Big dynorphin

{{Short description|Opioid peptide}} {{Chembox | ImageFile = Big dynorphin 2D.svg | ImageClass = skin-invert-image | OtherNames = {{Unbulleted list|big dyn|GTPL3669|Dynorphin (1-32)|Dynorphin-32|Dynorphin(1-32)}} | IUPACName = L-tyrosyl-glycyl-glycyl-L-phenylalanyl-L-leucyl-L-arginyl-L-arginyl-L-isoleucyl-L-arginyl-L-prolyl-L-lysyl-L-leucyl-L-lysyl-L-tryptophyl-L-alpha-aspartyl-L-asparagyl-L-glutaminyl-L-lysyl-L-arginyl-L-tyrosyl-glycyl-glycyl-L-phenylalanyl-L-leucyl-L-arginyl-L-arginyl-L-glutaminyl-L-phenylalanyl-L-lysyl-L-valyl-L-valyl-L-threonine | Reference=<ref>[https://pubchem.ncbi.nlm.nih.gov/compound/16132351 Big dynorphin - Compound Summary], PubChem.</ref> |Section1={{Chembox Identifiers | CASNo = 83328-95-4 | ChemSpiderID = 17289010 | PubChem = 16132351 | StdInChI = 1S/C185H292N58O41/c1-14-104(12)150(241-164(268)125(57-38-80-210-184(202)203)222-156(260)123(55-36-78-208-182(198)199)226-167(271)131(85-101(6)7)233-168(272)133(87-106-41-18-15-19-42-106)217-145(252)97-213-143(250)95-215-152(256)115(190)86-109-60-64-112(245)65-61-109)177(281)230-128(58-39-81-211-185(204)205)178(282)243-82-40-59-139(243)174(278)229-119(51-28-32-74-188)159(263)231-129(83-99(2)3)165(269)223-118(50-27-31-73-187)158(262)236-136(91-111-94-212-116-48-25-24-47-114(111)116)171(275)238-138(93-147(254)255)173(277)237-137(92-142(193)249)172(276)228-126(68-70-140(191)247)161(265)219-117(49-26-30-72-186)154(258)221-124(56-37-79-209-183(200)201)160(264)234-132(90-110-62-66-113(246)67-63-110)153(257)216-96-144(251)214-98-146(253)218-134(88-107-43-20-16-21-44-107)169(273)232-130(84-100(4)5)166(270)225-122(54-35-77-207-181(196)197)155(259)220-121(53-34-76-206-180(194)195)157(261)227-127(69-71-141(192)248)162(266)235-135(89-108-45-22-17-23-46-108)170(274)224-120(52-29-33-75-189)163(267)239-148(102(8)9)175(279)240-149(103(10)11)176(280)242-151(105(13)244)179(283)284/h15-25,41-48,60-67,94,99-105,115,117-139,148-151,212,244-246H,14,26-40,49-59,68-93,95-98,186-190H2,1-13H3,(H2,191,247)(H2,192,248)(H2,193,249)(H,213,250)(H,214,251)(H,215,256)(H,216,257)(H,217,252)(H,218,253)(H,219,265)(H,220,259)(H,221,258)(H,222,260)(H,223,269)(H,224,274)(H,225,270)(H,226,271)(H,227,261)(H,228,276)(H,229,278)(H,230,281)(H,231,263)(H,232,273)(H,233,272)(H,234,264)(H,235,266)(H,236,262)(H,237,277)(H,238,275)(H,239,267)(H,240,279)(H,241,268)(H,242,280)(H,254,255)(H,283,284)(H4,194,195,206)(H4,196,197,207)(H4,198,199,208)(H4,200,201,209)(H4,202,203,210)(H4,204,205,211)/t104-,105+,115-,117-,118-,119-,120-,121-,122-,123-,124-,125-,126-,127-,128-,129-,130-,131-,132-,133-,134-,135-,136-,137-,138-,139-,148-,149-,150-,151-/m0/s1 | StdInChIKey = VPZXNPNLCOYTOT-MBGMINRZSA-N | SMILES = Isomeric SMILES CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCNC(=N)N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC2=CNC3=CC=CC=C32)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](CC4=CC=C(C=C4)O)C(=O)NCC(=O)NCC(=O)N[C@@H](CC5=CC=CC=C5)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC6=CC=CC=C6)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)O)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC7=CC=CC=C7)NC(=O)CNC(=O)CNC(=O)[C@H](CC8=CC=C(C=C8)O)N }} |Section2={{Chembox Properties | C=185 | H=292 | N=58 | O=41 | MolarMass=3985 | Appearance= | Density= | MeltingPt= | BoilingPt= | Solubility= }} |Section3={{Chembox Hazards | MainHazards= | FlashPt= | AutoignitionPt = }} }}

