Abstract
The ability of the nervous system to detect a wide range of noxious stimuli is crucial to avoid life-threatening injury and to trigger protective behavioral and physiological responses. Pain represents a complex phenomenon, including nociception associated with cognitive and emotional processing. Animal experimental models have been developed to understand the mechanisms involved in pain response, as well as to discover novel pharmacological and non-pharmacological anti-pain therapies. Due to the genetic tractability, similar physiology, low cost, and rich behavioral repertoire, the zebrafish (Danio rerio) is a powerful aquatic model for modeling pain responses. Here, we summarize the molecular machinery of zebrafish responses to painful stimuli, as well as emphasize how zebrafish-based pain models have been successfully used to understand specific molecular, physiological, and behavioral changes following different algogens and/or noxious stimuli (e.g., acetic acid, formalin, histamine, Complete Freund's Adjuvant, cinnamaldehyde, allyl isothiocyanate, and fin clipping). We also discuss recent advances in zebrafish-based studies and outline the potential advantages and limitations of the existing models to examine the mechanisms underlying pain responses from evolutionary and translational perspectives. Finally, we outline how zebrafish models can represent emergent tools to explore pain behaviors and pain-related mood disorders, as well as to facilitate analgesic therapy screening in translational pain research.
Keywords: Non-traditional pain models, zebrafish, noxious stimuli, nociceptors, pain-related behaviors, anti-pain medication screening.
Graphical Abstract
[http://dx.doi.org/10.1016/j.pnpbp.2017.10.007]
[http://dx.doi.org/10.1016/j.pain.2010.07.015] [PMID: 20696526]
[http://dx.doi.org/10.1038/nrd.2017.87] [PMID: 28596533]
[http://dx.doi.org/10.1016/j.gene.2013.11.091] [PMID: 24333346]
[http://dx.doi.org/10.1016/j.tips.2004.04.008] [PMID: 15165744]
[http://dx.doi.org/10.1016/j.neuron.2007.07.012] [PMID: 17678852]
[http://dx.doi.org/10.1016/j.jpain.2013.06.008] [PMID: 24035349]
[http://dx.doi.org/10.1097/j.pain.0000000000001109] [PMID: 29140923]
[http://dx.doi.org/10.1007/s12035-017-0829-3] [PMID: 29250715]
[http://dx.doi.org/10.1016/j.cell.2009.09.028] [PMID: 19837031]
[http://dx.doi.org/10.1523/JNEUROSCI.12-09-03665.1992] [PMID: 1326610]
[http://dx.doi.org/10.1172/JCI45178] [PMID: 21041955]
[http://dx.doi.org/10.1002/jcp.24379] [PMID: 23559073]
[http://dx.doi.org/10.1016/j.jpain.2009.09.012] [PMID: 20338819]
[http://dx.doi.org/10.1016/j.jpain.2006.01.447] [PMID: 16750797]
[http://dx.doi.org/10.1067/S1526-5900(03)00717-X] [PMID: 14622663]
