title: The traditional Japanese medicine hangeshashinto alleviates oral ulcer-induced pain in a rat model.
abstract: OBJECTIVE
  Recent studies have demonstrated that mouthwash made with the traditional Japanese medicine hangeshashinto exhibits anti-inflammatory action and alleviates oral mucositis scores, including pain complaints, in patients undergoing chemoradiotherapy. However, no study has demonstrated the mechanism underlying how hangeshashinto provides pain relief in oral ulcers.
  
  
  METHODS
  The analgesic effects on pain-related behaviors following the topical application of hangeshashinto were evaluated in an oral ulcer rat model treated with acetic acid using recently developed methods. Indomethacin, the representative anti-inflammatory agent, was intraperitoneally administered. The tissue permeability of the oral mucosa was histologically evaluated after applying the fluorescent substance FluoroGold.
  
  
  RESULTS
  The topical application of hangeshashinto in ulcerative oral mucosa suppressed mechanical pain hypersensitivity over 60 min, without any effects on healthy mucosa. The same drug application also inhibited oral ulcer-induced spontaneous pain. Indomethacin administration failed to block the mechanical pain hypersensitivity, though it did largely block spontaneous pain. Topical anesthesia with lidocaine showed hyposensitivity to mechanical stimulation in healthy mucosa. In the ulcer regions in which the oral epithelial barrier was destroyed, deep parenchyma was stained with FluoroGold, in contrast to healthy oral mucosa, in which staining was limiting to the superficial site.
  
  
  CONCLUSIONS
  Hangeshashinto leads to long-lasting analgesic effects, specifically in the ulcer region by destroying the epithelial barrier. Hangeshashinto alleviates oral ulcer-induced pain in inflammation-dependent and/or independent manner.
authors.affiliation: Division of Physiology, Kyushu Dental University, 2-6-1 Manazuru, Kokurakita-ku, Kitakyushu, Fukuoka 803-8580, Japan.
authors.forename: Suzuro
authors.initials: S
authors.lastname: Hitomi
authors.affiliation: Division of Physiology, Kyushu Dental University, 2-6-1 Manazuru, Kokurakita-ku, Kitakyushu, Fukuoka 803-8580, Japan. Electronic address: ono@kyu-dent.ac.jp.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Ono
authors.affiliation: Division of Physiology, Kyushu Dental University, 2-6-1 Manazuru, Kokurakita-ku, Kitakyushu, Fukuoka 803-8580, Japan; Division of Dental Anesthesiology, Kyushu Dental University, 2-6-1 Manazuru, Kokurakita-ku, Kitakyushu, Fukuoka 803-8580, Japan.
authors.forename: Kiichiro
authors.initials: K
authors.lastname: Yamaguchi
authors.affiliation: Tsumura Research Laboratories, Kampo Scientific Strategies Division, Tsumura & Co., 3586 Yoshihara, Amicho, Inashiki-gun, Ibaraki 300-1192, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Terawaki
authors.affiliation: Tsumura Research Laboratories, Kampo Scientific Strategies Division, Tsumura & Co., 3586 Yoshihara, Amicho, Inashiki-gun, Ibaraki 300-1192, Japan.
authors.forename: Ryota
authors.initials: R
authors.lastname: Imai
authors.affiliation: Tsumura Research Laboratories, Kampo Scientific Strategies Division, Tsumura & Co., 3586 Yoshihara, Amicho, Inashiki-gun, Ibaraki 300-1192, Japan.
authors.forename: Kunitsugu
authors.initials: K
authors.lastname: Kubota
authors.affiliation: Tsumura Research Laboratories, Kampo Scientific Strategies Division, Tsumura & Co., 3586 Yoshihara, Amicho, Inashiki-gun, Ibaraki 300-1192, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Omiya
authors.affiliation: Tsumura Research Laboratories, Kampo Scientific Strategies Division, Tsumura & Co., 3586 Yoshihara, Amicho, Inashiki-gun, Ibaraki 300-1192, Japan.
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Hattori
authors.affiliation: Tsumura Research Laboratories, Kampo Scientific Strategies Division, Tsumura & Co., 3586 Yoshihara, Amicho, Inashiki-gun, Ibaraki 300-1192, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Kase
authors.affiliation: Division of Physiology, Kyushu Dental University, 2-6-1 Manazuru, Kokurakita-ku, Kitakyushu, Fukuoka 803-8580, Japan.
authors.forename: Kiyotoshi
authors.initials: K
authors.lastname: Inenaga
mesh_terms: D019342:Acetic Acid / Q000008:administration & dosage; D000287:Administration, Topical; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D004365:Drugs, Chinese Herbal / Q000008:administration & dosage*; D006967:Hypersensitivity / Q000188:drug therapy; D007213:Indomethacin / Q000494:pharmacology; D007564:Japan; D008012:Lidocaine / Q000494:pharmacology; D008297:Male; D009061:Mouth Mucosa / Q000166:cytology / Q000187:drug effects; D009067:Mouthwashes / Q000494:pharmacology; D019226:Oral Ulcer / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D010146:Pain / Q000188:drug therapy* / Q000209:etiology; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D013280:Stomatitis / Q000188:drug therapy / Q000473:pathology
chemical_list: D000700:Analgesics; D004365:Drugs, Chinese Herbal; D009067:Mouthwashes; C088236:hange-shashinto; D008012:Lidocaine; D019342:Acetic Acid; D007213:Indomethacin
keywords: Mechanical pain hypersensitivity; Mouth mucosa; Oral pain; Oral ulcer; Traditional Japanese (kampo) medicine