'''Big dynorphin''' is an endogenous opioid peptide of the dynorphin family. It forms when a precursor protein prodynorphin is not fully processed, resulting in a 32-amino acid molecule containing both dynorphin A and dynorphin B sequences. It has the amino acid sequence: Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-Lys-Trp-Asp-Asn-Gln-Lys-Arg-Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Gln-Phe-Lys-Val-Val-Thr.<ref name="IUPHAR - Big dynorphin - Biological activity">{{cite web | title = Big dynorphin: Biological activity | url = http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?tab=biology&ligandId=3669 | access-date = 20 October 2017 | work = IUPHAR/BPS Guide to PHARMACOLOGY | publisher = International Union of Basic and Clinical Pharmacology | quote = Principal endogenous agonists at κ receptor | archive-url = http://web.archive.org/web/20241211062952/https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?tab=biology&ligandId=3669 | archive-date = 2024-12-11 | url-status = live}}</ref><ref name="IUPHAR - Big dynorphin - Structure">{{cite web | title = Big dynorphin: Structure – Peptide Sequence | url = http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?tab=structure&ligandId=3669 | access-date = 20 October 2017 | work = IUPHAR/BPS Guide to PHARMACOLOGY | publisher = International Union of Basic and Clinical Pharmacology | quote = Peptide sequence YGGFLRRIRPKLKWDNQKRYGGFLRRQFKVVT Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-Lys-Trp-Asp-Asn-Gln-Lys-Arg-Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Gln-Phe-Lys-Val-Val-Thr | archive-url = http://web.archive.org/web/20241212021104/https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?tab=structure&ligandId=3669 | archive-date = 2024-12-12 | url-status = live}}</ref>

Big dynorphin is a highly efficiacious principal endogenous agonist at the human κ-opioid receptor (KOR).<ref name="IUPHAR - Big dynorphin - Biological activity" /><ref name="pmid16515546">{{cite journal | vauthors = Merg F, Filliol D, Usynin I | title = Big dynorphin as a putative endogenous ligand for the kappa-opioid receptor | journal = J. Neurochem. | volume = 97 | issue = 1 | pages = 292–301 | year = 2006 | doi = 10.1111/j.1471-4159.2006.03732.x | display-authors = etal | doi-access = free | issn = 0022-3042 | pmid = 16515546}}</ref> It produces one of the strongest responses at GPR139 receptor among dynorphins.<ref name="LiWintersPandey2025">{{cite journal | vauthors = Li X, Winters ND, Pandey S, Lankford C, Stoveken HM, Smith E, Chang CT, Zucca S, Scampavia L, Spicer T, Martemyanov KA | date = July 2025 | title = Homeostatic scaling of dynorphin signaling by a non-canonical opioid receptor | journal = Nature Communications | volume = 16 | issue = 1 | article-number = 6786 | doi = 10.1038/s41467-025-62133-x | doi-access = free | issn = 2041-1723 | pmid = 40701991 | pmc = 12287315 | bibcode = 2025NatCo..16.6786L}}</ref> Additionally, it uniquely modulates NMDA receptor and potentiates acid-sensing ion channel 1a (ASIC1a).<ref name="KuzminMadjid2005">{{cite journal | vauthors = Madjid N, Terenius L, Ogren SO, Bakalkin G | year = 2005 | title = Big Dynorphin, a Prodynorphin-Derived Peptide Produces NMDA Receptor-Mediated Effects on Memory, Anxiolytic-Like and Locomotor Behavior in Mice | journal = Neuropsychopharmacology | volume = 31 | issue = 9 | pages = 1928–1937 | doi = 10.1038/sj.npp.1300959 | issn = 0893-133X | pmid = 16292317 | doi-access = free}}</ref><ref name="Sherwood2009">{{cite journal | vauthors = Sherwood TW, Askwith CC | date = November 2009 | title = Dynorphin opioid peptides enhance acid-sensing ion channel 1a activity and acidosis-induced neuronal death | journal = The Journal of Neuroscience | volume = 29 | issue = 45 | pages = 14371–14380 | doi = 10.1523/JNEUROSCI.2186-09.2009 | issn = 0270-6474 | pmid = 19906984 | pmc = 2802056 | doi-access = free}}</ref>

