Kv7.2–7.5 voltage-gated potassium channel (KCNQ2–5) opener, retigabine, reduces capsaicin-induced visceral pain in mice

Hirano, Kazufumi; Kuratani, Kazuyoshi; Fujiyoshi, Masato; Tashiro, Nobuhiko; Hayashi, Etsuko; Kinoshita, Mine

doi:10.1016/j.neulet.2006.11.043

Cited by 48 publications

(37 citation statements)

References 21 publications

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“…Accordingly, M channel inhibition depolarizes neurons, making them more excitable, while M current augmentation has the opposite effect (20,(36)(37)(38). Growing evidence suggests that functional M channels are expressed in peripheral sensory fibers and their activity strongly contributes to fiber excitability in vivo (22,(39)(40)(41)(42). Here we show that BK inhibits M current in nociceptors, that M current inhibition is excitatory and causes nociception, and that the nociceptive effect of BK could be attenuated by the pre-application of a specific M channel opener (Figure 8).…”

Section: Discussionmentioning

confidence: 99%

The acute nociceptive signals induced by bradykinin in rat sensory neurons are mediated by inhibition of M-type K+ channels and activation of Ca2+-activated Cl– channels

Liu¹,

Linley²,

Du³

et al. 2010

J. Clin. Invest.

259

442

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Bradykinin (BK) is an inflammatory mediator and one of the most potent endogenous pain-inducing substances. When released at sites of tissue damage or inflammation, or applied exogenously, BK produces acute spontaneous pain and causes hyperalgesia (increased sensitivity to potentially painful stimuli). The mechanisms underlying spontaneous pain induced by BK are poorly understood. Here we report that in small nociceptive neurons from rat dorsal root ganglia, BK, acting through its B 2 receptors, PLC, and release of calcium from intracellular stores, robustly inhibits M-type K + channels and opens Ca 2+ -activated Cl -channels (CaCCs) encoded by Tmem16a (also known as Ano1). Summation of these two effects accounted for the depolarization and increase in AP firing induced by BK in DRG neurons. Local injection of inhibitors of CaCC and specific M-channel openers both strongly attenuated the nociceptive effect of local injections of BK in rats. These results provide a framework for understanding spontaneous inflammatory pain and may suggest new drug targets for treatment of such pain.

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Section: Discussionmentioning

confidence: 99%

The acute nociceptive signals induced by bradykinin in rat sensory neurons are mediated by inhibition of M-type K+ channels and activation of Ca2+-activated Cl– channels

Liu¹,

Linley²,

Du³

et al. 2010

J. Clin. Invest.

259

442

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“…Chemical agents designed to activate KCNQ/M-channels have been previously identified and developed, including the first KCNQ2/3 opener retigabine (Potiga), which was approved by the FDA in 2011 for the treatment of partial epilepsy [7][8][9] . Because of the broad action of retigabine on all neuronal Kv7 channels, retigabine has also been tested for the treatment of anxiety, pain, ophthalmic diseases and tinnitus in animal models [6,[10][11][12][13][14][15][16][17] . However, because retigabine acts on all neuronal Kv7 channels and has potential side effects, efforts have been devoted to searching for more specific KCNQ2/3…”

Section: Original Articlementioning

confidence: 99%

“…Horizontal locomotor activity was recorded with a video camera placed above the chamber and analyzed with Digbehv software (version 2.0, Shanghai Jiliang Software Technology Co Ltd, China) [13,24] . Mice were individually placed in a cage for 10 min to allow for adaptation to the new environment.…”

