{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T17:57:38Z","timestamp":1791050258306,"version":"4.1.0"},"reference-count":65,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T00:00:00Z","timestamp":1751328000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Grant-in-Aid for Scientific Research (C) from the Japanese Society for the Promotion of Science","award":["22K10232"],"award-info":[{"award-number":["22K10232"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>Objective: Given the side effects and reduced efficacy of conventional local anesthetics in inflammatory conditions, there is a compelling need for complementary alternative medicine (CAM), particularly those based on phytochemicals. While a previous study showed that in vivo local injection of (-)-epigallocatechin-3-gallate (EGCG) into the peripheral receptive field suppresses the excitability of rat trigeminal ganglion (TG) neurons in the absence of inflammation, the acute effects of EGCG in vivo, especially on TG neurons under inflammatory conditions, are still unknown. We aimed to determine if acute local EGCG administration into inflamed tissue effectively attenuates the excitability of nociceptive TG neurons evoked by mechanical stimulation. Methods: The escape reflex threshold was measured to assess hyperalgesia caused by complete Freund\u2019s adjuvant (CFA)-induced inflammation. To assess neuronal activity, extracellular single-unit recordings were performed on TG neurons in anesthetized CFA-inflamed rats in response to orofacial mechanical stimulation. Results: The mechanical escape threshold was significantly lower in CFA-inflamed rats compared to before CFA injection. EGCG (1\u201310 mM) reversibly and dose-dependently inhibited the mean firing frequency of TG neurons evoked by both non-noxious and noxious mechanical stimuli (p &lt; 0.05). For comparison, 1% lidocaine (37 mM), a local anesthetic, also caused reversible inhibition of the mean firing frequency in inflamed TG neurons responding to mechanical stimuli. Importantly, 10 mM EGCG produced a significantly greater magnitude of inhibition on TG neuronal discharge frequency than 1% lidocaine (noxious, lidocaine vs. EGCG, 19.7 \u00b1 3.3% vs. 42.3 \u00b1 3.4%, p &lt; 0.05). Conclusions: Local injection of EGCG into inflamed tissue effectively suppresses the excitability of nociceptive primary sensory TG neurons, as indicated by these findings. Significantly, locally administered EGCG exerted a more potent local analgesic action compared to conventional voltage-gated sodium channel blockers. This heightened efficacy originates from EGCG\u2019s ability to inhibit both generator potentials and action potentials directly at nociceptive primary nerve terminals. As a result, EGCG stands out as a compelling candidate for novel analgesic development, holding particular relevance for CAM strategies.<\/jats:p>","DOI":"10.3390\/metabo15070439","type":"journal-article","created":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T05:28:28Z","timestamp":1751347708000},"page":"439","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["(-)-Epigallocatechin-3-Gallate Suppresses Hyperexcitability in Rat Primary Nociceptive Neurons Innervating Inflamed Tissues: A Comparison with Lidocaine"],"prefix":"10.3390","volume":"15","author":[{"given":"Syogo","family":"Utugi","sequence":"first","affiliation":[{"name":"Laboratory of Food and Physiological Sciences, Department of Life and Food Sciences, School of Life and Environmental Sciences, Azabu University, 1-17-71, Fuchinobe, Chuo-ku, Sagamihara 252-5201, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukito","family":"Sashide","sequence":"additional","affiliation":[{"name":"Laboratory of Food and Physiological Sciences, Department of Life and Food Sciences, School of Life and Environmental Sciences, Azabu University, 1-17-71, Fuchinobe, Chuo-ku, Sagamihara 252-5201, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6890-0943","authenticated-orcid":false,"given":"Mamoru","family":"Takeda","sequence":"additional","affiliation":[{"name":"Laboratory of Food and Physiological Sciences, Department of Life and Food Sciences, School of Life and Environmental Sciences, Azabu University, 1-17-71, Fuchinobe, Chuo-ku, Sagamihara 252-5201, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.jopan.2007.05.003","article-title":"Complementary\/alternative medicine use among chronic pain clinic patients","volume":"23","author":"Konvicka","year":"2008","journal-title":"J. Perianesth. Nurs."