kþ channel research in this field is still in its infancy, Kv7 channels hold the most potential for treatment. This is not surprising because cancer pain is most likely fuelled by inflammatory and neuropathic components and Kv7 activity has extensively been implicated in both [19,37]. Thus, Kv7.2/ Kv7.3 subunits and corresponding currents are diminished in a bone cancer paradigm (albeit with a slow time course), whereas retigabine reverses mechanical and thermal pain by inhibiting both nociceptor and dorsal horn neuron hyperexcitability [54 ,55 ]. In addition, Duan et al. [56] documented expressional changes in rapidly inactivating A-type Kþ channels following bone cancer induction and showed that the antinociceptive effects of diclofenac in this model can be antagonized by Kv1.4 or Kv4.3 block. The mechanism of A-type channel dysregulation may involve interleukin-6 signalling, because deletion of its gp130 receptor from nociceptors leads to enhanced Kv1.4 expression, A-type currents and decreased excitability [57]. Thus, it is possible that increased interleukin-6 levels act as an A-type Kþ channel brake in bone cancer, and perhaps other pain syndromes such as rheumatoid arthritis and traumatic neuropathy [58]. A final family implicated in cancer pain is KATP channels. Thus, spinal Kir6.2 is reduced in cancer-induced rats and KATP openers or Kir6.2 small interfering RNA can either antagonize or potentiate mechanical pain in this model, &

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respectively [59]. Taken together, it appears that Kþ channel modulation holds therapeutic potential in cancer pain, including opportunities for synergistic actions with other analgesics [60].

Autoimmune pain Biochemical abnormalities that impact normal Kþ channel function, including autoimmunity, may give rise to idiopathic chronic pain disorders. As an example, neuromyotonia or Morvan’s and cramp fasciculation syndromes are correlated with high serum levels of antibodies against Kv1 or auxiliary proteins that guide juxtaparanodal assembly of the functional channels [61–63]. In one study, 50% of patients that tested positive for Kv-complex immunoglobulins had chronic pain and often presented signs of peripheral hyperexcitability. Importantly, immunotherapy significantly reduced pain in 14 out of 16 patients [62]. The relevance of Kv-complex autoimmunity in enigmatic pain states with no apparent cause remains to be systematically investigated but could open exciting new treatment avenues.

Postoperative pain &

In a recent study, Langford et al. [64 ] identified associations between genetic variation in Kv1.1, Kv4.2, GIRK1, GIRK2 and TASK3 and risk of developing persistent breast pain following mastectomy. Arguably, this pain represents a mixture of nociceptive [17], inflammatory [65], neuropathic and malignancy elements; nevertheless, the finding has important predictive value when considering surgical treatments, especially in combination with genetic markers of susceptibility to malignancy (e.g. BRCA) [66]. In addition, independent research has linked additional single-nucleotide polymorphisms in GIRK2 with not only pain sensitivity but also effectiveness of opioid treatment [16 ,67]. Therefore, it is very likely that in the future, knowledge of an individual’s Kþ channel genotype will decisively inform personalized pain management. &

KR channels in the central nervous system Several centrally located channels such as TREK1, GIRK1 and GIRK2 are relevant for spinal analgesia, because their activation is downstream of m-opioid receptor activation by opioids and endogenous pain modulators [68 ,69]. Crucially, however, these subunits do not participate in other opioid receptorassociated pathways responsible for adverse sideeffects of opioids. For instance, although the analgesic effectiveness of low morphine doses is lost in &&

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TREK1 knockout mice, measures of dependence, constipation and respiratory depression remain unchanged, suggesting that enhancing TREK1 function may provide analgesia equivalent to morphine but devoid of these contraindications [68 ]. Several TREK1 openers such as caffeic esters are in development and have exhibited encouraging antihyperalgesic properties in visceral pain [70]. A potential hurdle to this strategy is the likelihood of inducing depression; TREK1 knockout mice have depression-resistant phenotypes and indeed human depression is often treated with drugs that block TREK1 [6]. GIRK-dependent antinociceptive effects of opioids are reliant on postsynaptic agonism at spinal and supraspinal levels [71,72]. GIRK deletion reduces analgesia by high morphine doses, although the problem of dependence persists [69,73]. Interestingly, a recent study demonstrated that, in humans (but not mice), GIRK channels also confer peripheral opioid-mediated analgesia, suggesting that peripheral GIRK targeting could evade CNSdependent side-effects [74 ]. &&

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CONCLUSION Translation of pain research into real-world treatments can be a daunting task, as the many unfortunate attempts in the history of analgesic drug development exemplify. The rapidly expanding knowledge on the involvement of Kþ channels in antinociception provides a fresh angle in drug discovery with many attractive candidates. The success of this approach will be chiefly determined by rational prioritization of subunits with the most prominent roles, as well as the ability to accurately deliver interventions so that they do not impede physiological function. Acknowledgements None. Financial support and sponsorship This work was supported by the Medical Research Council (MR/J013129/1) and the Wellcome Trust (080504). Conflicts of interest There are no conflicts of interest.