[PMID: 29354920]
[http://dx.doi.org/10.1038/nrd4627] [PMID: 26361349]
[http://dx.doi.org/10.1016/j.tins.2014.02.011] [PMID: 24726051]
[http://dx.doi.org/10.1016/j.expneurol.2017.10.004]
[http://dx.doi.org/10.1016/j.tips.2013.12.002] [PMID: 24412421]
[http://dx.doi.org/10.1155/2016/9732780] [PMID: 27556045]
[http://dx.doi.org/10.3791/4196] [PMID: 23183629]
[http://dx.doi.org/10.3389/fnbeh.2015.00014] [PMID: 25729356]
[http://dx.doi.org/10.1016/j.jacbts.2017.01.004] [PMID: 30167552]
[http://dx.doi.org/10.1007/978-1-4939-3999-2_10] [PMID: 27858360]
[http://dx.doi.org/10.1016/bs.adgen.2016.04.002] [PMID: 27503354]
[http://dx.doi.org/10.3389/fimmu.2019.00832] [PMID: 31110502]
[http://dx.doi.org/10.1038/s41598-018-22828-2] [PMID: 29535354]
[http://dx.doi.org/10.1186/s13229-018-0204-x] [PMID: 29619162]
[http://dx.doi.org/10.1093/ilar.50.4.373] [PMID: 19949253]
[http://dx.doi.org/10.1089/zeb.2017.1436] [PMID: 28704145]
[http://dx.doi.org/10.1016/j.physbeh.2017.03.009] [PMID: 28288793]
[http://dx.doi.org/10.1016/j.bbr.2018.10.009] [PMID: 30296529]
[http://dx.doi.org/10.1016/j.jneumeth.2019.108433] [PMID: 31520651]
[http://dx.doi.org/10.1523/JNEUROSCI.5403-12.2013] [PMID: 23516290]
[http://dx.doi.org/10.1523/JNEUROSCI.2740-08.2008] [PMID: 18829968]
[http://dx.doi.org/10.1016/S0959-437X(00)00074-5] [PMID: 10826982]
[http://dx.doi.org/10.3354/dao075131] [PMID: 17578252]
[http://dx.doi.org/10.1007/s00359-007-0283-1] [PMID: 17987296]
[http://dx.doi.org/10.1016/j.applanim.2008.01.016]
[http://dx.doi.org/10.1016/j.neuroscience.2007.09.086] [PMID: 18082336]
[http://dx.doi.org/10.1016/j.neulet.2006.06.028] [PMID: 16842913]
[http://dx.doi.org/10.1016/S0169-328X(00)00152-2] [PMID: 11113526]
[http://dx.doi.org/10.1242/jeb.113118] [PMID: 25722005]
[http://dx.doi.org/10.1007/s00418-014-1264-4] [PMID: 25161120]
[http://dx.doi.org/10.1155/2012/159807] [PMID: 22811714]
[http://dx.doi.org/10.1016/j.fsi.2007.03.004] [PMID: 17442590]
[http://dx.doi.org/10.1016/j.aanat.2016.06.006] [PMID: 27513962]
[http://dx.doi.org/10.1098/rspb.2003.2349] [PMID: 12816648]
[http://dx.doi.org/10.3922/j.psns.2011.1.017]
[http://dx.doi.org/10.1242/dev.023200] [PMID: 18755773]
[http://dx.doi.org/10.1242/dev.076588] [PMID: 22190641]
[http://dx.doi.org/10.1089/zeb.2009.0594] [PMID: 19761379]
[http://dx.doi.org/10.1016/j.pharmthera.2013.06.003] [PMID: 23764370]
[http://dx.doi.org/10.1097/ACO.0b013e32834873e5] [PMID: 21659869]
[http://dx.doi.org/10.1038/sj.bjp.0706435] [PMID: 16402099]
[http://dx.doi.org/10.2741/3306] [PMID: 19273128]
[http://dx.doi.org/10.1038/s41386-018-0225-3] [PMID: 30250308]
[http://dx.doi.org/10.1016/j.tins.2012.11.002] [PMID: 23219016]
