{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T11:07:53Z","timestamp":1790075273240,"version":"4.0.1"},"reference-count":39,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,4,11]],"date-time":"2025-04-11T00:00:00Z","timestamp":1744329600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004807","name":"PRACTIS Clinician Scientist Program","doi-asserted-by":"publisher","award":["DFG ME 3696\/3"],"award-info":[{"award-number":["DFG ME 3696\/3"]}],"id":[{"id":"10.13039\/100004807","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: A large number of patients suffer from neuropathic pain, and systemic therapy often remains ineffective while inducing severe side effects. Topical therapy with the TRPV1-agonist capsaicin is an established alternative, and the identification of co-therapeutics that modulate TRPV1 may be a promising approach to reduce the dose of capsaicin while maintaining efficacy. Here, we aimed to determine if the antidepressant amitriptyline displays properties rendering it a potential co-therapeutic agent. Methods: We performed patch clamp and calcium imaging experiments on HEK293T cells expressing human (h) TRPV1 as well as on dorsal root ganglion (DRG) neurons from adult mice. Results: Amitriptyline induced an increase in intracellular calcium in both HEK293T and mouse DRG neurons expressing TRPV1. Patch clamp experiments revealed a concentration-dependent activation of hTRPV1 by amitriptyline that was also evident in cell-free inside-out patches. When hTRPV1 was fully activated by capsaicin, amitriptyline induced concentration-dependent and partly reversible current inhibition. In contrast, amitriptyline potentiated small responses to capsaicin, heat and protons. We also found that amitriptyline desensitized hTRPV1 to capsaicin. This effect was reduced by the intracellular application of the strong calcium chelator BAPTA. Furthermore, the non-desensitizing mutant hTRPV1-Y672K displayed a reduced amitriptyline-induced desensitization. Conclusions: Our data showed that amitriptyline can activate, sensitize, desensitize and even inhibit TRPV1. Together with its property as a strong local anesthetic, our data suggest that amitriptyline may be a promising adjunct to topical capsaicin.<\/jats:p>","DOI":"10.3390\/ph18040560","type":"journal-article","created":{"date-parts":[[2025,4,11]],"date-time":"2025-04-11T03:45:23Z","timestamp":1744343123000},"page":"560","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["High Concentrations of the Antidepressant Amitriptyline Activate and Desensitize the Capsaicin Receptor TRPV1"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4935-4390","authenticated-orcid":false,"given":"Sebastian","family":"Pantke","sequence":"first","affiliation":[{"name":"Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, 30625 Hannover, Germany"},{"name":"PRACTIS Clinician Scientist Program, Dean\u2019s Office for Academic Career Development, Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"}]},{"given":"Johanna","family":"Steinberg","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucas","family":"Weber","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-0958-1895","authenticated-orcid":false,"given":"Tabea","family":"Fricke","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, 30625 Hannover, Germany"},{"name":"PRACTIS Clinician Scientist Program, Dean\u2019s Office for Academic Career Development, Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-0309-0344","authenticated-orcid":false,"given":"In\u00eas","family":"Carvalheira Arnaut Pombeiro Stein","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, 30625 Hannover, Germany"},{"name":"PRACTIS Clinician Scientist Program, Dean\u2019s Office for Academic Career Development, Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-6964-8998","authenticated-orcid":false,"given":"George","family":"Oprita","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2375-6893","authenticated-orcid":false,"given":"Christine","family":"Herzog","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1121-6387","authenticated-orcid":false,"given":"Andreas","family":"Leffler","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1111\/j.1533-2500.2012.00547.x","article-title":"The impact and burden of chronic pain in the workplace: A qualitative systematic review","volume":"12","author":"Patel","year":"2012","journal-title":"Pain Pract."