{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T12:55:51Z","timestamp":1790081751525,"version":"4.0.1"},"reference-count":52,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2017,6,21]],"date-time":"2017-06-21T00:00:00Z","timestamp":1498003200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Marine Drugs"],"abstract":"<jats:p>Visceral pain is very common and represents a major unmet clinical need for which current pharmacological treatments are often insufficient. Tetrodotoxin (TTX) is a potent neurotoxin that exerts analgesic actions in both humans and rodents under different somatic pain conditions, but its effect has been unexplored in visceral pain. Therefore, we tested the effects of systemic TTX in viscero-specific mouse models of chemical stimulation of the colon (intracolonic instillation of capsaicin and mustard oil) and intraperitoneal cyclophosphamide-induced cystitis. The subcutaneous administration of TTX dose-dependently inhibited the number of pain-related behaviors in all evaluated pain models and reversed the referred mechanical hyperalgesia (examined by stimulation of the abdomen with von Frey filaments) induced by capsaicin and cyclophosphamide, but not that induced by mustard oil. Morphine inhibited both pain responses and the referred mechanical hyperalgesia in all tests. Conditional nociceptor\u2011specific Nav1.7 knockout mice treated with TTX showed the same responses as littermate controls after the administration of the algogens. No motor incoordination after the administration of TTX was observed. These results suggest that blockade of TTX-sensitive sodium channels, but not Nav1.7 subtype alone, by systemic administration of TTX might be a potential therapeutic strategy for the treatment of visceral pain.<\/jats:p>","DOI":"10.3390\/md15060188","type":"journal-article","created":{"date-parts":[[2017,6,22]],"date-time":"2017-06-22T02:39:15Z","timestamp":1498099155000},"page":"188","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Effects of Tetrodotoxin in Mouse Models of Visceral Pain"],"prefix":"10.3390","volume":"15","author":[{"given":"Rafael","family":"Gonz\u00e1lez-Cano","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Biomedical Research Centre and Institute of Neuroscience, Faculty of Medicine, University of Granada, 18016 Granada, Spain"},{"name":"Biosanitary Research Institute, University Hospital Complex of Granada, 18012 Granada, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel","family":"Tejada","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Biomedical Research Centre and Institute of Neuroscience, Faculty of Medicine, University of Granada, 18016 Granada, Spain"},{"name":"Biosanitary Research Institute, University Hospital Complex of Granada, 18012 Granada, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonia","family":"Artacho-Cord\u00f3n","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Biomedical Research Centre and Institute of Neuroscience, Faculty of Medicine, University of Granada, 18016 Granada, Spain"},{"name":"Biosanitary Research Institute, University Hospital Complex of Granada, 18012 Granada, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9555-0651","authenticated-orcid":false,"given":"Francisco","family":"Nieto","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Biomedical Research Centre and Institute of Neuroscience, Faculty of Medicine, University of Granada, 18016 Granada, Spain"},{"name":"Biosanitary Research Institute, University Hospital Complex of Granada, 18012 Granada, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9","family":"Entrena","sequence":"additional","affiliation":[{"name":"Animal Behavior Research Unit, Scientific Instrumentation Center, University of Granada, Armilla, 18100 Granada, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Wood","sequence":"additional","affiliation":[{"name":"Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cruz","family":"Cend\u00e1n","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Biomedical Research Centre and Institute of Neuroscience, Faculty of Medicine, University of Granada, 18016 Granada, Spain"},{"name":"Biosanitary Research Institute, University Hospital Complex of Granada, 18012 Granada, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2017,6,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2145","DOI":"10.1016\/S0140-6736(99)01306-9","article-title":"Visceral pain","volume":"353","author":"Cervero","year":"1999","journal-title":"Lancet"},{"key":"ref_2","first-page":"89","article-title":"Emerging