[http://dx.doi.org/10.1016/S0169-328X(97)00353-7] [PMID: 9555078]
[http://dx.doi.org/10.1038/383819a0] [PMID: 8893006]
[http://dx.doi.org/10.1124/mol.105.019109] [PMID: 16399848]
[http://dx.doi.org/10.1016/S0896-6273(00)80836-3] [PMID: 10677041]
[http://dx.doi.org/10.1038/nrd2572] [PMID: 18670432]
[http://dx.doi.org/10.1371/journal.pone.0010512] [PMID: 20463905]
[http://dx.doi.org/10.1073/pnas.0805590105] [PMID: 18832151]
[http://dx.doi.org/10.1006/bbrc.1998.8496] [PMID: 9571192]
[http://dx.doi.org/10.1677/jme.1.02136] [PMID: 17170080]
[http://dx.doi.org/10.1530/JME-10-0130] [PMID: 21247980]
[http://dx.doi.org/10.2119/molmed.2012.00318] [PMID: 23348513]
[http://dx.doi.org/10.1016/j.bbaexp.2003.08.001] [PMID: 14522087]
[http://dx.doi.org/10.1016/j.molbrainres.2003.09.012] [PMID: 14667571]
[http://dx.doi.org/10.1523/JNEUROSCI.3339-10.2011] [PMID: 21209207]
[http://dx.doi.org/10.1080/10253890.2020.1724948] [PMID: 32036720]
[http://dx.doi.org/10.1016/j.cub.2007.09.028] [PMID: 17919909]
[http://dx.doi.org/10.1016/j.neuroscience.2006.09.028] [PMID: 17069980]
[http://dx.doi.org/10.1016/j.neuroscience.2019.01.045] [PMID: 30710667]
[http://dx.doi.org/10.1016/j.pnpbp.2018.03.024] [PMID: 29604314]
[http://dx.doi.org/10.1124/jpet.105.093492] [PMID: 16207834]
[http://dx.doi.org/10.1016/j.tips.2017.08.004] [PMID: 28935293]
[http://dx.doi.org/10.3389/fnana.2020.00005] [PMID: 32153369]
[http://dx.doi.org/10.1016/S0014-2999(97)00142-8] [PMID: 9128831]
[http://dx.doi.org/10.1016/0006-8993(88)90997-3] [PMID: 3359215]
[http://dx.doi.org/10.1016/j.pnpbp.2010.11.035] [PMID: 21122812]
[http://dx.doi.org/10.1038/s41598-019-45464-w] [PMID: 31227751]
[http://dx.doi.org/10.1089/zeb.2018.1633] [PMID: 30153094]
[http://dx.doi.org/10.1242/jeb.146969] [PMID: 28424313]
[http://dx.doi.org/10.1371/journal.pone.0028340] [PMID: 22205946]
[http://dx.doi.org/10.1016/j.bbr.2009.12.004] [PMID: 20006651]
[http://dx.doi.org/10.1038/srep05602] [PMID: 24998697]
[http://dx.doi.org/10.1016/j.neuroscience.2006.12.073] [PMID: 17428610]
[http://dx.doi.org/10.1016/0006-8993(94)91053-7] [PMID: 7953621]
[http://dx.doi.org/10.1016/j.brainres.2006.01.095] [PMID: 16530171]
[http://dx.doi.org/10.1093/bjaceaccp/mki004]
[http://dx.doi.org/10.1016/j.lfs.2003.10.041] [PMID: 15158363]
[http://dx.doi.org/10.1007/s00213-006-0639-1] [PMID: 17219220]
[http://dx.doi.org/10.1016/j.peptides.2007.10.002] [PMID: 18022288]
[http://dx.doi.org/10.1016/0006-8993(95)00928-J] [PMID: 8624732]
[http://dx.doi.org/10.1016/S0301-0082(02)00008-4] [PMID: 12015197]
[http://dx.doi.org/10.1097/FBP.0b013e32834a1f2c] [PMID: 21836459]
[http://dx.doi.org/10.1016/j.semarthrit.2008.11.005] [PMID: 19217649]