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54. Zheng Q, Fang D, Liu M, et al. Suppression of KCNQ/M (Kv7) potassium channels in dorsal root ganglion neurons contributes to the development of bone cancer pain in a rat model. Pain 2013; 154:434–448. A report implicating Kv7 dysfunction in pain due to malignancies, particularly relevant to the clinic due to the availability of approved Kv7 enhancers. 55. Cai J, Fang D, Liu XD, et al. Suppression of KCNQ/M (Kv7) potassium & channels in the spinal cord contributes to the sensitization of dorsal horn WDR neurons and pain hypersensitivity in a rat model of bone cancer pain. Oncol Rep 2015; 33:1540–1550. A study extending the role of Kv7 in bone cancer by linking Kv7 dysfunction to pathological signalling in the spinal cord. It will be interesting to decipher whether such contribution to central sensitization also occurs in other pain states. 56. Duan KZ, Xu Q, Zhang XM, et al. Targeting A-type Kþ channels in primary sensory neurons for bone cancer pain in a rat model. Pain 2012; 153:562– 574. 57. Langeslag M, Malsch P, Welling A, et al. Reduced excitability of gp130deficient nociceptors is associated with increased voltage-gated potassium currents and Kcna4 channel upregulation. Pflugers Arch 2014; 466:2153– 2165. 58. Quarta S, Vogl C, Constantin CE, et al. Genetic evidence for an essential role of neuronally expressed IL-6 signal transducer gp130 in the induction and maintenance of experimentally induced mechanical hypersensitivity in vivo and in vitro. Mol Pain 2011; 7:73. 59. Xia H, Zhang D, Yang S, et al. Role of ATP-sensitive potassium channels in modulating nociception in rat model of bone cancer pain. Brain Res 2014; 1554:29–35. 60. Kolosov A, Goodchild CS, Williams ED, et al. Flupirtine enhances the antihyperalgesic effects of morphine in a rat model of prostate bone metastasis. Pain Med 2012; 13:1444–1456. 61. Irani SR, Pettingill P, Kleopa KA, et al. Morvan syndrome: clinical and serological observations in 29 cases. Ann Neurol 2012; 72:241–255. 62. Klein CJ, Lennon VA, Aston PA, et al. Chronic pain as a manifestation of potassium channel-complex autoimmunity. Neurology 2012; 79:1136– 1144. 63. Bennett DL, Vincent A. Autoimmune pain: an emerging concept. Neurology 2012; 79:1080–1081. 64. Langford DJ, Paul SM, West CM, et al. Variations in potassium channel genes & are associated with distinct trajectories of persistent breast pain following breast cancer surgery. Pain 2015; 156:371–380. A gene association study addressing the understudied problem of persistent pain after mastectomy. The authors identify genetic variation in Kþ channel genes that could be used to estimate postoperational trajectories and analgesic treatment outcomes in the clinic. 65. Stephens K, Cooper BA, West C, et al. Associations between cytokine gene variations and severe persistent breast pain in women following breast cancer surgery. J Pain 2014; 15:169–180. 66. Tsantoulas C. Genetic insights towards improved management of chronic pain after mastectomy. Pain 2015; 156:361–363. 67. Nishizawa D, Nagashima M, Katoh R, et al. Association between KCNJ6 (GIRK2) gene polymorphisms and postoperative analgesic requirements after major abdominal surgery. PLoS One 2009; 4:e7060. 68. Devilliers M, Busserolles J, Lolignier S, et al. Activation of TREK-1 by morphine && results in analgesia without adverse side effects. Nat Commun 2013; 4:2941. An important proof-of-concept study demonstrating that TREK1 treatments could harvest the analgesic benefits of opioids, without the incapacitating side-effects that limit opioid use in the clinic. 69. Marker CL, Stoffel M, Wickman K. Spinal G-protein-gated Kþ channels formed by GIRK1 and GIRK2 subunits modulate thermal nociception and contribute to morphine analgesia. J Neurosci 2004; 24:2806–2812. 70. Rodrigues N, Bennis K, Vivier D, et al. Synthesis and structure-activity relationship study of substituted caffeate esters as antinociceptive agents modulating the TREK-1 channel. Eur J Med Chem 2014; 75:391– 402. 71. Nakamura A, Fujita M, Ono H, et al. G protein-gated inwardly rectifying potassium (KIR3) channels play a primary role in the antinociceptive effect of oxycodone, but not morphine, at supraspinal sites. Br J Pharmacol 2014; 171:253–264. 72. Kanbara T, Nakamura A, Shibasaki M, et al. Morphine and oxycodone, but not fentanyl, exhibit antinociceptive effects mediated by G-protein inwardly rectifying potassium (GIRK) channels in an oxaliplatin-induced neuropathy rat model. Neurosci Lett 2014; 580:119–124. 73. Cruz HG, Berton F, Sollini M, et al. Absence and rescue of morphine withdrawal in GIRK/Kir3 knock-out mice. J Neurosci 2008; 28:4069– 4077. 74. Nockemann D, Rouault M, Labuz D, et al. The Kþ channel GIRK2 is both & necessary and sufficient for peripheral opioid-mediated analgesia. EMBO Mol Med 2013; 5:1263–1277. Clinically relevant work suggesting that peripherally restricted GIRK2 modulators could provide pain relief without the dose-limiting side-effects of CNS activity. &

Volume 9  Number 2  June 2015

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Emerging potassium channel targets for the treatment of pain.

Poor management of chronic pain remains a significant cause of misery with huge socioeconomic costs. Accumulating research in potassium (K+) channel p...
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