Opiate Sensitivity in Fruit Flies
Main Article Content
Abstract
Substance use disorder is a debilitating clinical condition in which behavioral dependence results from biological, environmental, genetic, and psychosocial factors. An epidemic surrounding the use and abuse of opioids is ravaging the world. While considerable efforts have explored the social drivers of addiction, a deeper understanding of biological causes and genetic vulnerabilities, preventative interventions, and effective treatments, have all proven elusive. This perspective article aims to remind readers that addictive natural compounds such as cocaine, nicotine, cathinone, or morphine, evolved as defensive metabolites to deter insect herbivory. The molecular mechanisms underlying motivational seeking and learning/reward show remarkable conservation since their early emergence in bilateral metazoans. An extended coevolutionary arms race subsequently weaponized these compounds into disruptors of learning, motivation, and incentivized attention. When plant chemical defenses attack insect physiology, humans are rendered susceptible due to strong conservation in the underlying molecular machinery. This perspective addresses the paradox that opiates were shaped to target insect neuropharmacology, even though this taxon appears to lack the recognized opioid receptor clade of mammals. We argue that the link is to be found in the allatostatin receptor, a basal ortholog of opioid receptors. Moreover, preliminary evidence indicates that morphine reduces Drosophila feeding and locomotion, concordant with a purported role as a defensive compound reducing herbivory. An implementation via allatostatin-mediated mechanisms is likely. This research argues for a broader heuristic perspective of substance abuse and a recognition of the evolutionary constraints that have likely shaped the biological drivers of opioid sensitivity and of its behavioral targets.
Keywords:
Substance use disorder, morphine, fentanyl, opioid addiction, plant-insect coevolution
Article Details
How to Cite
KARNIB, Nabil et al.
Opiate Sensitivity in Fruit Flies.
Medical Research Archives, [S.l.], v. 11, n. 4, apr. 2023.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/3711>. Date accessed: 26 dec. 2024.
doi: https://doi.org/10.18103/mra.v11i4.3711.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
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[9] Corbit LH, Nie H, Janak PH. Habitual alcohol seeking: time course and the contribution of subregions of the dorsal striatum. Biol Psychiatry. 2012;72(5):389-395.
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[18] Karnib N, van Staaden MJ. The Deep Roots of Addiction: A Comparative Perspective. Brain Behav Evol. 2020;95(5):222-229.
[19] Nargeot R, Bédécarrats A. Associative Learning in Invertebrates. The Oxford Handbook of Invertebrate Neurobiology. Published online 2019:536-558. doi:10.1093/oxfordhb/9780190456757.013.32
[20] Hawkins RD, Kandel ER, Bailey CH. Molecular mechanisms of memory storage in Aplysia. Biol Bull. 2006;210(3):174-191.
[21] Giurfa M, Sandoz JC. Invertebrate learning and memory: Fifty years of olfactory conditioning of the proboscis extension response in honeybees. Learn Mem. 2012;19(2):54-66.
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[27] Holden-Dye L, Walker RJ. Invertebrate models of behavioural plasticity and human disease. Brain Neurosci Adv. 2018;2:2398212818818068.
[28] Surguchov A. Invertebrate Models Untangle the Mechanism of Neurodegeneration in Parkinson’s Disease. Cells. 2021;10(2):407. doi:10.3390/cells10020407
[29] Walters ET, Williams AC de C. Evolution of mechanisms and behaviour important for pain. Philos Trans R Soc Lond B Biol Sci. 2019;374(1785):20190275.
[30] Walters ET. Nociceptive Biology of Molluscs and Arthropods: Evolutionary Clues About Functions and Mechanisms Potentially Related to Pain. Front Physiol. 2018;9:1049.
[31] van Staaden M, Huber R. Editorial: Invertebrate Models of Natural and Drug-Sensitive Reward. Front Physiol. 2019;10:490.
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[33] Dohrmann M, Wörheide G. Dating early animal evolution using phylogenomic data. Sci Rep. 2017;7(1):3599.
