title: Furanocoumarins are a novel class of modulators for the transient receptor potential vanilloid type 1 (TRPV1) channel.
abstract: Furanocoumarin imperatorin is the major active component of Angelica dahurica root extracts, widely used in traditional medicine to treat headache, toothache, and orbital eye pain. In this study, we investigated the mechanisms that may underlie the pain-relieving effects of the compound. We found that imperatorin significantly inhibited formalin- and capsaicin-induced nocifensive responses but did not alter baseline thermal withdrawal thresholds in the rat. We established that imperatorin is a weak agonist of TRPV1, a channel implicated in detecting several noxious stimuli, exhibiting a 50% effective concentration (EC50) of 12.6 ± 3.2 μM. A specific TRPV1 antagonist, JNJ-17203212 (0.5 μM), potently inhibited imperatorin-induced TRPV1 activation. Site-directed mutagenesis studies revealed that imperatorin most likely acted via a site adjacent to or overlapping with the TRPV1 capsaicin-binding site. TRPV1 recovery from desensitization was delayed in the presence of imperatorin. Conversely, imperatorin sensitized TRPV1 to acid activation but did not affect the current amplitude and/or the activation-inactivation properties of Na(v)1.7, a channel important for transmission of nociceptive information. Thus, our data indicate that furanocoumarins represent a novel group of TRPV1 modulators that may become important lead compounds in the drug discovery process aimed at developing new treatments for pain management.
authors.affiliation: From the Departments of Cellular and Integrative Physiology and.
authors.forename: Xingjuan
authors.initials: X
authors.lastname: Chen
authors.forename: Weiyang
authors.initials: W
authors.lastname: Sun
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Gianaris
authors.forename: Ashley M
authors.initials: AM
authors.lastname: Riley
authors.forename: Theodore R
authors.initials: TR
authors.lastname: Cummins
authors.forename: Jill C
authors.initials: JC
authors.lastname: Fehrenbacher
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Obukhov
mesh_terms: D000700:Analgesics / Q000737:chemistry / Q000494:pharmacology*; D029969:Angelica / Q000737:chemistry; D000818:Animals; D003879:Dermatologic Agents / Q000737:chemistry / Q000494:pharmacology*; D011564:Furocoumarins / Q000737:chemistry / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000235:genetics / Q000378:metabolism; D059225:Nociception / Q000187:drug effects / Q000502:physiology; D059408:Pain Management / Q000379:methods; D010147:Pain Measurement; D051381:Rats; D050916:TRPV Cation Channels / Q000819:agonists* / Q000235:genetics / Q000378:metabolism
chemical_list: D000700:Analgesics; D003879:Dermatologic Agents; D011564:Furocoumarins; D062556:NAV1.7 Voltage-Gated Sodium Channel; C486866:SCN9A protein, human; C503479:Scn9a protein, mouse; C503480:Scn9a protein, rat; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; C493921:TRPV1 protein, mouse; C493922:Trpv1 protein, rat
keywords: Calcium; Calcium Imaging; Calcium Signaling; Ion Channels; TRP Channels