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"409","DOI":"10.7326\/0003-4819-131-6-199909210-00003","article-title":"Use of complementary therapies for arthritis among patients of rheumatologists","volume":"131","author":"Rao","year":"1999","journal-title":"Ann. Intern. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1111\/j.1526-4637.2008.00477.x","article-title":"Complementary and alternative medicine use by primary care patients with chronic pain","volume":"9","author":"Rosenberg","year":"2008","journal-title":"Pain Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1097\/00002281-200303000-00012","article-title":"Complementary medicine","volume":"15","author":"Ernst","year":"2003","journal-title":"Curr. Opin. Rheumatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1238","DOI":"10.1097\/00000542-200111000-00031","article-title":"Consumption of soy diet before nerve injury preempts the development of neuro pathic pain in rats","volume":"95","author":"Shir","year":"2001","journal-title":"Anesthesiology"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Farah, C.S., Bal asubramaniam, R., and McCullough, M.J. (2017). Neurophysiology of Orofacial Pain. Contemporary Oral Medicine, Springer International.","DOI":"10.1007\/978-3-319-28100-1"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1016\/S1349-0079(11)80025-3","article-title":"Peripheral and central mechanisms of trigeminal neuropathic and inflammatory pain","volume":"53","author":"Takeda","year":"2011","journal-title":"J. Oral Biosci."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Sessle, B.J. (2021). Chronic orofacial pain: Models, mechanisms, and Genetic and related environmental influences. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22137112"},{"key":"ref_9","first-page":"117","article-title":"Peripheral and central mechanisms of orofacial pain and their clinical correlates","volume":"71","author":"Sessle","year":"2005","journal-title":"Minerva Anestesiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.job.2022.07.001","article-title":"Plastic changes in nociceptive pathways contributing to persistent orofacial pain","volume":"64","author":"Shinoda","year":"2022","journal-title":"J. Oral Biosci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1555","DOI":"10.1046\/j.1471-4159.2003.02291.x","article-title":"Cell signaling pathways in the neuroprotective actions of the green tea poly phenol (-)-epigallocatechin-3-gallate: Implication of neurodegenerative diseases","volume":"88","author":"Mandel","year":"2004","journal-title":"J. Neurochem."},{"key":"ref_12","first-page":"186","article-title":"Anticarcinogenic activity of green tea polyphenols","volume":"23","author":"Komori","year":"1993","journal-title":"Jpn. J. Clin. Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/S1383-5742(98)00019-2","article-title":"Antimutagenic and anticarcinogenic activity of tea polyphenols","volume":"436","author":"Kuroda","year":"1999","journal-title":"Mutat. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1023\/A:1007012403691","article-title":"Antioxidant properties of (-)-epigal locatechin-3-gallate and inhibition of Cr(VI)-induced DNA damage and Cr(IV)- or TPA-stimulated Nf-kappa B activation","volume":"206","author":"Shi","year":"2000","journal-title":"Mol. Cell Biochem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1021\/tx000080k","article-title":"Antioxidant chemistry of green tea catechins. New oxidation products of (-)-epigallocatechin-3-gallate and (-)-epigallocatechin from their reactions with peroxyl radicals","volume":"13","author":"Valcic","year":"2000","journal-title":"Chem. Res. Toxicol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"4335","DOI":"10.4049\/jimmunol.170.8.4335","article-title":"Neutrophil restraint by green tea: Inhibition of inflammation, associated angiogenesis and pulmonary fibrosis","volume":"170","author":"Dona","year":"2003","journal-title":"J. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/S0304-3940(01)02035-3","article-title":"Tea catechin (-)-epigallocatechin gallate, causes membrane depolarizations of myenteric neurons in the guinea-pig small intestine","volume":"309","author":"Homma","year":"2001","journal-title":"Neurosci. Lett."