[34] Birgül N, Weise C, Kreienkamp HJ, Richter D. Reverse physiology in drosophila: identification of a novel allatostatin-like neuropeptide and its cognate receptor structurally related to the mammalian somatostatin/galanin/opioid receptor family. EMBO J. 1999;18(21):5892-5900.
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[36] Konopka RJ, California Institute of Technology. Division of Biology. Circadian Clock Mutants of Drosophila Melanogaster.; 1972.
[37] Mariano V, Achsel T, Bagni C, Kanellopoulos AK. Modelling Learning and Memory in Drosophila to Understand Intellectual Disabilities. Neuroscience. 2020;445:12-30.
[38] Rajan A, Perrimon N. Of flies and men: insights on organismal metabolism from fruit flies. BMC Biol. 2013;11:38.
[39] Bangi E. Drosophila at the intersection of infection, inflammation, and cancer. Front Cell Infect Microbiol. 2013;3:103.
[40] Neely GG, Gregory Neely G, Hess A, Costigan M, Keene AC, Goulas S, et al. A Genome-wide Drosophila Screen for Heat Nociception Identifies α2δ3 as an Evolutionarily Conserved Pain Gene. Cell. 2010;143(4):628-638. doi:10.1016/j.cell.2010.09.047
[41] King EG, Macdonald SJ, Long AD. Properties and power of the Drosophila Synthetic Population Resource for the routine dissection of complex traits. Genetics. 2012;191(3):935-949.
[42] Baker BM, Carbone MA, Huang W, Anholt RRH, Mackay TFC. Genetic basis of variation in cocaine and methamphetamine consumption in outbred populations of. Proc Natl Acad Sci U S A. 2021;118(23). doi:10.1073/pnas.2104131118
[43] Kaun KR, Devineni AV, Heberlein U. Drosophila melanogaster as a model to study drug addiction. Hum Genet. 2012;131(6):959-975.
[44] Philyaw TJ, Rothenfluh A, Titos I. The Use of Drosophila to Understand Psychostimulant Responses. Biomedicines. 2022;10(1):119. doi:10.3390/biomedicines10010119
[45] Bainton RJ, Tsai LT, Singh CM, Moore MS, Neckameyer WS, Heberlein U. Dopamine modulates acute responses to cocaine, nicotine and ethanol in Drosophila. Curr Biol. 2000;10(4):187-194.
[46] Kanno M, Hiramatsu S, Kondo S, Tanimoto H, Ichinose T. Voluntary intake of psychoactive substances is regulated by the dopamine receptor Dop1R1 in Drosophila. Sci Rep. 2021;11(1):3432.
[47] Devineni AV, Heberlein U. Preferential ethanol consumption in Drosophila models features of addiction. Curr Biol. 2009;19(24):2126-2132.
[48] Kaun KR, Azanchi R, Maung Z, Hirsh J, Heberlein U. A Drosophila model for alcohol reward. Nat Neurosci. 2011;14(5):612-619.
[49] Petruccelli E, Feyder M, Ledru N, Jaques Y, Anderson E, Kaun KR. Alcohol Activates Scabrous-Notch to Influence Associated Memories. Neuron. 2018;100(5):1209-1223.e4.
[50] Lasek AW, Kapfhamer D, Kharazia V, Gesch J, Giorgetti F, Heberlein U. Lmo4 in the nucleus accumbens regulates cocaine sensitivity. Genes Brain Behav. 2010;9(7):817-824.
[51] Scholz H, Franz M, Heberlein U. The hangover gene defines a stress pathway required for ethanol tolerance development. Nature. 2005;436(7052):845-847.
[52] Elphick MR, Mirabeau O, Larhammar D. Evolution of neuropeptide signalling systems. J Exp Biol. 2018;221(Pt 3). doi:10.1242/jeb.151092
[53] Birgül N, Weise C, Kreienkamp HJ, Richter D. Reverse physiology in drosophila: identification of a novel allatostatin-like neuropeptide and its cognate receptor structurally related to the mammalian somatostatin/galanin/opioid receptor family. EMBO J. 1999;18(21):5892-5900.
