title: Evodiamine suppresses capsaicin-induced thermal hyperalgesia through activation and subsequent desensitization of the transient receptor potential V1 channels.
abstract: Evodiae fructus (EF), a fruit of Evodia rutaecarpa Bentham, has long been used as an analgesic drug in traditional Chinese and Japanese medicine. However, the underlying molecular mechanism of its pharmacological action is unclear. Here, using calcium imaging, whole-cell patch-clamp recording, and behavioral analysis, we investigated the pharmacological action of EF and its principal compound, evodiamine, on the transient receptor potential (TRP) V1 channels. Dorsal root ganglion (DRG) neurons and TRPV1- or TRPA1-transfected human embryonic kidney-derived (HEK) 293 cells were used for calcium imaging or whole-cell patch-clamp recording. Twenty male adult Sprague-Dawley rats were used for the capsaicin-induced thermal hyperalgesia behavioral analyses. We found that evodiamine induced significant increases in intracellular calcium and robust inward currents in a subpopulation of isolated rat DRG neurons, most of which were also sensitive to capsaicin. The effect of evodiamine was completely blocked by capsazepine, a competitive antagonist of TRPV1. Evodiamine induced significant inward currents in TRPV1-, but not TRPA1-transfected HEK293 cells. Pretreatment with evodiamine reduced capsaicin-induced currents significantly. Furthermore, the in vivo pre-treatment of evodiamine suppressed thermal hyperalgesia induced by intraplantar injection of capsaicin in rats. These results identify that the analgesic effect of EF and evodiamine may be due to the activation and subsequent desensitization of TRPV1 in sensory neurons.
authors.affiliation: Department of Pharmacy, School of Pharmacy, Hyogo University of Health Sciences, 1-3-6 Minatojima, Chuo-ku, Kobe, Hyogo, 6508530, Japan.
authors.forename: Emiko
authors.initials: E
authors.lastname: Iwaoka
authors.affiliation: Department of Pharmacy, School of Pharmacy, Hyogo University of Health Sciences, 1-3-6 Minatojima, Chuo-ku, Kobe, Hyogo, 6508530, Japan.|Traditional Medicine Research Center, Chinese Medicine Confucius Institute, Hyogo College of Medicine, Kobe, Hyogo, 6508530, Japan.
authors.forename: Shenglan
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Pharmacy, School of Pharmacy, Hyogo University of Health Sciences, 1-3-6 Minatojima, Chuo-ku, Kobe, Hyogo, 6508530, Japan.|FALCO Pharmacies Ltd., Kyoto, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Matsuyoshi
authors.affiliation: Department of Pharmacy, School of Pharmacy, Hyogo University of Health Sciences, 1-3-6 Minatojima, Chuo-ku, Kobe, Hyogo, 6508530, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Kogure
authors.affiliation: Department of Pharmacy, School of Pharmacy, Hyogo University of Health Sciences, 1-3-6 Minatojima, Chuo-ku, Kobe, Hyogo, 6508530, Japan.
authors.forename: Shunji
authors.initials: S
authors.lastname: Aoki
authors.affiliation: Department of Pharmacy, School of Pharmacy, Hyogo University of Health Sciences, 1-3-6 Minatojima, Chuo-ku, Kobe, Hyogo, 6508530, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamamoto
authors.affiliation: Traditional Medicine Research Center, Chinese Medicine Confucius Institute, Hyogo College of Medicine, Kobe, Hyogo, 6508530, Japan.|Department of Anatomy and Neuroscience, Hyogo College of Medicine, Nishinomiya, Hyogo, 6638501, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Noguchi
authors.affiliation: Department of Pharmacy, School of Pharmacy, Hyogo University of Health Sciences, 1-3-6 Minatojima, Chuo-ku, Kobe, Hyogo, 6508530, Japan. ydai@huhs.ac.jp.|Traditional Medicine Research Center, Chinese Medicine Confucius Institute, Hyogo College of Medicine, Kobe, Hyogo, 6508530, Japan. ydai@huhs.ac.jp.|Department of Anatomy and Neuroscience, Hyogo College of Medicine, Nishinomiya, Hyogo, 6638501, Japan. ydai@huhs.ac.jp.
authors.forename: Yi
authors.initials: Y
authors.lastname: Dai
mesh_terms: D000470:Alkaloids / Q000494:pharmacology*; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D002211:Capsaicin / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D032086:Evodia / Q000737:chemistry; D005727:Ganglia, Spinal / Q000502:physiology; D057809:HEK293 Cells; D006358:Hot Temperature; D006801:Humans; D006930:Hyperalgesia / Q000139:chemically induced / Q000378:metabolism*; D008297:Male; D008516:Medicine, Chinese Traditional; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects; D018408:Patch-Clamp Techniques; D010936:Plant Extracts / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000074025:TRPA1 Cation Channel; D050916:TRPV Cation Channels / Q000819:agonists*; D050051:Transient Receptor Potential Channels / Q000378:metabolism
chemical_list: D000470:Alkaloids; D000700:Analgesics; D015220:Calcium Channels; C406544:Gosyuyu; D009419:Nerve Tissue Proteins; D010936:Plant Extracts; D011799:Quinazolines; D011804:Quinolines; D000074025:TRPA1 Cation Channel; C473350:TRPA1 protein, human; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; D050051:Transient Receptor Potential Channels; C049639:evodiamine; C071423:capsazepine; D002211:Capsaicin; D002118:Calcium
keywords: Desensitization; Evodiamine; Goshuyu; Hyperalgesia; TRPV1; Wu-Zhu-Yu