Section: Locomotor Activitymentioning

confidence: 99%

Activation of neuronal Kv7/KCNQ/M-channels by the opener QO58-lysine and its anti-nociceptive effects on inflammatory pain in rodents

et al. 2016

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Aim: The aim of this study was to examine the activation of neuronal Kv7/KCNQ channels by a novel modified Kv7 opener QO58-lysine and to test the anti-nociceptive effects of QO58-lysine on inflammatory pain in rodent models. Methods: Assays including whole-cell patch clamp recordings, HPLC, and in vivo pain behavioral evaluations were employed. Results: QO58-lysine caused instant activation of Kv7.2/7.3 currents, and increasing the dose of QO58-lysine resulted in a dosedependent activation of Kv7.2/Kv7.3 currents with an EC 50 of 1.2±0.2 μmol/L. QO58-lysine caused a leftward shift of the voltagedependent activation of Kv7.2/Kv7.3 to a hyperpolarized potential at V 1/2 =-54.4±2.5 mV from V 1/2 =-26.0±0.6 mV. The half-life in plasma (t 1/2 ) was derived as 2.9, 2.7, and 3.0 h for doses of 12.5, 25, and 50 mg/kg, respectively. The absolute bioavailabilities for the three doses (12.5, 25, and 50 mg/kg) of QO58-lysine (po) were determined as 13.7%, 24.3%, and 39.3%, respectively. QO58-lysine caused a concentration-dependent reduction in the licking times during phase II pain induced by the injection of formalin into the mouse hindpaw. In the Complete Freund's adjuvant (CFA)-induced inflammatory pain model in rats, oral or intraperitoneal administration of QO58-lysine resulted in a dose-dependent increase in the paw withdrawal threshold, and the anti-nociceptive effect on mechanical allodynia could be reversed by the channel-specific blocker XE991 (3 mg/kg). Conclusion: Taken together, our findings show that a modified QO58 compound (QO58-lysine) can specifically activate Kv7.2/7.3/ M-channels. Oral or intraperitoneal administration of QO58-lysine, which has improved bioavailability and a half-life of approximately 3 h in plasma, can reverse inflammatory pain in rodent animal models.

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“…Inhibition of M current depolarises neurons making them more excitable, while augmentation has the opposite effect [56, 70,113,117,127]. Functional M channels are expressed in peripheral sensory fibres, and their activity strongly contributes to fibre excitability in vivo [17,65,80,86,124]. Recently, we found that intraplantar injection of the M channel blocker XE991 into the hind paw of rats induces moderate pain and that the inhibition of M channels within peripheral nociceptive fibres may contribute to the spontaneous component of pain produced by the activation of proinflammatory proteases [86].…”

Section: Ionic Mechanisms Of Spontaneous Painmentioning

confidence: 99%

Understanding inflammatory pain: ion channels contributing to acute and chronic nociception

Linley

Rose

Ooi

et al. 2010

Pflugers Arch - Eur J Physiol

117

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Inflammatory pain results from the increased excitability of peripheral nociceptive sensory fibres produced by the action of inflammatory mediators. This excitatory effect, in turn, is a result of the altered activity of ion channels within affected sensory fibres. This review will consider the molecular consequences of inflammation within the peripheral nerves with particular focus on the effects of different inflammatory mediators on the ion channels in sensory neurons. We will discuss the main signalling pathways triggered in neurons by inflammatory mediators; the ionic mechanisms underlying inflammatory hyperalgesia and spontaneous inflammatory pain and finally will briefly consider ion channels underlying pain in chronic inflammation.

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Kv7.2–7.5 voltage-gated potassium channel (KCNQ2–5) opener, retigabine, reduces capsaicin-induced visceral pain in mice

Cited by 48 publications

References 21 publications

The acute nociceptive signals induced by bradykinin in rat sensory neurons are mediated by inhibition of M-type K+ channels and activation of Ca2+-activated Cl– channels

The acute nociceptive signals induced by bradykinin in rat sensory neurons are mediated by inhibition of M-type K+ channels and activation of Ca2+-activated Cl– channels

Activation of neuronal Kv7/KCNQ/M-channels by the opener QO58-lysine and its anti-nociceptive effects on inflammatory pain in rodents

Understanding inflammatory pain: ion channels contributing to acute and chronic nociception

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