[54] Hewes RS. Neuropeptides and Neuropeptide Receptors in the Drosophila melanogaster Genome. Genome Research. 2001;11(6):1126-1142. doi:10.1101/gr.169901
[55] Hauser F. Identifying neuropeptide and protein hormone receptors in Drosophila melanogaster by exploiting genomic data. Briefings in Functional Genomics and Proteomics. 2006;4(4):321-330. doi:10.1093/bfgp/eli003
[56] Kelley LA, Mezulis S, Yates CM, Wass MN, Sternberg MJE. The Phyre2 web portal for protein modeling, prediction and analysis. Nature Protocols. 2015;10(6):845-858. doi:10.1038/nprot.2015.053
[57] Stevens CW. The evolution of vertebrate opioid receptors. Front Biosci . 2009;14(4):1247-1269.
[58] Schmidtke P, Le Guilloux V, Maupetit J, Tuffery P. fpocket: online tools for protein ensemble pocket detection and tracking. Nucleic Acids Research. 2010;38(Web Server):W582-W589. doi:10.1093/nar/gkq383
[59] Guilloux VL, Le Guilloux V, Schmidtke P, Tuffery P. Fpocket: An open source platform for ligand pocket detection. BMC Bioinformatics. 2009;10(1). doi:10.1186/1471-2105-10-168
[60] Panksepp J, Moskal J. Dopamine and SEEKING: Subcortical “Reward” Systems and Appetitive Urges. Handbook of Approach and Avoidance Motivation. doi:10.4324/9780203888148.ch5
[61] Hergarden AC, Tayler TD, Anderson DJ. Allatostatin-A neurons inhibit feeding behavior in adult Drosophila. Proceedings of the National Academy of Sciences. 2012;109(10):3967-3972. doi:10.1073/pnas.1200778109
[62] Bendena WG, Boudreau JR, Papanicolaou T, Maltby M, Tobe SS, Chin-Sang ID. A Caenorhabditis elegans allatostatin/galanin-like receptor NPR-9 inhibits local search behavior in response to feeding cues. Proc Natl Acad Sci U S A. 2008;105(4):1339-1342.
[63] Hentze JL, Carlsson MA, Kondo S, Nässel DR, Rewitz KF. The Neuropeptide Allatostatin A Regulates Metabolism and Feeding Decisions in Drosophila. Sci Rep. 2015;5:11680.
[64] Kubrak O, Koyama T, Ahrentløv N, Jensen L, Malita A, Naseem MT, et al. The gut hormone Allatostatin C/Somatostatin regulates food intake and metabolic homeostasis under nutrient stress. Nat Commun. 2022;13(1):692.
[65] Hergarden AC, Tayler TD, Anderson DJ. Allatostatin-A neurons inhibit feeding behavior in adult Drosophila. Proc Natl Acad Sci U S A. 2012;109(10):3967-3972.
[66] Yamagata N, Hiroi M, Kondo S, Abe A, Tanimoto H. Suppression of Dopamine Neurons Mediates Reward. PLoS Biol. 2016;14(12):e1002586.
[67] Donelson NC, Kim EZ, Slawson JB, Vecsey CG, Huber R, Griffith LC. High-resolution positional tracking for long-term analysis of Drosophila sleep and locomotion using the “tracker” program. PLoS One. 2012;7(5):e37250.
[68] Murphy KR, Park JH, Huber R, Ja WW. Simultaneous measurement of sleep and feeding in individual Drosophila. Nature Protocols. 2017;12(11):2355-2359. doi:10.1038/nprot.2017.096
[69] Wink M. Plant Secondary Metabolites Modulate Insect Behavior-Steps Toward Addiction? Frontiers in Physiology. 2018;9. doi:10.3389/fphys.2018.00364
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