Activation of neuronal Kv7/KCNQ/M-channels by the opener QO58-lysine and its anti-nociceptive effects on inflammatory pain in rodents.
OBJECTIVE
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 dose-dependent activation of Kv7.2/Kv7.3 currents with an EC50 of 1.2±0.2 μmol/L. QO58-lysine caused a leftward shift of the voltage-dependent activation of Kv7.2/Kv7.3 to a hyperpolarized potential at V1/2=-54.4±2.5 mV from V1/2=-26.0±0.6 mV. The half-life in plasma (t1/2) 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).


CONCLUSIONS
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.
Shenzhen-Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen 518036, China.
Bo-Chuan
BC
Teng
Department of Molecular and Cellular Pharmacology, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
Yan
Y
Song
Department of Biochemistry, Hebei Medical University, Shijiazhuang 050017, China.
Fan
F
Zhang
Department of Molecular and Cellular Pharmacology, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
Tian-Yang
TY
Ma
Department of Pharmacology, Hebei Medical University, Shijiazhuang 050017, China.
Jin-Long
JL
Qi
Department of Pharmacology, Hebei Medical University, Shijiazhuang 050017, China.
Hai-Lin
HL
Zhang
Shenzhen-Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen 518036, China.
Gang
G
Li
Shenzhen-Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen 518036, China.|Department of Molecular and Cellular Pharmacology, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.|Department of Pharmacology, Qingdao University School of Pharmacy, Qingdao 266021, China.
KeWei
K
Wang
D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D001682:Biological Availability; D002219:Carbamates / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D051656:KCNQ Potassium Channels / Q000819:agonists*; D008239:Lysine / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D010147:Pain Measurement / Q000187:drug effects*; D010655:Phenylenediamines / Q000494:pharmacology; D051381:Rats
C112297:10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone; D000873:Anthracenes; D002219:Carbamates; D051656:KCNQ Potassium Channels; D010655:Phenylenediamines; C101866:ezogabine; D008239:Lysine