title: Selective Activation of Nociceptor TRPV1 Channel and Reversal of Inflammatory Pain in Mice by a Novel Coumarin Derivative Muralatin L from Murraya alata.
abstract: Coumarin and its derivatives are fragrant natural compounds isolated from the genus Murraya that are flowering plants widely distributed in East Asia, Australia, and the Pacific Islands. Murraya plants have been widely used as medicinal herbs for relief of pain, such as headache, rheumatic pain, toothache, and snake bites. However, little is known about their analgesic components and the molecular mechanism underlying pain relief. Here, we report the bioassay-guided fractionation and identification of a novel coumarin derivative, named muralatin L, that can specifically activate the nociceptor transient receptor potential vanilloid 1 (TRPV1) channel and reverse the inflammatory pain in mice through channel desensitization. Muralatin L was identified from the active extract of Murraya alata against TRPV1 transiently expressed in HEK-293T cells in fluorescent calcium FlexStation assay. Activation of TRPV1 current by muralatin L and its selectivity were further confirmed by whole-cell patch clamp recordings of TRPV1-expressing HEK-293T cells and dorsal root ganglion neurons isolated from mice. Furthermore, muralatin L could reverse inflammatory pain induced by formalin and acetic acid in mice but not in TRPV1 knock-out mice. Taken together, our findings show that muralatin L specifically activates TRPV1 and reverses inflammatory pain, thus highlighting the potential of coumarin derivatives from Murraya plants for pharmaceutical and medicinal applications such as pain therapy.
authors.affiliation: From the Department of Neurobiology and Neuroscience Research Institute, School of Basic Medical Sciences, Peking University Health Science Center.
authors.forename: Ning-Ning
authors.initials: NN
authors.lastname: Wei
authors.affiliation: the State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191.
authors.forename: Hai-Ning
authors.initials: HN
authors.lastname: Lv
authors.affiliation: the Department of Molecular and Cellular Pharmacology, IDG/McGovern Institute for Brain Research, Peking University School of Pharmaceutical Sciences, Beijing 100191.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wu
authors.affiliation: the Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, Yunnan, and.
authors.forename: Shi-Long
authors.initials: SL
authors.lastname: Yang
authors.affiliation: the Department of Pharmacology, Qingdao University School of Pharmacy, Qingdao 266021, China.
authors.forename: Xiao-Ying
authors.initials: XY
authors.lastname: Sun
authors.affiliation: the Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, Yunnan, and.
authors.forename: Ren
authors.initials: R
authors.lastname: Lai
authors.affiliation: the State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, yongjiang@bjmu.edu.cn.
authors.forename: Yong
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: From the Department of Neurobiology and Neuroscience Research Institute, School of Basic Medical Sciences, Peking University Health Science Center, the Department of Molecular and Cellular Pharmacology, IDG/McGovern Institute for Brain Research, Peking University School of Pharmaceutical Sciences, Beijing 100191, the Department of Pharmacology, Qingdao University School of Pharmacy, Qingdao 266021, China wangkw@bjmu.edu.cn.
authors.forename: KeWei
authors.initials: K
authors.lastname: Wang
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D002211:Capsaicin / Q000494:pharmacology / Q000627:therapeutic use; D003374:Coumarins / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D005727:Ganglia, Spinal / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000188:drug therapy*; D015640:Ion Channel Gating / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008958:Models, Molecular; D008969:Molecular Sequence Data; D032101:Murraya / Q000737:chemistry*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009619:Nociceptors / Q000378:metabolism*; D010146:Pain / Q000150:complications / Q000188:drug therapy*; D051381:Rats; D050916:TRPV Cation Channels / Q000819:agonists / Q000737:chemistry / Q000378:metabolism*
chemical_list: D003374:Coumarins; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; C000607589:muralatin L; D002211:Capsaicin; D002118:Calcium
keywords: calcium; calcium imaging; drug discovery; drug screening; ion channel; neuron; pain; transient receptor potential channels (TRP channels)