therapies and novel approaches to visceral pain","volume":"6","author":"Wesselmann","year":"2009","journal-title":"Drug Discov. Today"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Taylor, B.K., and Finn, D.P. (2014). Visceral Pain. Behavioral Neurobiology of Chronic Pain, Springer. Current Topics in Behavioral Neurosciences.","DOI":"10.1007\/978-3-662-45094-9"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Davis, M.P. (2012). Drug Management of Visceral Pain: Concepts from Basic Research. Pain Res. Treat., 2012.","DOI":"10.1155\/2012\/265605"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1159\/000268115","article-title":"Visceral versus Somatic Pain: Similarities and Differences","volume":"27","author":"Cervero","year":"2010","journal-title":"Dig. Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/S0304-3959(02)00023-4","article-title":"Psychophysical analysis of visceral and cutaneous pain in human subjects","volume":"97","author":"Strigo","year":"2002","journal-title":"Pain"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1124\/mi.8.5.9","article-title":"Inside information\u2014The unique features of visceral sensation","volume":"8","author":"Robinson","year":"2008","journal-title":"Mol. Interv."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Ma, C., and Zhang, J.-M. (2011). Animal Models of Visceral Pain. Animal Models of Pain, Neuromethods; Humana Press.","DOI":"10.1007\/978-1-60761-880-5"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"6384","DOI":"10.3390\/md13106384","article-title":"Tetrodotoxin, an Extremely Potent Marine Neurotoxin: Distribution, Toxicity, Origin and Therapeutical Uses","volume":"13","author":"Lago","year":"2015","journal-title":"Mar. Drugs"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.toxicon.2012.11.026","article-title":"The molecular mystique of tetrodotoxin","volume":"63","author":"Moczydlowski","year":"2013","journal-title":"Toxicon"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Zhao, F., Li, X., Jin, L., Zhang, F., Inoue, M., Yu, B., and Cao, Z. (2016). Development of a Rapid Throughput Assay for Identification of hNav1.7 Antagonist Using Unique Efficacious Sodium Channel Agonist, Antillatoxin. Mar. Drugs, 14.","DOI":"10.3390\/md14020036"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1254\/jjp.88.365","article-title":"Molecular Diversity of Structure and Function of the Voltage-Gated Na+ Channels","volume":"88","author":"Ogata","year":"2002","journal-title":"Jpn. J. Pharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1093\/bja\/ael096","article-title":"Antinociceptive effects of tetrodotoxin (TTX) in rodents","volume":"96","author":"Marcil","year":"2006","journal-title":"Br. J. Anaesth."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1097\/00000542-200607000-00022","article-title":"Effects of Bupivacaine and Tetrodotoxin on Carrageenan-induced Hind Paw Inflammation in Rats (Part 1)Hyperalgesia, Edema, and Systemic Cytokines","volume":"105","author":"Beloeil","year":"2006","journal-title":"J. Am. Soc. Anesthesiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1093\/bja\/aen066","article-title":"Subcutaneous tetrodotoxin and inflammatory pain","volume":"100","author":"Alguacil","year":"2008","journal-title":"Br. J. Anaesth."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1016\/j.neuroscience.2015.10.059","article-title":"Antihyperalgesic Effect of Tetrodotoxin in Rat Models of Persistent Muscle Pain","volume":"311","author":"Alvarez","year":"2015","journal-title":"Neuroscience"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1016\/j.pain.2007.10.012","article-title":"Tetrodotoxin inhibits the development and expression of neuropathic pain induced by paclitaxel in mice","volume":"137","author":"Nieto","year":"2008","journal-title":"Pain"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1016\/j.neuropharm.2009.09.003","article-title":"Differential anti-neuropathic pain effects of tetrodotoxin in sciatic nerve-versus infraorbital nerve-ligated rats\u2014Behavioral, pharmacological and immunohistochemical investigations","volume":"58","author":"Kayser","year":"2010","journal-title":"Neuropharmacology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/S0006-8993(00)02451-3","article-title":"Low dose of tetrodotoxin reduces neuropathic pain behaviors in an animal model","volume":"871","author":"Lyu","year":"2000","journal-title":"Brain Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1016\/j.jpainsymman.2007.05.011","article-title":"Tetrodotoxin for Moderate to Severe Cancer Pain: A Randomized, Double Blind, Parallel Design Multicenter Study","volume":"35","author":"Hagen","year":"2008","journal-title":"J. Pain Symptom Manag."