KCNQ Channels in Nociceptive Cold-Sensing Trigeminal Ganglion Neurons as Therapeutic Targets for Treating Orofacial Cold Hyperalgesia

Abstract

BackgroundHyperexcitability of nociceptive afferent fibers is an underlying mechanism of neuropathic pain and ion channels involved in neuronal excitability are potentially therapeutic targets. KCNQ channels, a subfamily of voltage-gated K+ channels mediating M-currents, play a key role in neuronal excitability. It is unknown whether KCNQ channels are involved in the excitability of nociceptive cold-sensing trigeminal afferent fibers and if so, whether they are therapeutic targets for orofacial cold hyperalgesia, an intractable trigeminal neuropathic pain.MethodsPatch-clamp recording technique was used to study M-currents and neuronal excitability of cold-sensing trigeminal ganglion neurons. Orofacial operant behavioral assessment was performed in animals with trigeminal neuropathic pain induced by oxaliplatin or by infraorbital nerve chronic constrictive injury.ResultsWe showed that KCNQ channels were expressed on and mediated M-currents in rat nociceptive cold-sensing trigeminal ganglion (TG) neurons. The channels were involved in setting both resting membrane potentials and rheobase for firing action potentials in these cold-sensing TG neurons. Inhibition of KCNQ channels by linopirdine significantly decreased resting membrane potentials and the rheobase of these TG neurons. Linopirdine directly induced orofacial cold hyperalgesia when the KCNQ inhibitor was subcutaneously injected into rat orofacial regions. On the other hand, retigabine, a KCNQ channel potentiator, suppressed the excitability of nociceptive cold-sensing TG neurons. We further determined whether KCNQ channel could be a therapeutic target for orofacial cold hyperalgesia. Orofacial cold hyperalgesia was induced in rats either by the administration of oxaliplatin or by infraorbital nerve chronic constrictive injury. Using the orofacial operant test, we showed that retigabine dose-dependently alleviated orofacial cold hyperalgesia in both animal models.ConclusionTaken together, these findings indicate that KCNQ channel plays a significant role in controlling cold sensitivity and is a therapeutic target for alleviating trigeminal neuropathic pain that manifests orofacial cold hyperalgesia.

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

“…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). Moreover, flupirtine, a retigabine-analogue also acting as a Kv7 activator (Martire et al, 2004) suppressed axonal hyperexcitability of peripheral nerve exposed to oxaliplatin (Sittl et al, 2010).…”

Electrophysiological properties of lumbosacral primary afferent neurons innervating urothelial and non-urothelial layers of mouse urinary bladder

“…Isolation of Na + or K + currents was not performed in this study. To examine M-currents in bladder DRG neurons, deactivating tail currents were measured following the voltage step of −20 mV as described previously [35]. …”

Silent cold-sensing neurons drive cold allodynia in neuropathic pain states

“…The KCNQ voltage-gated potassium channel activators retigabine and flupirtine have been shown to reduce cold allodynia evoked by oxaliplatin and nerve injury. 77,78 Selectivity of these compounds remains a problem and could be overcome using gene therapy. AAV-mediated overexpression of KV1.2 RNA impairs the development of cold allodynia induced by nerve injury in rats.…”