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1506","DOI":"10.1006\/bbrc.2002.6372","article-title":"EGCG attenuates AMPA-induced intracellular calcium increase in hippocampal neurons","volume":"290","author":"Bae","year":"2002","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/S0304-3940(01)02545-9","article-title":"Tea catechin, (-)-epigallocatechin gallate, facilitates cholinergic ganglion transmission in the myenteric plexus of the guinea-pig small intestine","volume":"319","author":"Katayama","year":"2002","journal-title":"Neurosci. Lett."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/j.brainres.2005.04.033","article-title":"Modulation of neuronal activity by EGCG","volume":"1047","author":"Jeong","year":"2005","journal-title":"Brain Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1038\/sj.bjp.0706897","article-title":"Inhibition of cardiac voltage-gated sodium channels by grape pol yphenols","volume":"149","author":"Wallace","year":"2006","journal-title":"Br. J. Pharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2147","DOI":"10.1016\/j.lfs.2007.04.005","article-title":"Effect of (-)-epigallocatechin-3-gallate in Ca2+-permeable non-selective cation channels and voltage-operated Ca2+ channels in vascular smooth muscle cells","volume":"80","author":"Orallo","year":"2007","journal-title":"Life Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.ejphar.2008.12.015","article-title":"Effects of (-)-epigallocatechin-3-gallate on Na(+) currents in rat dorsal root ganglion neurons","volume":"604","author":"Kim","year":"2009","journal-title":"Eur. J. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1124\/jpet.110.169391","article-title":"In vitro electrocardiographic and cardiac ion channel effects of (-)-epigallo catechin-3-gallate, the main catechin of green tea","volume":"334","author":"Kang","year":"2010","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1111\/cns.12979","article-title":"Subtype-selective inhibition of acid-sensing ion channel 3 by a natural flavonoid","volume":"25","author":"Yan","year":"2019","journal-title":"CNS Neurosci. Ther."},{"key":"ref_26","first-page":"46","article-title":"KCNQ5 potassium channel activation underlies vasodilation by tea","volume":"30","author":"Redford","year":"2012","journal-title":"Cell Physiol. Biochem."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Utugi, S., Chida, R., Yamaguchi, S., Sashide, Y., and Takeda, M. (2025). Local Administration of (-)-Epigallocatechin-3-Gallate as a Local Anesthetic Agent Inhibits the Excitability of Rat Nociceptive Primary Sensory Neurons. Cells, 14.","DOI":"10.3390\/cells14010052"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1097\/ALN.0b013e3181eaa58a","article-title":"A role for acid-sensing ion channel 3, but not acid-sensing ion channel 2, in sensing dynamic mechanical stimuli","volume":"113","author":"Borzan","year":"2010","journal-title":"Anesthesiology"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Kang, S., Jang, J.H., Price, M.P., Gautam, M., Benson, C.J., Gong, H., Welsh, M.J., Brennan, T.J., and Matsunami, H. (2012). Simultaneous disruption of mouse ASIC1a, ASIC2 and ASIC3 genes enhances cutaneous mechanosensitivity. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0035225"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"4808","DOI":"10.1523\/JNEUROSCI.5380-08.2009","article-title":"TRPA1 modulates mechanotransduction in cutaneous sensory neurons","volume":"29","author":"Kwan","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1016\/S0896-6273(01)00547-5","article-title":"The DRASIC cation channel contributes to the detection of cutaneous touch and acid stimuli in mice","volume":"32","author":"Price","year":"2001","journal-title":"Neuron"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1111\/j.1600-0714.1987.tb00674.x","article-title":"Evaluation of pH changes in inflammation of the subcutaneous air pouch lining in the rat, induced by carrageenan, dextran and Staphylococcus aureus","volume":"16","year":"1987","journal-title":"J. Oral Pathol."