Furanocoumarins Are a Novel Class of Modulators for the Transient Receptor Potential Vanilloid Type 1 (TRPV1) Channel*

Background: Furanocoumarin imperatorin is a major active component of Angelica dahurica root extracts exhibiting analgesic properties. Results: Imperatorin inhibited formalin- and capsaicin-induced nocifensive responses, facilitated TRPV1 desensitization, and sensitized TRPV1 to acid activation. Conclusion: Furanocoumarins represent a novel class of TRPV1 partial agonists exhibiting analgesic potential. Significance: Imperatorin is a lead compound for drug discovery aimed at developing new analgesics. 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 Nav1.7, 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.

• Publication year

  2014

• Venue

  Journal of Biological Chemistry

• Publication date

  2014-02-25

• Fields of study

  Medicine, Chemistry

• Identifiers
  DOI 10.1074/jbc.M113.536862PMID 24569998PMCID PMC3975010
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Structural modeling and identification of imperatorin as novel L-type calcium channel blocker.

  2013cited by this paper
• Transient receptor potential channels - emerging novel drug targets for the treatment of pain.

  2013cited by this paper
• Tetraspanin proteins promote multiple cancer stages

  2013cited by this paper
• Mapping the Binding Site of TRPV1 on AKAP79: Implications for Inflammatory Hyperalgesia

  2013cited by this paper
• Regulation of transient receptor potential channels by the phospholipase C pathway.

  2013cited by this paper
• Targeting TRP channels for pain relief.

  2013cited by this paper
• Suppression of voltage-gated Na(+) channels and neuronal excitability by imperatorin.

  2013cited by this paper
• TRP channels and analgesia.

  2013cited by this paper
• Promiscuous Activation of Transient Receptor Potential Vanilloid 1 (TRPV1) Channels by Negatively Charged Intracellular Lipids

  2013cited by this paper
• Pharmacology of Modality-Specific Transient Receptor Potential Vanilloid-1 Antagonists That Do Not Alter Body Temperature

  2012cited by this paper
• Mechanisms controlling neurite outgrowth in a pheochromocytoma cell line: The role of TRPC channels

  2012cited by this paper
• The NaV1.7 sodium channel: from molecule to man

  2012cited by this paper
• Inducible nitric oxide synthase and cyclooxygenase-2 participate in anti-inflammatory activity of imperatorin from Glehnia littoralis.

  2012cited by this paper
• Crystal Structure of the Calcium Release–Activated Calcium Channel Orai

  2012cited by this paper
• Suppression of inflammatory and neuropathic pain by uncoupling CRMP-2 from the presynaptic Ca2+ channel complex

  2011cited by this paper
• Complex regulation of TRPV1 and related thermo-TRPs: implications for therapeutic intervention.

  2011cited by this paper
• Capsaicin patch (Qutenza) for postherpetic neuralgia.

  2011cited by this paper
• Bromoenol Lactone Inhibits Voltage-Gated Ca2+ and Transient Receptor Potential Canonical Channels

  2011cited by this paper
• Sodium channels in normal and pathological pain.

  2010cited by this paper
• Ion channels as novel therapeutic targets in the treatment of pain

  2010cited by this paper
• TRP channels and pain.

  2009cited by this paper
• Anticonvulsant and acute neurotoxic effects of imperatorin, osthole and valproate in the maximal electroshock seizure and chimney tests in mice: a comparative study.

  2009cited by this paper
• Rapid separation and identification of furocoumarins in Angelica dahurica by high-performance liquid chromatography with diode-array detection, time-of-flight mass spectrometry and quadrupole ion trap mass spectrometry.

  2009cited by this paper
• TRPV1 shows dynamic ionic selectivity during agonist stimulation

  2008cited by this paper
• Tarantula Huwentoxin-IV Inhibits Neuronal Sodium Channels by Binding to Receptor Site 4 and Trapping the Domain II Voltage Sensor in the Closed Configuration*

  2008cited by this paper
• Homologous and heterologous desensitization of capsaicin and mustard oil responses utilize different cellular pathways in nociceptors

  2008cited by this paper
• Influence of TRPV1 on diabetes-induced alterations in thermal pain sensitivity

  2008cited by this paper
• TRPA1 mediates formalin-induced pain

  2007cited by this paper
• Morphological and immunohistochemical characterization of the trigeminal ganglion neurons innervating the cornea and upper eyelid of the rat.

