Editing Poison dart frog (section)

== Toxicity and medicine ==

[[File:Epipedobates tricolor close.jpg|left|thumb|The skin of the [[phantasmal poison frog]] contains [[epibatidine]]]]
The chemical defense mechanisms of the Dendrobates family are the result of exogenous means.<ref name="Darst-2005">{{Cite journal |last1=Darst |first1=Catherine R. |last2=Menéndez-Guerrero |first2=Pablo A. |last3=Coloma |first3=Luis A. |last4=Cannatella |first4=David C. |year=2005 |editor-last=Pagel |editor-first=Mark |title=Evolution of Dietary Specialization and Chemical Defense in Poison Frogs (Dendrobatidae): A Comparative Analysis |url=https://www.journals.uchicago.edu/doi/10.1086/426599 |journal=The American Naturalist |publisher=University of Chicago Press |volume=165 |issue=1 |pages=56–69 |doi=10.1086/426599 |pmid=15729640 |s2cid=22454251 |access-date=2022-12-31|url-access=subscription }}</ref> Essentially, this means that their ability to defend has come through the consumption of a particular diet – in this case, toxic arthropods – from which they absorb and reuse the consumed toxins.<ref name="Darst-2005" /> The secretion of these chemicals is released by the granular glands of the frog.<ref name="Darst-2005" /> The chemicals secreted by the Dendrobatid family of frogs are alkaloids that differ in chemical structure and toxicity.<ref name="Darst-2005" /> 

Many poison dart frogs secrete [[lipophilic]] [[alkaloid]] toxins such as [[allopumiliotoxin 267A]], [[batrachotoxin]], [[epibatidine]], [[histrionicotoxin]], and [[pumiliotoxin 251D]] through their skin. Alkaloids in the skin glands of poison dart frogs serve as a chemical defense against predation, and they are therefore able to be active alongside potential predators during the day. About 28 structural classes of alkaloids are known in poison dart frogs.<ref name="amphibiaweb1" /><ref>{{cite web |last=Cannatella |first=David |year=1995 |title=Dendrobatidae. Poison-arrow frogs, Dart-poison frogs, Poison-dart frogs |url=http://tolweb.org/Dendrobatidae/16956/1995.01.01 |publisher=The Tree of Life Project |access-date=2008-10-23}}</ref> The most toxic of poison dart frog species is ''[[Phyllobates terribilis]]''. It is believed that dart frogs do not synthesize their poisons, but sequester the chemicals from arthropod prey items, such as ants, centipedes and mites – the diet-toxicity hypothesis.<ref name="Darst et al. 2005">{{cite journal |last1=Darst |first1=Catherine R. |last2=Menéndez-Guerrero |first2=Pablo A. |last3=Coloma |first3=Luis A. |last4=Cannatella |first4=David C. |year=2005 |title=Evolution of dietary specialization and chemical defense in poison frogs (Dendrobatidae): a comparative analysis |journal= The American Naturalist |volume=165 |pages=56–69 |pmid=15729640 |doi=10.1086/426599 |issue=1 |s2cid=22454251 }}</ref><ref>{{cite journal |doi= 10.1016/0041-0101(94)90081-7 |last1=Daly |first1=John W. |last2=Gusovsky |first2=Fabian |last3=Myers |first3=Charles W. |last4=Yotsu-Yamashita |first4=Mari |last5=Yasumoto |first5=Takeshi |title=First occurrence of tetrodotoxin in a dendrobatid frog (''Colostethus inguinalis''), with further reports for the bufonid genus ''Atelopus'' |journal= Toxicon |volume=32 |issue= 3 |year=1994 |pages=279–285 |pmid=8016850 }}</ref> Because of this, captive-bred animals do not possess significant levels of toxins as they are reared on diets that do not contain the alkaloids sequestered by wild populations. Nonetheless, the captive-bred frogs retain the ability to accumulate alkaloids when they are once again provided an alkaloidal diet.<ref>{{cite journal |last1=Saporito |first1=R. |last2=Donnelly |first2=M. |last3=Norton |first3=R. |last4=Garraffo |first4=H. |last5=Spande |first5=T. |last6=Daly |first6=J. |year=2007 |title=Oribatid mites as a major dietary source for alkaloids in poison frogs |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=104 |issue=21 |pages=8885–8890 |doi=10.1073/pnas.0702851104 |pmid=17502597 |pmc=1885597 |bibcode=2007PNAS..104.8885S |doi-access=free }}</ref> <!-- UNREFERENCED Most wild species are not lethal to their predators, but rather taste foul enough that frogs are released immediately. -->Despite the toxins used by some poison dart frogs, some predators have developed the ability to withstand them. One is the snake ''[[Erythrolamprus epinephalus]]'', which has developed immunity to the poison.<ref>{{cite journal |last1=Myers |first1=C. W. |author2=Daly, J. W. |author3=Malkin, B. |name-list-style=amp |year=1978 |title=A dangerously toxic new frog (''Phyllobates'') used by the Emberá Indians of western Colombia, with discussion of blowgun fabrication and dart poisoning |journal=Bulletin of the American Museum of Natural History |volume=161 |issue=2 |pages=307–365 + color pls. 1–2 |hdl=2246/1286}}</ref>

