The Natural Flavonoid Naringenin Elicits Analgesia through Inhibition of NaV1.8 Voltage-Gated Sodium Channels
Autor: | May Khanna, Song Cai, David D. Scott, Yuan Zhou, Zhiming Shan, Aubin Moutal, Angie Dorame, Marcel Patek, Samantha Perez-Miller, Nancy Yen Ngan Pham, Rajesh Khanna, Liberty François-Moutal, Maria J. Serafini, Jie Yu, Kimberly Gomez, Cynthia L. Madura |
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Rok vydání: | 2019 |
Předmět: |
Male
Models Molecular Nociception Naringenin Protein Conformation Physiology Pharmacology Biochemistry Rats Sprague-Dawley Mice chemistry.chemical_compound 0302 clinical medicine Dorsal root ganglion Ganglia Spinal Protein Interaction Mapping Analgesics Pain Postoperative 0303 health sciences Voltage-dependent calcium channel food and beverages General Medicine Specific Pathogen-Free Organisms medicine.anatomical_structure Hyperalgesia Flavanones Tetrodotoxin Intercellular Signaling Peptides and Proteins Female medicine.symptom Acetylcholine Sodium Channel Blockers medicine.drug Sensory Receptor Cells Cognitive Neuroscience Nerve Tissue Proteins NAV1.8 Voltage-Gated Sodium Channel Structure-Activity Relationship 03 medical and health sciences medicine Animals Calcium Signaling 030304 developmental biology Calcium channel Sodium channel Sodium Excitatory Postsynaptic Potentials Cell Biology Rats Mechanism of action chemistry Neuralgia Calcium Channels 030217 neurology & neurosurgery |
Zdroj: | ACS Chemical Neuroscience. 10:4834-4846 |
ISSN: | 1948-7193 |
Popis: | Naringenin (2S)-5,7-dihydroxy-2-(4-hydroxyphenyl)-3,4-dihydro-2H-1-benzopyran-4-one is a natural flavonoid found in fruits from the citrus family. Because (2S)-naringenin is known to racemize, its bioactivity might be related to one or both enantiomers. Computational studies predicted that (2R)-naringenin may act on voltage-gated ion channels, particularly the N-type calcium channel (CaV2.2) and the NaV1.7 sodium channel-both of which are key for pain signaling. Here we set out to identify the possible mechanism of action of naringenin. Naringenin inhibited depolarization-evoked Ca2+ influx in acetylcholine-, ATP-, and capsaicin-responding rat dorsal root ganglion (DRG) neurons. This was corroborated in electrophysiological recordings from DRG neurons. Pharmacological dissection of each of the voltage-gated Ca2+ channels subtypes could not pinpoint any selectivity of naringenin. Instead, naringenin inhibited NaV1.8-dependent and tetrodotoxin (TTX)-resistant while sparing tetrodotoxin sensitive (TTX-S) voltage-gated Na+ channels as evidenced by the lack of further inhibition by the NaV1.8 blocker A-803467. The effects of the natural flavonoid were validated ex vivo in spinal cord slices where naringenin decreased both the frequency and amplitude of sEPSC recorded in neurons within the substantia gelatinosa. The antinociceptive potential of naringenin was evaluated in male and female mice. Naringenin had no effect on the nociceptive thresholds evoked by heat. Naringenin's reversed allodynia was in mouse models of postsurgical and neuropathic pain. Here, driven by a call by the National Center for Complementary and Integrative Health's strategic plan to advance fundamental research into basic biological mechanisms of the action of natural products, we advance the antinociceptive potential of the flavonoid naringenin. |
Databáze: | OpenAIRE |
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