  2007cited by this paper
• The vanilloid receptor TRPV1: 10 years from channel cloning to antagonist proof-of-concept

  2007cited by this paper
• An SCN9A channelopathy causes congenital inability to experience pain

  2006cited by this paper
• Prolactin Modulates TRPV1 in Female Rat Trigeminal Sensory Neurons

  2006cited by this paper
• Eye-wiping test: a sensitive animal model for acute trigeminal pain studies.

  2005cited by this paper
• Natural medicine: the genus Angelica.

  2004cited by this paper
• Preparative isolation and purification of coumarins from Angelica dahurica (Fisch. ex Hoffn) Benth, et Hook. f (Chinese traditional medicinal herb) by high-speed counter-current chromatography.

  2004cited by this paper
• Inhibitory effects of furanocoumarins isolated from the roots of Angelica dahurica on prostaglandin E2 production.

  2003cited by this paper
• Molecular basis for species-specific sensitivity to "hot" chili peppers.

  2002cited by this paper
• Bradykinin and nerve growth factor release the capsaicin receptor from PtdIns(4,5)P2-mediated inhibition

  2001cited by this paper
• Induction of vanilloid receptor channel activity by protein kinase C

  2000cited by this paper
• Immunocytochemical localization of the vanilloid receptor 1 (VR1): relationship to neuropeptides, the P2X3 purinoceptor and IB4 binding sites

  1999cited by this paper
• The formalin test in mice: dissociation between inflammatory and non‐inflammatory pain

  1987cited by this paper
• A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia

  1987influential reference
• The formalin test: A quantitative study of the analgesic effects of morphine, meperidine, and brain stem stimulation in rats and cats

  1977cited by this paper
• Sensory effects of capsaicin congeners I. Relationship between chemical structure and pain-producing potency of pungent agents.

  1975cited by this paper

• Advances in the Study for Modulators of Transient Receptor Potential Vanilloid (TRPV) Channel Family.

  2025cites this paper
• Rapid characterization of the constituents in Jingfang Granules by ultra-high performance liquid chromatography with quadrupole time-of-flight mass spectrometry.

  2025cites this paper
• Imperatorin activates TRPV1/GRPR pathway to induce scratching behaviors in mice.

  2025cites this paper
• Human assembloid model of the ascending neural sensory pathway

  2025cites this paper
• TRPC1 downregulation enhances catecholamine secretion in adrenal chromaffin cells under metabolic syndrome conditions.

  2025cites this paper
• Umbelliferone presents orofacial antinociceptive and anti-inflammatory activity via reduction of TNF-α in mice.

  2025cites this paper
• New options for targeting TRPV1 receptors for cancer treatment: odorous Chinese herbal medicine

  2025cites this paper
• Phytochemical-based therapeutics from traditional eastern medicine: analgesic effects and ion channel modulation

  2025cites this paper
• Sens-ocular model: Cell-based assay to evaluate eye stinging potential of chemicals and baby cosmetic formulations.

  2024cites this paper
• Genomic and metabolomic insights into the selection and differentiation of bioactive compounds in citrus.

  2024cites this paper
• Clinical Efficacy of Hexue Tongbi Formula on Oxaliplatin-Induced Peripheral Neuropathy: A Randomized Controlled Study

  2024cites this paper
• A systematic review on botany, ethnopharmacology, phytochemistry and pharmacology of Potentilla anserina L.

  2024cites this paper
• Exploration and structure-activity relationship research of benzenesulfonamide derivatives as potent TRPV4 inhibitors for treating acute lung injury.

  2024cites this paper
• TRPV1 analgesics disturb core body temperature via a biased allosteric mechanism involving conformations distinct from that for nociception.

  2024cites this paper
• Impact of TRP Channels in Oral Pathology and Therapeutic Targeting Options: A Narrative Review.

  2023cites this paper
• Ultrasonic assisted extraction of coumarins from Angelicae Pubescentis Radix by betaine-based natural deep eutectic solvents

  2023cites this paper
• Exploring the scientific rationality of “Different dosage forms of the same prescription” base on Q-markers of pulvis and pill of Chuanxiong Chatiao Prescription

  2023cites this paper
• A review of the historical records, chemistry, pharmacology, pharmacokinetics and edibility of Angelica dahurica

  2023cites this paper
• Dihydroceramides Derived from Bacteroidetes Species Sensitize TRPV1 Channels

  2023cites this paper
• Neuropathic ocular surface pain: Emerging drug targets and therapeutic implications

  2022cites this paper
• Molecular Mechanism of the Saposhnikovia divaricata–Angelica dahurica Herb Pair in Migraine Therapy Based on Network Pharmacology and Molecular Docking

  2022cites this paper
• Research progress and challenges of TRPV1 channel modulators as a prospective therapy for diabetic neuropathic pain.

