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

Abstract

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.

Activation of Neuronal Voltage-Gated Potassium Kv7/KCNQ/M-Current by a Novel Channel Opener SCR2682 for Alleviation of Chronic Pain

“…We further examined the effect of SCR2682 on mechanical allodynia and thermal hyperalgesia in CFA-induced inflammatory pain in rats. As shown in Figure 2A and B, subcutaneous (s.c.) injection of CFA resulted in development of hypersensitivity to both mechanical and thermal stimuli at 24 h after the injection, and the hyperalgesic effect was observed and maintained for 5 days before a slow recovery over time to baseline, consistent with our previous observations (Teng et al, 2016). In contrast, administrations of SCR2682 at different concentrations (0.5, 1 and 2 mg/kg, i.p.)…”

“…Rats in the sham control group underwent the same procedures, except saline injected into the right hindpaw (Teng et al, 2016). SCR2682 (0.5, 1 and 2 mg/kg, i.p.)…”

M‐type K+ channels in peripheral nociceptive pathways

“…Acrylamides share the site of action and specificity profile with retigabine (Bentzen et al, ) and display analgesic efficacy in rodent models of migraine (Wu et al, ), inflammatory and neuropathic pain (Wu et al, ). A QO series of openers is based on pyrazolo[1,5‐a]pyrimidin‐7(4H)‐one (Jia et al, ; Qi et al, ; Zhang et al, ; Teng et al, ); the lead compound, QO‐58 (and QO‐58‐lysine, which has improved bioavailability), has analgesic efficacy in neuropathic and inflammatory pain models (Zhang et al, ; Teng et al, ). QO‐58 potentiates all K v 7 channels except K v 7.3.…”

KCNQ2/3/5 channels in dorsal root ganglion neurons can be therapeutic targets of neuropathic pain in diabetic rats

“…Activation of KCNQ channels has proven to be effective on reducing pain in peripheral nerve injury and inflammation models. 9 , 10 …”