},{"key":"ref_33","first-page":"E510","article-title":"Failure of locoregional anesthesia in dental practice. Review of the literature","volume":"11","author":"Diago","year":"2006","journal-title":"Med. Oral Patol. Oral Cir. Bucal"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1111\/1440-1681.12510","article-title":"Acid-sensing ion channels in trigeminal ganglion neurons innervating the orofacial region contribute to orofacial inflammatory pain","volume":"43","author":"Fu","year":"2016","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/0304-3959(83)90201-4","article-title":"Ethical guidelines for investigations of experimental pain in conscious animals","volume":"16","author":"Zimmermann","year":"1983","journal-title":"Pain"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1016\/j.jpain.2023.10.004","article-title":"Local administration of the phytochemical, quercetin, attenuates the hyperexcitability of rat nociceptive primary sensory neurons following inflammation comparable to lidocaine","volume":"25","author":"Sashide","year":"2024","journal-title":"J. Pain"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1016\/j.jpain.2022.10.014","article-title":"Suppression of the excitability of rat nociceptive primary sensory neurons follow ing local administration of the phytochemical quercetin","volume":"24","author":"Toyota","year":"2023","journal-title":"J. Pain"},{"key":"ref_38","unstructured":"Paxinos, G., and Watson, C. (1986). The Rat Brain in Stereotaxic Coordinates, Academic Press. [2nd ed.]."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/1744-8069-6-9","article-title":"Alternation of primary afferent activity following inferior alveolar nerve transec tion in rats","volume":"6","author":"Nakagawa","year":"2010","journal-title":"Mol. Pain"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1007\/s11916-009-0034-9","article-title":"Contribution of primary afferent channels to neuropathic pain","volume":"13","author":"Harriott","year":"2009","journal-title":"Curr. Pain Headache Rep."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1016\/j.neuron.2007.07.008","article-title":"Signaling pathways in sensitization: Toward a nociceptor cell biology","volume":"55","author":"Hucho","year":"2007","journal-title":"Neuron"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1062","DOI":"10.1038\/nn942","article-title":"Can we conquer pain?","volume":"5","author":"Scholz","year":"2002","journal-title":"Nat. Neurosci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1111\/j.1365-2982.2004.00596.x","article-title":"Inflammation-induced hyperexcitability of nociceptive gastrointestinal DRG neurons: Role of voltage gated ion channels","volume":"17","author":"Beyak","year":"2005","journal-title":"Neurogastroenterol. Motil."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"G573","DOI":"10.1152\/ajpgi.00258.2003","article-title":"Gastric ulcers reduce A-type potassium currents in rat gastric sensory ganglion neurons","volume":"286","author":"Dang","year":"2004","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"G1045","DOI":"10.1152\/ajpgi.00406.2001","article-title":"TNBS ileitis evokes hyperexcitability and changes in ionic membrane properties of nociceptive DRG neurons","volume":"282","author":"Moore","year":"2002","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1016\/j.jpain.2008.01.326","article-title":"Characterization of a model of chronic orofacial hyperalgesia in the rat: Contribution of NA(V) 1.8","volume":"9","author":"Morgan","year":"2008","journal-title":"J. Pain"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1113\/jphysiol.2003.046409","article-title":"Ileitis modulates potassium and sodium currents in guinea pig dorsal root ganglia sensory neurons","volume":"552","author":"Stewart","year":"2003","journal-title":"J. Physiol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"4644","DOI":"10.1523\/JNEUROSCI.19-11-04644.1999","article-title":"Increased excitability of afferent neurons innervating rat urinary bladder after chronic bladder inflammation","volume":"19","author":"Yoshimura","year":"1999","journal-title":"J. Neurosci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.ejphar.2018.10.013","article-title":"Sumatriptan inhibits the electrophysiological activity of ASICs in rat trigeminal ganglion neurons","volume":"841","author":"Guo","year":"2018","journal-title":"Eur. J. Pharmacol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"C1","DOI":"10.1152\/ajpcell.00028.2015","article-title":"Mechanotransduction of trigeminal ganglion neurons innervating inner walls of rat anterior eye chambers","volume":"309","author":"Meng","year":"2015","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/j.pain.2003.12.035","article-title":"Changes in the expression of tetrodotoxin-sensitive sodium channels within dorsal root ganglia neurons in inflammatory pain","volume":"108","author":"Liu","year":"2004","journal-title":"Pain"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"RC43","DOI":"10.1523\/JNEUROSCI.19-24-j0001.1999","article-title":"A novel persistent tetrodotoxin-resistant sodium current in SNS-null and wild-type small primary sensory neurons","volume":"19","author":"Cummins","year":"1999","journal-title":"J. Neurosci."