Chemicals extracted from the skin of ''[[Epipedobates tricolor]]'' may have medicinal value. Scientists use this poison to make a painkiller.<ref>{{cite web |url=https://www.newscientist.com/article/mg13418232.900-science-potent-painkiller-from-poisonous-frog-.html |title=Science: Potent painkiller from poisonous frog |date=30 May 1992 |publisher=[[New Scientist]] |author=Emsley, John |url-status=dead |archive-url=https://web.archive.org/web/20100407072739/http://www.newscientist.com/article/mg13418232.900-science-potent-painkiller-from-poisonous-frog-.html |archive-date=April 7, 2010 }}</ref> One such chemical is a [[painkiller]] 200 times as potent as [[morphine]], called [[epibatidine]]; however, the therapeutic dose is very close to the fatal dose.<ref>{{cite journal |last1=Prince |first1=R. J. |author2=Sine, S. M. |year=2008 |title=Epibatidine activates muscle acetylcholine receptors with unique site selectivity |journal=Biophysical Journal |volume=75 |issue=4 |pages=1817–1827 |pmid=9746523
|pmc=1299853 |doi=10.1016/S0006-3495(98)77623-4 }}</ref> A derivative, [[ABT-594]], developed by [[Abbott Laboratories]], was named as Tebanicline and got as far as Phase II trials in humans,<ref>{{Cite journal |last1=Decker |first1=M. |last2=Meyer |first2=M. |last3=Sullivan |first3=J. |title=The therapeutic potential of nicotinic acetylcholine receptor agonists for pain control |journal=Expert Opinion on Investigational Drugs |volume=10 |issue=10 |pages=1819–1830 |year=2001 |pmid=11772288 |doi=10.1517/13543784.10.10.1819 |s2cid=24924290}}</ref> but was dropped from further development due to dangerous [[gastrointestinal]] side effects.<ref>{{cite journal |last1=Meyer|first1=Michael D.|title=Neuronal nicotinic acetylcholine receptors as a target for the treatment of neuropathic pain |journal=Drug Development Research |date=2006 |volume=67 |issue=4 |pages=355–359 |doi=10.1002/ddr.20099|s2cid=84222640}}</ref> Secretions from dendrobatids are also showing promise as [[muscle relaxant]]s, heart [[stimulant]]s and [[appetite suppressant]]s.<ref>{{cite web|url=http://www.sandiegozoo.org/animalbytes/t-poison_frog.html |title=San Diego Zoo's Animal Bytes: Poison Frog |publisher=Zoological Society of San Diego |access-date=2008-10-10}}</ref> The most poisonous of these frogs, the [[golden poison frog]] (''Phyllobates terribilis''), has enough toxin on average to kill ten to twenty men or about twenty thousand mice.<ref>{{Cite web |title=Golden Poison Frog {{!}} AMNH |url=https://www.amnh.org/exhibitions/frogs-a-chorus-of-colors/poison-dart-frog-vivarium/golden-poison-frog |access-date=2022-11-16 |website=American Museum of Natural History |language=en-US}}</ref> Most other dendrobatids, while colorful and toxic enough to discourage predation, pose far less risk to humans or other large animals.{{Citation needed|date=December 2023}}[[File:Ranitomeya_amazonica.jpg|thumb|''[[Ranitomeya amazonica]]'']]

