Activation of Peripheral KCNQ Channels Attenuates Inflammatory Pain

Abstract

BackgroundRefractory chronic pain dramatically reduces the quality of life of patients. Existing drugs cannot fully achieve effective chronic pain control because of their lower efficacy and/or accompanying side effects. Voltage-gated potassium channels (KCNQ) openers have demonstrated their analgesic effect in preclinical and clinical studies, and are thus considered to be a potential therapeutic target as analgesics. However, these drugs exhibit a narrow therapeutic window due to their imposed central nerve system (CNS) side effects. To clarify the analgesic effect by peripheral KCNQ channel activation, we investigated whether the analgesic effect of the KCNQ channel opener, retigabine, is inhibited by intracerebroventricular (i.c.v.) administration of the KCNQ channel blocker, 10, 10-bis (4-Pyridinylmethyl)-9(10H) -anthracenone dihydrochloride (XE-991) in rats.ResultsOral administration (p.o.) of retigabine showed an anticonvulsant effect on maximal electronic seizures and an analgesic effect on complete Freund’s adjuvant-induced thermal hyperalgesia. However, impaired motor coordination and reduced exploratory behavior were also observed at the analgesic doses of retigabine. Administration (i.c.v.) of XE-991 reversed the retigabine-induced anticonvulsant effect, impaired motor coordination and reduced exploratory behavior but not the analgesic effect. Moreover, intraplantar administration of retigabine or an additional KCNQ channel opener, N-(6-Chloro-pyridin-3-yl)-3,4-difluoro-benzamide (ICA-27243), inhibited formalin-induced nociceptive behavior.ConclusionsOur findings suggest that the peripheral sensory neuron is the main target for KCNQ channel openers to induce analgesia. Therefore, peripheral KCNQ channel openers that do not penetrate the CNS may be suitable analgesic drugs as they would prevent CNS side effects.

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

“…Importantly, XE991 reverted H 2 S donors effects at dosages that did not modify oxaliplatinhypersensitivity per se (present data). Furthermore, XE991 did not show anti-nociceptive properties since it did not modify the normal pain threshold of naïve animals (Blackburn-Munro and Jensen, 2003;Hayashi et al, 2014). These data led us to hypothesize that H 2 S, by activating Kv7 channels, reduces neuronal hyperexcitability both in DRG and in central neurons, thus normalizing the altered electrophysiological activity occurring during chemotherapyinduced neuropathic pain (Di Cesare Mannelli et al, 2015b).…”

Antinociceptive Efficacy of Retigabine in the Monosodium Lodoacetate Rat Model for Osteoarthritis Pain

“…The Kv7 channel opening activity may produce an analgesic effect by blocking action potentials throughout the CNS and peripheral nerves. Recent studies have shown that peripheral sensory neurons may be the main target through which retigabine induces analgesia [28]. …”

Suppression of KCNQ/M Potassium Channel in Dorsal Root Ganglia Neurons Contributes to the Development of Osteoarthritic Pain

“…Coassembled KCNQ2 and KCNQ3 subunits were originally identified as components of the classic M channel [4]. KCNQ2/Q3 channels are expressed at a number of key locations in the pain transmission pathway, including the cerebral cortex, the spinal cord and the nociceptive dorsal root ganglia (DRG) neurons [5]. Functional studies have shown that firing in these neurons can be inhibited by a KCNQ2/Q3 activator.…”