title: KCNQ channels in nociceptive cold-sensing trigeminal ganglion neurons as therapeutic targets for treating orofacial cold hyperalgesia.
abstract: BACKGROUND
  Hyperexcitability of nociceptive afferent fibers is an underlying mechanism of neuropathic pain and ion channels involved in neuronal excitability are potentially therapeutic targets. KCNQ channels, a subfamily of voltage-gated K(+) channels mediating M-currents, play a key role in neuronal excitability. It is unknown whether KCNQ channels are involved in the excitability of nociceptive cold-sensing trigeminal afferent fibers and if so, whether they are therapeutic targets for orofacial cold hyperalgesia, an intractable trigeminal neuropathic pain.
  
  
  METHODS
  Patch-clamp recording technique was used to study M-currents and neuronal excitability of cold-sensing trigeminal ganglion neurons. Orofacial operant behavioral assessment was performed in animals with trigeminal neuropathic pain induced by oxaliplatin or by infraorbital nerve chronic constrictive injury.
  
  
  RESULTS
  We showed that KCNQ channels were expressed on and mediated M-currents in rat nociceptive cold-sensing trigeminal ganglion (TG) neurons. The channels were involved in setting both resting membrane potentials and rheobase for firing action potentials in these cold-sensing TG neurons. Inhibition of KCNQ channels by linopirdine significantly decreased resting membrane potentials and the rheobase of these TG neurons. Linopirdine directly induced orofacial cold hyperalgesia when the KCNQ inhibitor was subcutaneously injected into rat orofacial regions. On the other hand, retigabine, a KCNQ channel potentiator, suppressed the excitability of nociceptive cold-sensing TG neurons. We further determined whether KCNQ channel could be a therapeutic target for orofacial cold hyperalgesia. Orofacial cold hyperalgesia was induced in rats either by the administration of oxaliplatin or by infraorbital nerve chronic constrictive injury. Using the orofacial operant test, we showed that retigabine dose-dependently alleviated orofacial cold hyperalgesia in both animal models.
  
  
  CONCLUSIONS
  Taken together, these findings indicate that KCNQ channel plays a significant role in controlling cold sensitivity and is a therapeutic target for alleviating trigeminal neuropathic pain that manifests orofacial cold hyperalgesia.
authors.affiliation: Department of Anesthesiology and the Graduate Program in Neuroscience, The University of Cincinnati College of Medicine, PO Box 670531, 231 Albert Sabin Way, Cincinnati, OH, 45267-0531, USA. alaaawny@hotmail.com.|Department of Anesthesiology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA. alaaawny@hotmail.com.
authors.forename: Alaa A
authors.initials: AA
authors.lastname: Abd-Elsayed
authors.affiliation: Department of Anesthesiology and the Graduate Program in Neuroscience, The University of Cincinnati College of Medicine, PO Box 670531, 231 Albert Sabin Way, Cincinnati, OH, 45267-0531, USA. kneeikeda@gmail.com.|Department of Orthopedic Surgery, Jikei University School of Medicine, 3-25-8 Nishi-Shinbashi, Minato-ku, Tokyo, 105-8461, Japan. kneeikeda@gmail.com.
authors.forename: Ryo
authors.initials: R
authors.lastname: Ikeda
authors.affiliation: Department of Anesthesiology and the Graduate Program in Neuroscience, The University of Cincinnati College of Medicine, PO Box 670531, 231 Albert Sabin Way, Cincinnati, OH, 45267-0531, USA. jia_zf75@hotmail.com.|Department of Pharmacology, Hebei Medical University, 361 East Zhongshan Road, Shijiazhuang, 050017, Hebei, China. jia_zf75@hotmail.com.
authors.forename: Zhanfeng
authors.initials: Z
authors.lastname: Jia
authors.affiliation: Department of Anesthesiology and Perioperative Medicine, College of Medicine, University of Alabama at Birmingham, 901 19th Street South, BMR II 210, Birmingham, AL, 35294, USA. jling1964@gmail.com.|Department of Anesthesiology and the Graduate Program in Neuroscience, The University of Cincinnati College of Medicine, PO Box 670531, 231 Albert Sabin Way, Cincinnati, OH, 45267-0531, USA. jling1964@gmail.com.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Ling
authors.affiliation: Department of Anesthesiology and the Graduate Program in Neuroscience, The University of Cincinnati College of Medicine, PO Box 670531, 231 Albert Sabin Way, Cincinnati, OH, 45267-0531, USA. zxzlavender@yahoo.com.cn.
authors.forename: Xiaozhuo
authors.initials: X
authors.lastname: Zuo
authors.affiliation: Department of Neuroscience and High Throughput Biology Center, Johns Hopkins University School of Medicine, 733 N. Broadway 311 BRB, Baltimore, MD, 21205, USA. min.x.li@gsk.com.|GlaxoSmithKline, New York, NY, USA. min.x.li@gsk.com.
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Anesthesiology and Perioperative Medicine, College of Medicine, University of Alabama at Birmingham, 901 19th Street South, BMR II 210, Birmingham, AL, 35294, USA. gujo@uab.edu.|Department of Anesthesiology and the Graduate Program in Neuroscience, The University of Cincinnati College of Medicine, PO Box 670531, 231 Albert Sabin Way, Cincinnati, OH, 45267-0531, USA. gujo@uab.edu.
authors.forename: Jianguo G
authors.initials: JG
authors.lastname: Gu
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002219:Carbamates / Q000494:pharmacology; D002908:Chronic Disease; D003080:Cold Temperature; D003250:Constriction; D004195:Disease Models, Animal; D005145:Face; D006930:Hyperalgesia / Q000378:metabolism* / Q000503:physiopathology / Q000628:therapy*; D051656:KCNQ Potassium Channels / Q000378:metabolism*; D008297:Male; D058990:Molecular Targeted Therapy; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D059225:Nociception; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D010655:Phenylenediamines / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D013697:Thermosensing; D012668:Trigeminal Ganglion / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology
chemical_list: D002219:Carbamates; D051656:KCNQ Potassium Channels; D009944:Organoplatinum Compounds; D010655:Phenylenediamines; D000077150:Oxaliplatin; C101866:ezogabine