[http://dx.doi.org/10.1016/0196-9781(89)90135-6] [PMID: 2550910]
[http://dx.doi.org/10.1002/(SICI)1096-9861(19990927)412:3<429:AID-CNE4>3.0.CO;2-L] [PMID: 10441231]
[http://dx.doi.org/10.1074/jbc.271.31.18789] [PMID: 8702536]
[http://dx.doi.org/10.1016/0014-2999(96)00431-1] [PMID: 8891611]
[http://dx.doi.org/10.1016/S0304-3940(00)01239-8] [PMID: 10889344]
[http://dx.doi.org/10.1016/S0196-9781(00)00227-8] [PMID: 10998524]
[http://dx.doi.org/10.1016/S0304-3940(97)13414-0] [PMID: 9089686]
[http://dx.doi.org/10.1124/jpet.106.106120] [PMID: 16766718]
[http://dx.doi.org/10.1124/jpet.102.046979] [PMID: 12721334]
[http://dx.doi.org/10.1016/S0896-6273(00)81183-6] [PMID: 10839369]
[http://dx.doi.org/10.1146/annurev-cellbio-101011-155833] [PMID: 24099085]
[http://dx.doi.org/10.1038/nature02196] [PMID: 14654832]
[http://dx.doi.org/10.1016/S0092-8674(02)00670-0] [PMID: 11893331]
[http://dx.doi.org/10.1097/FBP.0000000000000524] [PMID: 31833970]
[http://dx.doi.org/10.1002/dvdy.24041] [PMID: 24038627]
[http://dx.doi.org/10.1152/physiolgenomics.00322.2005] [PMID: 16926268]
[http://dx.doi.org/10.1038/nature03066] [PMID: 15483558]
[http://dx.doi.org/10.1002/dvdy.24020] [PMID: 23908157]
[http://dx.doi.org/10.1387/ijdb.120033gb] [PMID: 23585356]
[http://dx.doi.org/10.3389/fcell.2017.00005] [PMID: 28271061]
[http://dx.doi.org/10.1038/s41598-019-38852-9] [PMID: 30787340]
[http://dx.doi.org/10.1080/23328940.2014.1000702] [PMID: 27227025]
[http://dx.doi.org/10.1038/nature08848] [PMID: 20237474]
[http://dx.doi.org/10.1038/srep37460] [PMID: 27874100]
[http://dx.doi.org/10.1093/chemse/bjv091] [PMID: 26826723]
[http://dx.doi.org/10.1124/pr.114.009555] [PMID: 25361914]
[http://dx.doi.org/10.1038/39807] [PMID: 9349813]
[http://dx.doi.org/10.1186/1744-8069-1-3] [PMID: 15813989]
[http://dx.doi.org/10.1038/22761] [PMID: 10440374]
[http://dx.doi.org/10.1016/0306-4522(89)90269-8] [PMID: 2747924]
[http://dx.doi.org/10.1371/journal.pone.0116766] [PMID: 25587718]
[http://dx.doi.org/10.1016/j.abb.2019.02.009] [PMID: 30772259]
[http://dx.doi.org/10.1016/j.biopha.2018.08.089] [PMID: 30257314]
[http://dx.doi.org/10.1016/j.cbi.2018.11.018] [PMID: 30496739]
[http://dx.doi.org/10.1016/j.biopha.2018.08.160] [PMID: 30236850]
[http://dx.doi.org/10.1101/gad.1568407] [PMID: 17785522]
[http://dx.doi.org/10.1371/journal.pone.0100150] [PMID: 24936652]
[http://dx.doi.org/10.1111/jnc.14098] [PMID: 28608560]
[http://dx.doi.org/10.1007/s00213-019-05193-4] [PMID: 30820632]
[http://dx.doi.org/10.1073/pnas.0711278105] [PMID: 18263732]
[http://dx.doi.org/10.1124/pr.110.003004] [PMID: 21079038]
[http://dx.doi.org/10.1073/pnas.87.5.1932] [PMID: 2308954]
[http://dx.doi.org/10.1038/365061a0] [PMID: 7689702]
