title: Activation of peripheral KCNQ channels attenuates inflammatory pain.
abstract: 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.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Hayashi
authors.forename: Masashi
authors.initials: M
authors.lastname: Iwata
authors.affiliation: Pharmaceutical Research Division, Inflammation Drug Discovery Unit, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan. noboru.tsuchimori@takeda.com.
authors.forename: Noboru
authors.initials: N
authors.lastname: Tsuchimori
authors.forename: Tatsumi
authors.initials: T
authors.lastname: Matsumoto
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D000927:Anticonvulsants / Q000627:therapeutic use; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use; D002219:Carbamates / Q000627:therapeutic use; D004195:Disease Models, Animal; D004558:Electric Stimulation / Q000009:adverse effects; D005106:Exploratory Behavior / Q000187:drug effects; D005557:Formaldehyde / Q000494:pharmacology; D005620:Freund's Adjuvant / Q000633:toxicity; D007839:Functional Laterality; D006930:Hyperalgesia / Q000188:drug therapy / Q000503:physiopathology; D007249:Inflammation / Q000139:chemically induced / Q000150:complications* / Q000188:drug therapy; D051656:KCNQ Potassium Channels / Q000378:metabolism*; D019957:Motor Skills Disorders / Q000188:drug therapy / Q000209:etiology; D010146:Pain / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism*; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D010655:Phenylenediamines / Q000627:therapeutic use; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats
chemical_list: C112297:10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone; D000873:Anthracenes; D000927:Anticonvulsants; D001549:Benzamides; D002219:Carbamates; D051656:KCNQ Potassium Channels; C527835:N-(6-Chloropyridin-3-yl)-3,4-difluorobenzamide; D010655:Phenylenediamines; D026902:Potassium Channel Blockers; D011725:Pyridines; C101866:ezogabine; D005557:Formaldehyde; D005620:Freund's Adjuvant