=== Conspicuousness ===
Conspicuous coloration in these frogs is further associated with diet specialization, body mass, aerobic capacity, and chemical defense.<ref name="j2" /> Conspicuousness and toxicity may be inversely related, as polymorphic poison dart frogs that are less conspicuous are more toxic than the brightest and most conspicuous species.<ref>{{cite journal |last=Wang |first=I. |author2=H. B. Shaffer |journal=Evolution |year=2008 |volume=62 |issue=11 |pages=2742–2759 |doi=10.1111/j.1558-5646.2008.00507.x |pmid=18764916 |title=Rapid Color Evolution in an Aposematic Species: A Phylogenetic Analysis of Color Variation in the Strikingly Polymorphic Strawberry Poison-Dart Frog|s2cid=6439333 |doi-access= }}</ref> Energetic costs of producing toxins and bright color pigments lead to potential trade-offs between toxicity and bright coloration,<ref>{{cite journal |last=Speed |first=I. |author2=M. A. Brockhurst |author3=G. D. Ruxton |author3-link=Graeme Ruxton |title=The dual benefits of aposematism: Predator avoidance and enhanced resource collection |journal=Evolution |year=2010 |volume=64 |issue=6 |pages=1622–1633 |doi=10.1111/j.1558-5646.2009.00931.x |pmid=20050915|s2cid=21509940 |doi-access=free }}</ref> and prey with strong secondary defenses have less to gain from costly signaling. Therefore, prey populations that are more toxic are predicted to manifest less bright signals, opposing the classical view that increased conspicuousness always evolves with increased toxicity.<ref>{{cite journal |last=Speed |first=I. |author2=G. D. Ruxton |author2-link=Graeme Ruxton |author3=J. D. Blount |author4=P. A. Stephens |title=Diversification of honest signals in a predator-prey system |journal=Ecology Letters |year=2010 |volume=13 |issue=6 |pages=744–753 |doi=10.1111/j.1461-0248.2010.01469.x|pmid=20597158 |bibcode=2010EcolL..13..744S }}</ref>

=== Aposematism ===
Skin toxicity evolved alongside bright coloration,<ref>{{cite journal |last1=Summers |first1=K. |last2=Clough |first2=M. |year=2000 |title=The evolution of coloration and toxicity in the poison frog family (Dendrobatidae) |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=98 |issue=11 |pages=6227–6232 |doi=10.1073/pnas.101134898 |pmc=33450 |pmid=11353830 |doi-access=free}}</ref> perhaps preceding it.<ref name="SantosEtAl03" /> Toxicity may have relied on a shift in diet to alkaloid-rich arthropods,<ref name="Darst et al. 2005" /> which likely occurred at least four times among the dendrobatids.<ref name="Darst et al. 2005" /> Either [[aposematism]] and aerobic capacity preceded greater resource gathering, making it easier for frogs to go out and gather the ants and mites required for diet specialization, contrary to classical aposematic theory, which assumes that toxicity from diet arises before signaling. Alternatively, diet specialization preceded higher aerobic capacity, and aposematism evolved to allow dendrobatids to gather resources without predation.<ref name="j2" /> Prey mobility could also explain the initial development of aposematic signaling. If prey have characteristics that make them more exposed to predators, such as when some dendrobatids shifted from nocturnal to diurnal behavior, then they have more reason to develop aposematism.<ref name="SantosEtAl03">{{cite journal |last=Santos |first=J. C. |author2=L. A. Coloma |author3=D. C. Cannatella |title=Multiple, recurring origins of aposematism and diet specialization in poison frogs |journal=[[PNAS]] |year=2003 |volume=100 |issue=22 |pages=12792–12797 |doi=10.1073/pnas.2133521100 |pmid=14555763 |pmc=240697|doi-access=free }}</ref> After the switch, the frogs had greater ecological opportunities, causing dietary specialization to arise. Thus, aposematism is not merely a signaling system, but a way for organisms to gain greater access to resources and increase their reproductive success.<ref>{{cite journal |last=Summers |first=K. |title=Convergent evolution of bright coloration and toxicity in frogs |journal=[[PNAS]] |year=2003 |volume=100 |issue=22 |pages=12533–12534 |doi=10.1073/pnas.2335928100 |pmid=14569014 |pmc=240648|bibcode=2003PNAS..10012533S |doi-access=free }}</ref>

=== Other factors ===
[[Dietary conservatism]] (long-term [[neophobia]]) in predators could facilitate the evolution of warning coloration, if predators avoid novel morphs for a long enough period of time.<ref>{{cite journal |last1=Marples |first1=N. M. |year=2005 |title=Perspective: The evolution of warning coloration is not paradoxical |journal=Evolution |volume=59 |pages=933–940 |pmid=16136793 |last2=Kelly |first2=D. J. |last3=Thomas |first3=R. J. |issue=5 |doi=10.1111/j.0014-3820.2005.tb01032.x |s2cid=24118222 |doi-access=free }}</ref> Another possibility is genetic drift, the so-called gradual-change hypothesis, which could strengthen weak pre-existing aposematism.<ref>{{cite journal |last1=Lindström |first1=L. |year=1999 |title=Can aposematic signals evolve by gradual change? |url=http://users.jyu.fi/~lilema/papers_files/1999_Nature.pdf|journal=Nature |volume=397 |pages=249–251 |doi=10.1038/16692 |last2=Alatalo |first2=Rauno V. |last3=Mappes |first3=Johanna |last4=Riipi |first4=Marianna |last5=Vertainen |first5=Laura |issue=6716|bibcode=1999Natur.397..249L |s2cid=4330762 }}</ref>

