A novel and potent neuronal Kv7 channel opener SCR2682 alleviates chronic pain in rats

Activation of neuronal Kv7/KCNQ/M‐current emerges as an effective intervention for treatment of hyperexcitability‐related neurological diseases including chronic pain that is prevalent and unmet medical need. The aim of this study was to evaluate the anti‐nociceptive effects of a novel and potent Kv7/KCNQ/M channel opener SCR2682 on chronic pain in rats. The pharmacological effects of SCR2682 on native M current and firing of dorsal root ganglia (DRG) neurons were examined using electrophysiological recordings. Two in vivo rat models of complete Freund’s adjuvant (CFA)‐induced inflammatory pain and spared nerve injury (SNI)‐induced neuropathic pain were used to evaluate anti‐nociceptive effects of SCR2682 by measuring the paw withdrawal mechanical threshold (PWMT) and/or thermal latency (PWTL). Locomotor activity in normal rats was tested for safety evaluation. The expression of KCNQ2 in L4 and L5 DRGs of rat SNI model was detected by quantitative RT‐PCR and western blot. We found that SCR2682 (0.1 μM) or an FDA approved anti‐epileptic drug retigabine (RTG) (10 μM) increased M current in rat DRG neurons approximately 30%, which was blocked by Kv7 channel inhibitor XE991 (3 μM). SCR2682 caused the resting membrane potential (RMP) hyperpolarization to −66.4 ± 3.7 mV from −56.7 ± 2.8 mV. Current clamp recordings revealed that perfusion of SCR2682 abolished the firing spikes of DRG neurons. In rat model of CFA‐induced inflammatory pain, intraperitoneal (i.p.) administration of SCR2682 at doses of 0.5, 1 and 2 mg/kg increased the PWMT and PWTL in a dose‐dependent manner, as compared with RTG (7 mg/kg) that also increased the PWMT and PWTL. In the model of SNI‐induced neuropathic pain, SCR2682 (0.5, 1 and 2 mg/kg) or RTG (7 mg/kg) increased the PWMT, and the anti‐nociceptive effect of SCR2682 (2 mg/kg) could be reversed by the channel specific blocker XE991 (3 mg/kg, i.p.). Furthermore, SCR2682 (2 mg/kg.) or RTG (7 mg/kg) significantly increased the expression of KCNQ2 mRNA and protein in DRG of SNI rats, and co‐injection of XE991 (3 mg/kg) with SCR2682 reduced the expression levels of KCNQ2. In the open field test, there was no significant difference in the travel total distance and mean speed of rats treated with RTG (7 mg/kg) or SCR2682 (0.5, 1 and 2 mg/kg). Taken together, our data show that the novel compound SCR2682 reduces the excitability of DRG sensory neurons by activating Kv7 channel, and intraperitoneal administration of SCR2682 alleviates chronic pain in rats. Support or Funding Information This project was supported by grants awarded to K.W. from National Natural Sciences Foundation of China (81573410) and the Ministry of Science and Technology of China (2018ZX09711001‐004‐006) and Science and Technology Program of Guangdong (2018B030334001).