  2022cites this paper
• Regulation of transient receptor potential channels by traditional Chinese medicines and their active ingredients

  2022cites this paper
• The Angelica dahurica: A Review of Traditional Uses, Phytochemistry and Pharmacology

  2022cites this paper
• Desensitization of TRPV1 Involved in the Antipruritic Effect of Osthole on Histamine-Induced Scratching Behavior in Mice

  2021cites this paper
• Capsaicin and TRPV1 Channels in the Cardiovascular System: The Role of Inflammation

  2021cites this paper
• Imperatorin: A review of its pharmacology, toxicity and pharmacokinetics.

  2020cites this paper
• Herbal Medicine and Local Acupuncture Point Stimulation Administration and Their Clinical Effect on Quality of Life for Cervicogenic Dizziness (CGD) Patient: A CARE Guideline Compliant Case Report

  2020cites this paper
• Corneal Nerve abnormalities in ocular and systemic diseases.

  2020cites this paper
• Modulation of TRPV1 channel function by natural products in the treatment of pain.

  2020cites this paper
• Dual opposing actions of STW 5 on TRP receptors mediate neuronal desensitisation in vitro.

  2020cites this paper
• Blood-to-Retina Transport of Imperatorin Involves the Carrier-Mediated Transporter System at the Inner Blood-Retinal Barrier.

  2019cites this paper
• Coumarins as potential supportive medication for the treatment of epilepsy.

  2019cites this paper
• Ameliorative effect of imperatorin in chemically induced fibromyalgia: Role of NMDA/NFkB mediated downstream signaling.

  2019cites this paper
• Biomolecular Targets of Oxyprenylated Phenylpropanoids and Polyketides.

  2019cites this paper
• Chinese herbal medicine for headache: A systematic review and meta-analysis of high-quality randomized controlled trials.

  2019cites this paper
• Long-Term Diabetic Microenvironment Augments the Decay Rate of Capsaicin-Induced Currents in Mouse Dorsal Root Ganglion Neurons

  2019cites this paper
• Sterically induced conformational restriction: Discovery and preclinical evaluation of novel pyrrolo[3,2-d]pyrimidines as microtubule targeting agents.

  2018cites this paper
• Anti-inflammatory activity of prenyl and geranyloxy furanocoumarins from Citrus garrawayi (Rutaceae)

  2018cites this paper
• Sensitive skin: review of an ascending concept*

  2017cites this paper
• Pellitorine, an extract of Tetradium daniellii, is an antagonist of the ion channel TRPV1.

  2017cites this paper
• Antagonism of human formyl peptide receptor 1 with natural compounds and their synthetic derivatives.

  2016cites this paper
• Osthole inhibits histamine-dependent itch via modulating TRPV1 activity

  2016cites this paper
• The Potential of Traditional Chinese Medicine in the Treatment and Modulation of Pain.

  2016cites this paper
• Determination of coumarins in the roots of Angelica dahurica by supercritical fluid chromatography.

  2016cites this paper
• Inhibitory effect of imperatorin on insulin-like growth factor-1-induced sebum production in human sebocytes cultured in vitro.

  2016cites this paper
• Hendersine A, a novel isoquinoline alkaloid from Corydalis hendersonii

  2016cites this paper
• Selective Activation of Nociceptor TRPV1 Channel and Reversal of Inflammatory Pain in Mice by a Novel Coumarin Derivative Muralatin L from Murraya alata*

  2015influential citation
• A pharmacological basis of herbal medicines for epilepsy.

  2015cites this paper
• A Multicenter, Double-Blind, Randomized, Placebo-Controlled Trial to Evaluate the Efficacy and Safety of Duliang Soft Capsule in Patients with Chronic Daily Headache

  2015cites this paper
• Inhibitory effects of imperatorin on voltage-gated K^+ channels and ATP-sensitive K^+ channels

  2015cites this paper
• Mechanisms underlying capsaicin effects in canine coronary artery: implications for coronary spasm.

  2014cites this paper
• The Therapeutic Effects of HexueTongbi to Combat the Oxaliplatin-Induced Peripheral Neuropathy Using Network Analysis in Rats

  year unknowncites this paper