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1016\/S0895-4356(00)00204-3","article-title":"Which chronic conditions are associated with better or poorer quality of life?","volume":"53","author":"Sprangers","year":"2000","journal-title":"J. Clin. Epidemiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1016\/j.pain.2013.11.013","article-title":"Neuropathic pain in the general population: A systematic review of epidemiological studies","volume":"155","author":"Austin","year":"2014","journal-title":"Pain"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/S1474-4422(14)70251-0","article-title":"Pharmacotherapy for neuropathic pain in adults: A systematic review and meta-analysis","volume":"14","author":"Finnerup","year":"2015","journal-title":"Lancet Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"American Geriatrics Society Beers Criteria Update Expert Panel (2012). American geriatrics society updated beers criteria for potentially inappropriate medication use in older adults. J. Am. Geriatr. Soc., 60, 616\u2013631.","DOI":"10.1111\/j.1532-5415.2012.03923.x"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1016\/j.clpt.2003.09.019","article-title":"Cyclic antidepressants and the risk of sudden cardiac death","volume":"75","author":"Ray","year":"2004","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1124\/jpet.106.109025","article-title":"Use-dependent block by lidocaine but not amitriptyline is more pronounced in tetrodotoxin (ttx)-resistant nav1.8 than in ttx-sensitive na+ channels","volume":"320","author":"Leffler","year":"2007","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1016\/S0022-3565(24)37206-4","article-title":"Inhibition of neuronal na+ channels by antidepressant drugs","volume":"284","author":"Pancrazio","year":"1998","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1097\/00115550-200409000-00008","article-title":"Neurologic and histopathologic evaluation after high-volume intrathecal amitriptyline","volume":"29","author":"Sudoh","year":"2004","journal-title":"Reg. Anesth. Pain Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1016\/j.jpain.2020.11.002","article-title":"Analgesic effects of topical amitriptyline in patients with chemotherapy-induced peripheral neuropathy: Mechanistic insights from studies in mice","volume":"22","author":"Genevois","year":"2021","journal-title":"J. Pain"},{"key":"ref_11","first-page":"289","article-title":"Topical amitriptyline in healthy volunteers","volume":"28","author":"Gerner","year":"2003","journal-title":"Reg. Anesth. Pain Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1097\/00000542-200104000-00021","article-title":"Amitriptyline versus bupivacaine in rat sciatic nerve blockade","volume":"94","author":"Gerner","year":"2001","journal-title":"Anesthesiology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1707","DOI":"10.1213\/01.ANE.0000060456.91215.90","article-title":"Cutaneous analgesia after transdermal application of amitriptyline versus lidocaine in rats","volume":"96","author":"Haderer","year":"2003","journal-title":"Anesth. Analg."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1097\/00000542-200201000-00023","article-title":"Amitriptyline for prolonged cutaneous analgesia in the rat","volume":"96","author":"Khan","year":"2002","journal-title":"Anesthesiology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1111\/j.1533-2500.2011.00477.x","article-title":"High doses of topical amitriptyline in neuropathic pain: Two cases and literature review","volume":"12","author":"Kopsky","year":"2012","journal-title":"Pain Pract."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1111\/jcpt.12297","article-title":"Systematic review of topical amitriptyline for the treatment of neuropathic pain","volume":"40","author":"Thompson","year":"2015","journal-title":"J. Clin. Pharm. Ther."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1097\/AAP.0b013e31820c2c30","article-title":"Prolonged cutaneous analgesia with transdermal application of amitriptyline and capsaicin","volume":"36","author":"Colvin","year":"2011","journal-title":"Reg. Anesth. Pain Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1038\/39807","article-title":"The capsaicin receptor: A heat-activated ion channel in the pain pathway","volume":"389","author":"Caterina","year":"1997","journal-title":"Nature"},{"key":"ref_19","first-page":"CD007393","article-title":"Topical capsaicin (high concentration) for chronic neuropathic pain in adults","volume":"1","author":"Derry","year":"2017","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1093\/bja\/aer260","article-title":"Topical capsaicin for pain management: Therapeutic potential and mechanisms of action of the new high-concentration capsaicin 8% patch","volume":"107","author":"Anand","year":"2011","journal-title":"Br. J. Anaesth."},{"key":"ref_21","first-page":"763","article-title":"The vanilloid receptor trpv1 is activated and sensitized by local anesthetics in rodent sensory neurons","volume":"118","author":"Leffler","year":"2008","journal-title":"J. Clin. Investig."