Suppression of KCNQ/M (Kv7) potassium channels in dorsal root ganglion neurons contributes to the development of bone cancer pain in a rat model

Abstract

Bone cancer pain has a strong impact on the quality of life of patients, but is difficult to treat. Better understanding of the pathogenic mechanisms underlying bone cancer pain will likely lead to the development of more effective treatments. In the present study, we investigated whether inhibition of KCNQ/M channels contributed to the hyperexcitability of primary sensory neurons and to the pathogenesis of bone cancer pain. By using a rat model of bone cancer pain based on intratibial injection of MRMT-1 tumour cells, we documented a prominent decrease in expression of KCNQ2 and KCNQ3 proteins and a reduction of M-current density in small-sized dorsal root ganglia (DRG) neurons, which were associated with enhanced excitability of these DRG neurons and the hyperalgesic behaviours in bone cancer rats. Coincidently, we found that inhibition of KCNQ/M channels with XE-991 caused a robust increase in the excitability of small-sized DRG neurons and produced an obvious mechanical allodynia in normal rats. On the contrary, activation of the KCNQ/M channels with retigabine not only inhibited the hyperexcitability of these small DRG neurons, but also alleviated mechanical allodynia and thermal hyperalgesia in bone cancer rats, and all of these effects of retigabine could be blocked by KCNQ/M-channel antagonist XE-991. These results suggest that repression of KCNQ/M channels leads to the hyperexcitability of primary sensory neurons, which in turn causes bone cancer pain. Thus, suppression of KCNQ/M channels in primary DRG neurons plays a crucial role in the development of bone cancer pain.

Polyunsaturated fatty acids are potent openers of human M‐channels expressed in Xenopus laevis oocytes

“…These computer simulations in combination with our experimental findings in DRG neurons and on isolated M-channels suggest that PUFA-induced augmentation of the M-current contributes to the anti-excitable effect of PUFAs. This is further supported by a comparison of the PUFA effects found in the present work and previously reported effects of the clinically approved M-channel opener retigabine; the PUFA effects on the resting membrane potential and the firing threshold in DRG neurons, and on the voltage dependence of the isolated human M-channel expressed in Xenopus oocytes are, on the whole, similar to, but quantitatively smaller than, the effect of retigabine (Main et al 2000;Zheng et al 2013;Du et al 2014). Our finding that DHA methyl ester and oleic acid were ineffective suggests that possible anti-excitable effects of PUFA methyl esters and monounsaturated fatty acids are not mediated via the M-channel.…”

Kv7 channels regulate pairwise spiking covariability in health and disease

“…These channels are present throughout the nervous system (Brown and Passmore 2009;Delmas and Brown 2005;Jentsch 2000), and their dysfunction is involved in several disease states (Cooper and Jan 2003;Li et al 2013;Passmore et al 2003;Shah and Aizenman 2014;Zheng et al 2012). Using a well-established theoretical framework to study correlation transfer in spiking neurons (de la Rocha et al 2007), we showed that the recruitment of Kv7 conductances provides an input-driven negative feedback that cancels correlating inputs and reduces the covariability of pairwise spiking activity in model neurons.…”

Effects of natural and synthetic isothiocyanate-based H 2 S-releasers against chemotherapy-induced neuropathic pain: Role of Kv7 potassium channels

“…Notably, although Kv7.5 subunits are also abundantly expressed in C-fibers and control excitability of nociceptive neurons (King and Scherer, 2012), the pharmacological profile of the M currents recorded from nociceptive DRG neurons speaks against a strong contribution of Kv7.5 (Du and Gamper, 2013). Inhibition of Kv7 channels with XE-991, a specific and potent blocker of the currents carried by Kv7 channels (Wang et al, 1998), leads to hyperexcitability of primary sensory neurons (Zheng et al, 2013). On the other hand, retigabine, an activator of neuronal Kv7 channels (Miceli et al, 2008), was neuroprotective against cisplatin- (Nodera et al, 2011) andoxaliplatin-(Abd-Elsayed et al, 2015) induced neuropathy, decreased osteoarticular and neuropathic pain Brown and Passmore, 2009), and suppressed the excitability of nociceptive cold-sensing trigeminal ganglion neurons (Abd-Elsayed et al, 2015).…”

“…Nonetheless, several studies have suggested significant pain relieving effects of H 2 S donors against neuropathic and visceral pain (Distrutti et al, 2006;Lin et al, 2014;Kida et al, 2015). Recently, some isothiocyanate derivatives, slow releasing H 2 Sdonor moieties, and NaHS, a prototypical H 2 S-generating agent, were described as activators of Kv7 potassium channels (Testai et al, 2015;Martelli et al, 2013a), a class of the voltage-gated potassium channels which plays a pivotal role in pain modulation (Zheng et al, 2013;Busserolles et al, 2016). A decreased expression of Kv7 channels contributes to neuropathic hyperalgesia (Rose et al, 2011) since channel activation inhibits C and Ad fibermediated responses of dorsal horn neurons (Passmore et al, 2003) and reduces the ectopic generation of action potentials in neuropathic pain (Lang et al, 2008).…”