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e109","DOI":"10.3747\/co.v18i3.732","article-title":"A multicentre open-label safety and efficacy study of tetrodotoxin for cancer pain","volume":"18","author":"Hagen","year":"2011","journal-title":"Curr. Oncol."},{"key":"ref_22","unstructured":"Wex Pharmaceuticals Inc. (2017, April 04). The Purpose of This Study Is to Determine If Tetrodotoxin (TTX) Is Effective in the Treatment of Pain Resulting From Chemotherapy Treatment (TTX-CINP-201), Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT01655823NMLIdentifier:NCT01655823."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"281","DOI":"10.3390\/md10020281","article-title":"Tetrodotoxin (TTX) as a Therapeutic Agent for Pain","volume":"10","author":"Nieto","year":"2012","journal-title":"Mar. Drugs"},{"key":"ref_24","first-page":"691","article-title":"\u03c31Receptors Are Involved in the Visceral Pain Induced by Intracolonic Administration of Capsaicin in Mice","volume":"118","author":"Merlos","year":"2013","journal-title":"J. Am. Soc. Anesthesiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.jpain.2012.10.003","article-title":"Stimulation of Cutaneous Low Threshold Mechanoreceptors in Mice After Intracolonic Capsaicin Increases Spinal c-Fos Labeling in an NKCC1-Dependent Fashion","volume":"14","author":"Pitcher","year":"2013","journal-title":"J. Pain"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/S0304-3959(01)00275-5","article-title":"A new model of visceral pain and referred hyperalgesia in the mouse","volume":"92","author":"Laird","year":"2001","journal-title":"Pain"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2661","DOI":"10.1113\/JP272837","article-title":"Visceral and somatic pain modalities reveal NaV1.7-independent visceral nociceptive pathways","volume":"595","author":"Hockley","year":"2017","journal-title":"J. Physiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1016\/j.neulet.2007.05.043","article-title":"Pharmacological validation of a model of cystitis pain in the mouse","volume":"421","author":"Wantuch","year":"2007","journal-title":"Neurosci. Lett."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/S0074-7742(08)60329-3","article-title":"Tetrodotoxin, saxitoxin, and related substances: Their applications in neurobiology","volume":"15","author":"Evans","year":"1972","journal-title":"Int. Rev. Neurobiol."},{"key":"ref_30","first-page":"371","article-title":"Toxicity of tetrodotoxin towards mice and rabbits","volume":"32","author":"Xu","year":"2003","journal-title":"Wei Sheng Yan Jiu"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1016\/S0031-6997(24)01514-X","article-title":"Animal Models of Nociception","volume":"53","author":"LeBars","year":"2001","journal-title":"Pharmacol. Rev."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1016\/j.ejpain.2007.08.010","article-title":"Viscero-somatic reflexes in referred pain areas evoked by capsaicin stimulation of the human gut","volume":"12","author":"Schipper","year":"2008","journal-title":"Eur. J. Pain"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/S0304-3959(03)00039-3","article-title":"Gut pain and hyperalgesia induced by capsaicin: A human experimental model","volume":"104","author":"Drewes","year":"2003","journal-title":"Pain"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1136\/gut.2003.029793","article-title":"Chemical nociception in the jejunum induced by capsaicin","volume":"53","author":"Schmidt","year":"2004","journal-title":"Gut"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1053\/eujp.1998.0105","article-title":"Cyclophosphamide cystitis in mice: Behavioural characterisation and correlation with bladder inflammation","volume":"3","author":"Olivar","year":"1999","journal-title":"Eur. J. Pain"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Malcangio, M. (2009). Spinal Mechanisms of Visceral Pain and Hyperalgesia. Synaptic Plasticity in Pain, Springer.","DOI":"10.1007\/978-1-4419-0226-9"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1007\/s00213-005-0127-z","article-title":"Antinociceptive effects of haloperidol and its metabolites in the formalin test in mice","volume":"182","author":"Pujalte","year":"2005","journal-title":"Psychopharmacology"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/j.pain.2009.03.011","article-title":"Sigma-1 receptors are essential for capsaicin-induced mechanical hypersensitivity: Studies with selective sigma-1 ligands and sigma-1 knockout mice","volume":"143","author":"Entrena","year":"2009","journal-title":"Pain"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1146\/annurev-cellbio-101011-155833","article-title":"TRP Channels and Pain","volume":"29","author":"Julius","year":"2013","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1016\/j.cub.2011.01.031","article-title":"The Capsaicin Receptor TRPV1 Is a Crucial Mediator of the Noxious Effects of Mustard Oil","volume":"21","author":"Everaerts","year":"2011","journal-title":"Curr. Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1016\/S0306-4522(00)00148-2","article-title":"Deficits in visceral pain and hyperalgesia of mice with a disruption of the tachykinin NK1 receptor gene","volume":"98","author":"Laird","year":"2000","journal-title":"Neuroscience"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1213\/01.ane.0000184828.39754.a3","article-title":"Nonsteroidal antiinflammatory drugs suppress pain-related behaviors, but not referred hyperalgesia of visceral pain in mice","volume":"102","author":"Shin","year":"2006","journal-title":"Anesth. Analg."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.neulet.2015.09.031","article-title":"Tetrodotoxin suppresses thermal hyperalgesia and mechanical allodynia in a rat full thickness thermal injury pain model","volume":"607","author":"Salas","year":"2015","journal-title":"Neurosci. Lett."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Schaible, H.-G. (2015). Sodium Channels and Pain. Pain Control, Springer. Handbook of Experimental Pharmacology.","DOI":"10.1007\/978-3-662-46450-2"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2585","DOI":"10.1093\/brain\/aws225","article-title":"Neurological perspectives on voltage-gated sodium channels","volume":"135","author":"Eijkelkamp","year":"2012","journal-title":"Brain"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1749","DOI":"10.1016\/j.pain.2013.05.032","article-title":"An animal model of oxaliplatin-induced cold allodynia reveals a crucial role for Nav1.6 in peripheral pain pathways","volume":"154","author":"Deuis","year":"2013","journal-title":"Pain"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/j.neuroscience.2015.02.010","article-title":"Local knockdown of the NaV1.6 sodium channel reduces pain behaviors, sensory neuron excitability, and sympathetic sprouting in rat models of neuropathic pain","volume":"291","author":"Xie","year":"2015","journal-title":"Neuroscience"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2618","DOI":"10.1152\/jn.00717.2014","article-title":"Experimental and computational evidence for an essential role of NaV1.6 in spike initiation at stretch-sensitive colorectal afferent endings","volume":"113","author":"Feng","year":"2015","journal-title":"J. Neurophysiol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1038\/nature17976","article-title":"Selective spider toxins reveal a role for Nav1.1 channel in mechanical pain","volume":"534","author":"Osteen","year":"2016","journal-title":"Nature"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"12706","DOI":"10.1073\/pnas.0404915101","article-title":"Nociceptor-specific gene deletion reveals a major role for Nav1.7 (PN1) in acute and inflammatory pain","volume":"101","author":"Nassar","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/0165-0270(94)90144-9","article-title":"Quantitative assessment of tactile allodynia in the rat paw","volume":"53","author":"Chaplan","year":"1994","journal-title":"J. Neurosci. Methods"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1021\/np300783a","article-title":"Antiallodynic and Analgesic Effects of Maslinic Acid, a Pentacyclic Triterpenoid from Olea europaea","volume":"76","author":"Nieto","year":"2013","journal-title":"J. Nat. Prod."}],"container-title":["Marine Drugs"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1660-3397\/15\/6\/188\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T18:39:53Z","timestamp":1760207993000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1660-3397\/15\/6\/188"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,6,21]]},"references-count":52,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2017,6]]}},"alternative-id":["md15060188"],"URL":"https:\/\/doi.org\/10.3390\/md15060188","relation":{},"ISSN":["1660-3397"],"issn-type":[{"value":"1660-3397","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,6,21]]}}}