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1016\/j.ejpain.2011.03.011","article-title":"Differential effects on sensory functions and measures of epidermal nerve fiber density after application of a lidocaine patch (5%) on healthy human skin","volume":"15","author":"Wehrfritz","year":"2011","journal-title":"Eur. J. Pain"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Olah, Z., Josvay, K., Pecze, L., Letoha, T., Babai, N., Budai, D., Otvos, F., Szalma, S., and Vizler, C. (2007). Anti-calmodulins and tricyclic adjuvants in pain therapy block the trpv1 channel. PLoS ONE, 2.","DOI":"10.1371\/journal.pone.0000545"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.ceca.2017.10.003","article-title":"Differential cytotoxicity and intracellular calcium-signalling following activation of the calcium-permeable ion channels trpv1 and trpa1","volume":"68","author":"Stueber","year":"2017","journal-title":"Cell Calcium"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"50080","DOI":"10.1074\/jbc.M306619200","article-title":"Desensitization of capsaicin-activated currents in the vanilloid receptor trpv1 is decreased by the cyclic amp-dependent protein kinase pathway","volume":"278","author":"Mohapatra","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1016\/S1044-7431(03)00054-X","article-title":"A tyrosine residue in tm6 of the vanilloid receptor trpv1 involved in desensitization and calcium permeability of capsaicin-activated currents","volume":"23","author":"Mohapatra","year":"2003","journal-title":"Mol. Cell. Neurosci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2508","DOI":"10.1111\/bph.12532","article-title":"Transient receptor potential ion channels in primary sensory neurons as targets for novel analgesics","volume":"171","author":"Andreou","year":"2014","journal-title":"Br. J. Pharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"107474","DOI":"10.1016\/j.pharmthera.2020.107474","article-title":"Hyperthermia induced by transient receptor potential vanilloid-1 (trpv1) antagonists in human clinical trials: Insights from mathematical modeling and meta-analysis","volume":"208","author":"Garami","year":"2020","journal-title":"Pharmacol. Ther."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1097\/ALN.0000000000005027","article-title":"Safety and efficacy of vocacapsaicin for management of postsurgical pain: A randomized clinical trial","volume":"141","author":"Shafer","year":"2024","journal-title":"Anesthesiology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1080\/14728222.2024.2416961","article-title":"Targeting the trpv1 pain pathway in osteoarthritis of the knee","volume":"28","author":"Mobasheri","year":"2024","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1097\/00002508-200309000-00007","article-title":"A pilot study examining topical amitriptyline, ketamine, and a combination of both in the treatment of neuropathic pain","volume":"19","author":"Lynch","year":"2003","journal-title":"Clin. J. Pain"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1097\/00000542-200507000-00021","article-title":"Topical 2% amitriptyline and 1% ketamine in neuropathic pain syndromes: A randomized, double-blind, placebo-controlled trial","volume":"103","author":"Lynch","year":"2005","journal-title":"Anesthesiology"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Stepanenko, Y.D., Boikov, S.I., Sibarov, D.A., Abushik, P.A., Vanchakova, N.P., Belinskaia, D., Shestakova, N.N., and Antonov, S.M. (2019). Dual action of amitriptyline on nmda receptors: Enhancement of ca-dependent desensitization and trapping channel block. Sci. Rep., 9.","DOI":"10.1038\/s41598-019-56072-z"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1016\/j.physbeh.2018.08.006","article-title":"Capsaicin produces antidepressant-like effects in the forced swimming test and enhances the response of a sub-effective dose of amitriptyline in rats","volume":"195","year":"2018","journal-title":"Physiol. Behav."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1038\/sj.bjp.0707253","article-title":"Tricyclic antidepressant pharmacology and therapeutic drug interactions updated","volume":"151","author":"Gillman","year":"2007","journal-title":"Br. J. Pharmacol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1111\/j.1471-4159.1993.tb03190.x","article-title":"Ca2+ release from inositol 1,4,5-trisphosphate-sensitive Ca2+ store by antidepressant drugs in cultured neurons of rat frontal cortex","volume":"60","author":"Shimizu","year":"1993","journal-title":"J. Neurochem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1023\/A:1020937717260","article-title":"High concentrations of tricyclic antidepressants increase intracellular Ca2+ in cultured neural cells","volume":"24","author":"Joshi","year":"1999","journal-title":"Neurochem. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3617","DOI":"10.1111\/bph.15193","article-title":"The arrive guidelines 2.0: Updated guidelines for reporting animal research","volume":"177","author":"Hurst","year":"2020","journal-title":"Br. J. Pharmacol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3611","DOI":"10.1111\/bph.15178","article-title":"Arrive 2.0 and the british journal of pharmacology: Updated guidance for 2020","volume":"177","author":"Lilley","year":"2020","journal-title":"Br. J. Pharmacol."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/4\/560\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T10:46:23Z","timestamp":1790073983000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/4\/560"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,11]]},"references-count":39,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2025,4]]}},"alternative-id":["ph18040560"],"URL":"https:\/\/doi.org\/10.3390\/ph18040560","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,11]]}}}