Activation of peripheral KCNQ channels attenuates inflammatory pain

Molecular Pain

Tatsumi Matsumoto¹  Noboru Tsuchimori¹  Masashi Iwata¹  Hiroki Hayashi¹ 

[1] Pharmaceutical Research Division, Inflammation Drug Discovery Unit, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan

关键词: Inflammatory pain;    XE-991;    ICA-27243;    Retigabine;    KCNQ;   

Others  :  861795
DOI  :  10.1186/1744-8069-10-15

 received in 2013-10-28, accepted in 2014-02-10,  发布年份 2014

【 摘 要 】

Background

Refractory 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.

Results

Oral 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.

Conclusions

Our 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.

【 授权许可】

   
2014 Hayashi et al.; licensee BioMed Central Ltd.

【 图 表 】

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