[http://dx.doi.org/10.1126/science.1115740] [PMID: 16224028]
[http://dx.doi.org/10.1111/adb.12367] [PMID: 26833913]
[http://dx.doi.org/10.1016/j.neuron.2011.11.018] [PMID: 22284189]
[http://dx.doi.org/10.1038/npp.2012.123] [PMID: 22850737]
[http://dx.doi.org/10.2174/0929867054020891] [PMID: 15974990]
[http://dx.doi.org/10.1073/pnas.0409888102] [PMID: 15705714]
[http://dx.doi.org/10.1126/science.1063545] [PMID: 11976437]
[http://dx.doi.org/10.1016/S0306-4522(98)00524-7] [PMID: 10218792]
[http://dx.doi.org/10.1523/JNEUROSCI.4362-08.2009] [PMID: 19494144]
[http://dx.doi.org/10.1080/19336950.2019.1619436] [PMID: 31096838]
[http://dx.doi.org/10.1016/j.neuroscience.2005.10.069] [PMID: 16368195]
[http://dx.doi.org/10.1016/j.gene.2006.09.016] [PMID: 17126498]
[http://dx.doi.org/10.1016/j.gene.2015.07.036] [PMID: 26192460]
[http://dx.doi.org/10.1016/j.mce.2008.11.014] [PMID: 19071191]
[PMID: 10496968]
[http://dx.doi.org/10.1016/j.aquatox.2013.12.005] [PMID: 24411165]
[http://dx.doi.org/10.1016/j.bbr.2017.09.028] [PMID: 28935439]
[http://dx.doi.org/10.1007/3-540-26573-2_17] [PMID: 16596786]
[http://dx.doi.org/10.1093/pm/pnx058] [PMID: 28387833]
[http://dx.doi.org/10.3389/fnmol.2020.00054] [PMID: 32410959]
[http://dx.doi.org/10.1016/S0091-3057(98)00012-4] [PMID: 9632241]
[http://dx.doi.org/10.1007/978-981-13-1756-9_4] [PMID: 30306513]
[http://dx.doi.org/10.1016/S0014-5793(00)01403-4] [PMID: 10767424]
[http://dx.doi.org/10.1038/386173a0] [PMID: 9062189]
[http://dx.doi.org/10.1073/pnas.95.17.10240] [PMID: 9707631]
[http://dx.doi.org/10.1074/jbc.271.14.7879] [PMID: 8626462]
[http://dx.doi.org/10.1074/jbc.272.47.29778] [PMID: 9368048]
[http://dx.doi.org/10.1074/jbc.272.34.20975] [PMID: 9261094]
[http://dx.doi.org/10.1097/00001756-200007140-00031] [PMID: 10923674]
[http://dx.doi.org/10.1152/ajpcell.00127.2004] [PMID: 15115705]
[http://dx.doi.org/10.1074/jbc.M313507200] [PMID: 14701823]
[http://dx.doi.org/10.1046/j.1471-4159.1999.0720051.x] [PMID: 9886053]
[http://dx.doi.org/10.1097/00001756-200006050-00003] [PMID: 10852210]
[http://dx.doi.org/10.1074/jbc.M608002200] [PMID: 17012229]
[http://dx.doi.org/10.1016/j.bbrc.2005.09.054] [PMID: 16185661]
[http://dx.doi.org/10.1074/jbc.M401477200] [PMID: 14970195]
[http://dx.doi.org/10.1016/j.pain.2005.01.021] [PMID: 15777880]
[http://dx.doi.org/10.1016/j.expneurol.2005.10.009] [PMID: 16297914]
[http://dx.doi.org/10.1016/j.applanim.2016.12.003]
[http://dx.doi.org/10.1016/0091-3057(86)90043-2] [PMID: 3945666]
[http://dx.doi.org/10.1016/j.conb.2010.08.005] [PMID: 20817512]
[http://dx.doi.org/10.1155/2017/9724371] [PMID: 28706741]
[http://dx.doi.org/10.1016/S0301-0082(00)00039-3] [PMID: 11164999]