Sexual selection may have played a role in the diversification of skin color and pattern in poison frogs.<ref>{{cite journal|last=Mann |first=M.E. |author2=Cummings, M. E. |title=Sexual dimorphism and directional sexual selection on aposematic signals in a poison frog |journal=PNAS |year=2009 |issue=45 |pages=19072–19077 |doi=10.1073/pnas.0903327106 |volume=106 |pmid=19858491 |pmc=2776464 |bibcode=2009PNAS..10619072M |doi-access=free }}</ref><ref>{{cite journal |last=Summers |first=K. |author2=L. Bermingham |author3=S. Weigt |author4=S. McCafferty |author5=L. Dahlstrom |title=Phenotypic and genetic divergence in three species of dart-poison frogs with contrasting parental behavior |journal=The Journal of Heredity |year=1997 |volume=88 |issue=1 |pages=8–13 |pmid=9048443 |doi=10.1093/oxfordjournals.jhered.a023065|doi-access=free }}</ref><ref>{{cite journal|last=Rudh |first=A. |author2=B. Rogell |author3=J. Hoglund|title=Non-gradual variation in color morphs of the strawberry poison frog Dendrobates pumilio: genetic and geographical isolation suggest a role for selection in maintaining polymorphism |journal=Molecular Ecology |year=2007 |volume=16 |issue=20 |pages=4282–4294 |pmid=17868297 |doi=10.1111/j.1365-294X.2007.03479.x|s2cid=41814698 }}</ref><ref>{{cite journal|last=Maan |first=M. E. |author2=M. E. Cummings |title=Sexual dimorphism and directional selection on aposematic signals in a poison frog |journal=PNAS |year=2009 |volume=106|issue=45 |pages=19072–19077 |doi=10.1073/pnas.0903327106 |pmid=19858491 |pmc=2776464|bibcode=2009PNAS..10619072M |doi-access=free }}</ref> With female preferences in play, male coloration could evolve rapidly. Sexual selection is influenced by many things. The parental investment may shed some light on the evolution of coloration in relation to female choice. In ''[[Oophaga pumilio]]'', the female provides care for the offspring for several weeks whereas the males provides care for a few days, implying a strong female preference. Sexual selection increases phenotypic variation drastically. In populations of ''O. pumilio'' that participated in sexual selection, the phenotypic polymorphism was evident.<ref>{{cite journal |last=Tazzyman |first=S.J. |author2=Iwasa, Y. |title=Sexual selection can increase the effect of random genetic drift-a quantitative genetic model of polymorphism in oophaga pumilio, the strawberry poison-dart frog |journal=Evolution |year=2010 |issue=6 |pages=1719–1728 |doi=10.1111/j.1558-5646.2009.00923.x |volume=64 |pmid=20015236|s2cid=37757687 |doi-access= }}</ref> The lack of [[sexual dimorphism]] in some dendrobatid populations however suggests that sexual selection is not a valid explanation.<ref>{{cite journal |last=Rudh |first=Andreas |author2=B. Rogell |author3=O. Håstad |author4=A. Qvarnström |title=Rapid population divergence linked with co-variation between coloration and sexual display in strawberry poison frogs |journal=Evolution |year=2011 |issue=5 |pages=1271–1282 |doi=10.1111/j.1558-5646.2010.01210.x |volume=65 |pmid=21166789|s2cid=10785432 }}</ref>

Functional trade-offs are seen in poison frog defense mechanisms relating to toxin resistance. Poison dart frogs containing epibatidine have undergone a 3 amino acid mutation on receptors of the body, allowing the frog to be resistant to its own poison. Epibatidine-producing frogs have evolved poison resistance of body receptors independently three times. This target-site insensitivity to the potent toxin epibatidine on nicotinic acetylcholine receptors provides a toxin resistance while reducing the affinity of acetylcholine binding.<ref>{{Cite journal |last1=Tarvin |first1=Rebecca D. |last2=Borghese |first2=Cecilia M. |last3=Sachs |first3=Wiebke |last4=Santos |first4=Juan C. |last5=Lu |first5=Ying |last6=O'Connell |first6=Lauren A. |author-link6=Lauren O'Connell (scientist) |last7=Cannatella |first7=David C. |last8=Harris |first8=R. Adron |last9=Zakon |first9=Harold H. |date=2017-09-22 |title=Interacting amino acid replacements allow poison frogs to evolve epibatidine resistance |journal=Science |volume=357 |issue=6357 |pages=1261–1266 |bibcode=2017Sci...357.1261T |doi=10.1126/science.aan5061 |issn=0036-8075 |pmc=5834227 |pmid=28935799}}</ref>