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1016\/j.neuroscience.2005.11.024","article-title":"Enhanced excitability of rat trigeminal root ganglion neurons via decrease in A-type potassium currents following temporomandibular joint inflammation","volume":"138","author":"Takeda","year":"2006","journal-title":"Neuroscience"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/1744-8069-7-5","article-title":"Potassium channels as a potential therapeutic target for trigeminal neuropathic and inflammatory pain","volume":"7","author":"Takeda","year":"2011","journal-title":"Mol. Pain"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/j.neures.2012.10.003","article-title":"Iontophoretic application of an A-type potassium channel blocker to the trigeminal ganglion neurons enhances the excitability of A\u03b4- and C-neurons innervating the temporomandibular joint","volume":"74","author":"Hara","year":"2012","journal-title":"Neurosci. Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1016\/S0028-3908(02)00130-2","article-title":"The peripheral antinociceptive effect of resveratrol is associated with acti vation of potassium channels","volume":"43","author":"Ortiz","year":"2002","journal-title":"Neuropharmacology"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"9374","DOI":"10.1523\/JNEUROSCI.0068-12.2012","article-title":"Presynaptic Cav3.2 channels regulate excitatory neurotransmission in nociceptive dorsal horn neurons","volume":"32","author":"Jacus","year":"2012","journal-title":"J. Neurosci."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"238","DOI":"10.4161\/chan.4953","article-title":"Regulation of T- type calcium channels in the peripheral pain pathway","volume":"1","author":"Todorovic","year":"2007","journal-title":"Channels"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1177\/1744806920901890","article-title":"Trigeminal neuralgia: An overview from pathophysiology to pharmacological treatments","volume":"16","author":"Gambeta","year":"2020","journal-title":"Mol. Pain"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/s12990-015-0011-8","article-title":"Small organic molecule disruptors of Cav3.2-USP5 interactions reverse in flammatory and neuropathic pain","volume":"11","author":"Gadotti","year":"2015","journal-title":"Mol. Pain"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2315","DOI":"10.1097\/j.pain.0000000000002651","article-title":"Cav 3.2 calcium channels contribute to trigeminal neuralgia","volume":"163","author":"Gambeta","year":"2022","journal-title":"Pain"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1859","DOI":"10.1021\/acschemneuro.3c00083","article-title":"Icariside, Aa prenyl- flavonol, alleviates inflammatory and neuropathic pain by inhib iting T-type calcium channels and USP5-cav3.2 interactions","volume":"14","author":"Ali","year":"2023","journal-title":"ACS Chem. Neurosci."},{"key":"ref_63","unstructured":"Katzung, B.G. (1996). Local anesthetics. Basic and Clinical Pharmacology, Lange Medical Books\/McGraw-Hill."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1159\/000047887","article-title":"Orofacial deep and cutaneous tissue inflammation and trigeminal neuronal activation","volume":"169","author":"Imbe","year":"2001","journal-title":"Cells Tissues Organs"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1724","DOI":"10.1126\/science.8085162","article-title":"Molecular determinants of state-dependent block of Na+ channel by local anes thetics","volume":"265","author":"Ragsdale","year":"1994","journal-title":"Science"}],"container-title":["Metabolites"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-1989\/15\/7\/439\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:02:06Z","timestamp":1760032926000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-1989\/15\/7\/439"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,1]]},"references-count":65,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2025,7]]}},"alternative-id":["metabo15070439"],"URL":"https:\/\/doi.org\/10.3390\/metabo15070439","relation":{},"ISSN":["2218-1989"],"issn-type":[{"value":"2218-1989","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,1]]}}}