[http://dx.doi.org/10.1002/cne.1390] [PMID: 11745628]
[http://dx.doi.org/10.1016/j.bcp.2007.01.014] [PMID: 17266939]
[http://dx.doi.org/10.1073/pnas.0705924104] [PMID: 17686976]
[http://dx.doi.org/10.1016/0304-3959(77)90130-0] [PMID: 564014]
[http://dx.doi.org/10.1007/s12038-020-00064-z] [PMID: 32713857]
[http://dx.doi.org/10.3181/00379727-95-23345] [PMID: 13465785]
[http://dx.doi.org/10.3390/ph4040665]
[http://dx.doi.org/10.1016/j.neulet.2019.134336] [PMID: 31220523]
[http://dx.doi.org/10.1056/NEJMra1201534] [PMID: 23902484]
[http://dx.doi.org/10.1097/j.pain.0000000000001384] [PMID: 30586067]
[http://dx.doi.org/10.1037/0033-2909.133.4.581] [PMID: 17592957]
[http://dx.doi.org/10.1016/j.neuroscience.2019.05.025] [PMID: 31125603]
[http://dx.doi.org/10.1016/j.bbr.2012.01.001] [PMID: 22245257]
[http://dx.doi.org/10.1002/da.20633] [PMID: 19957279]
[http://dx.doi.org/10.1016/S0140-6736(18)31948-2] [PMID: 30396512]
[http://dx.doi.org/10.1155/2013/340473] [PMID: 23710115]
[http://dx.doi.org/10.1016/j.mcna.2015.08.012] [PMID: 26614719]
[http://dx.doi.org/10.1007/s00441-019-03003-z] [PMID: 30778732]
[http://dx.doi.org/10.1126/scisignal.aaj1549] [PMID: 28325815]
[http://dx.doi.org/10.1007/s13311-012-0118-9] [PMID: 22460561]
[http://dx.doi.org/10.1007/s00213-015-4195-4] [PMID: 26728893]
[http://dx.doi.org/10.1016/j.aquatox.2014.08.014] [PMID: 25245382]
[http://dx.doi.org/10.1111/ejn.12932] [PMID: 25900095]
[http://dx.doi.org/10.1089/zeb.2012.0861] [PMID: 23590400]
[http://dx.doi.org/10.1016/j.neuropharm.2013.03.006] [PMID: 23541719]
[http://dx.doi.org/10.1089/zeb.2014.0976] [PMID: 24979389]
[http://dx.doi.org/10.1242/jeb.147058] [PMID: 28855318]
[http://dx.doi.org/10.3389/fncir.2013.00063] [PMID: 23580329]
[http://dx.doi.org/10.1186/1471-2164-13-246] [PMID: 22702965]
[PMID: 30476525]
[http://dx.doi.org/10.1016/j.jep.2020.113383] [PMID: 32918992]
[http://dx.doi.org/10.1016/j.pbb.2020.172928] [PMID: 32289330]
[http://dx.doi.org/10.1126/sciadv.aav1966] [PMID: 30402545]
[http://dx.doi.org/10.1038/nature12111] [PMID: 23594743]
[http://dx.doi.org/10.1080/01677063.2019.1698565] [PMID: 31902276]
[http://dx.doi.org/10.1016/0168-9525(89)90103-0] [PMID: 2686119]
[http://dx.doi.org/10.1016/bs.mcb.2016.04.023] [PMID: 27443924]
[http://dx.doi.org/10.1016/bs.adgen.2015.09.002] [PMID: 26639914]
[http://dx.doi.org/10.1016/j.expneurol.2018.10.008] [PMID: 30316835]
[http://dx.doi.org/10.3389/fcell.2020.00525] [PMID: 32695781]
[http://dx.doi.org/10.1098/rsob.160312] [PMID: 28148823]
[http://dx.doi.org/10.1002/glia.22856] [PMID: 25976648]
[http://dx.doi.org/10.1177/2472630319841412] [PMID: 31013465]
[http://dx.doi.org/10.1089/zeb.2018.1662] [PMID: 30625048]