It plays a role in pain and stress responses. It exhibits both analgesic and pro-nociceptive properties.<ref name="pmid12363399" /> In mice it modulates memory and learning, and has anxiolytic properties, contributing to homeostatic regulation of opioid signaling in the central nervous system.<ref name="IUPHAR - Big dynorphin - Structure" /><ref name="KuzminMadjid2005" /><ref name="pmid12363399">{{cite journal | display-authors = etal | vauthors = Tan-No K, Esashi A, Nakagawasai O | year = 2002 | title = Intrathecally administered big dynorphin, a prodynorphin-derived peptide, produces nociceptive behavior through an N-methyl-D-aspartate receptor mechanism | journal = Brain Res. | volume = 952 | issue = 1 | pages = 7–14 | doi = 10.1016/S0006-8993(02)03180-3 | s2cid = 1734522 | issn = 0006-8993 | pmid = 12363399}}</ref>

== Fragments == Big dynorphin1-32 is the primary endogenously documented big dynorphin form, but various shorter big dynorphin fragments have been synthesized for research purposes. These include (2-32), (2-26), (9-19) forms.<ref name="Sherwood2009" />

== Synthesis == Big dynorphin is generated through the proteolytic processing of prodynorphin (PDYN), a 26-kilodalton precursor protein by proprotein convertase 1.<ref name="Marchette2025">{{cite journal | vauthors = Marchette RC, Vendruscolo LF, Koob GF | date = February 2025 | title = The Dynorphin/-Opioid Receptor System at the Interface of Hyperalgesia/Hyperkatifeia and Addiction | url = https://doi.org/10.1007/s40429-025-00618-x | journal = Current Addiction Reports | language = en | volume = 12 | issue = 1 | article-number = 11 | doi = 10.1007/s40429-025-00618-x | issn = 2196-2952 | pmid = 40124896 | pmc = 11925990 | doi-access = free}}</ref> The synthesis occurs within the neuronal cell body through translation of prodynorphin mRNA. Following translation, prodynorphin undergoes sequential processing by proprotein convertases, primarily PC1/3 and PC2, as well as the cysteine protease cathepsin L.<ref name="pmid16515546" /><ref name="Day1998">{{cite journal | vauthors = Day R, Lazure C, Basak A, Boudreault A, Limperis P, Dong W, Lindberg I | title = Prodynorphin processing by proprotein convertase 2. Cleavage at single basic residues and enhanced processing in the presence of carboxypeptidase activity | journal = J. Biol. Chem. | volume = 273 | issue = 2 | pages = 829–836 | date = January 1998 | doi = 10.1074/jbc.273.2.829 | doi-access = free | issn = 0021-9258 | pmid = 9422738}}</ref>

Under normal circumstances, in the presence of carboxypeptidase E, prodynorphin is fully processed by sequential cleavage at dibasic amino acid sites to generate individual dynorphin peptides: dynorphin A1-17, dynorphin B, and α-neoendorphin.<ref name="Marchette2025" /> Big dynorphin forms when this proteolytic processing is incomplete, typically resulting from insufficient proprotein convertase activity or altered intracellular calcium levels during neurotransmitter release events.<ref name="Walker1982">{{cite journal | vauthors = Walker JM, Moises HC, Coy DH, Baldrighi G, Akil H | date = December 1982 | title = Nonopiate Effects of Dynorphin and Des-Tyr-Dynorphin | url = https://www.science.org/doi/10.1126/science.6128791 | journal = Science | language = en | volume = 218 | issue = 4577 | pages = 1136–1138 | doi = 10.1126/science.6128791 | issn = 0036-8075 | pmid = 6128791 | bibcode = 1982Sci...218.1136W | url-access = subscription | archive-url = http://web.archive.org/web/20230708114807/https://www.science.org/doi/10.1126/science.6128791 | archive-date = 2023-07-08 | url-status = live}}</ref> The 32-amino acid peptide comprises the complete dynorphin A sequence (residues 1-17) joined to the complete dynorphin B sequence, with two C-terminal amino acids.

=== Release mechanism ===

Peptide's release occurs primarily in a calcium-dependent manner through exocytosis of large dense core vesicles in the presynaptic terminal.<ref name="Chavkin1982">{{cite journal | vauthors = Chavkin C, James IF, Goldstein A | title = Dynorphin is a selective endogenous ligand of the κ-opioid receptor | journal = Science | volume = 215 | issue = 4534 | pages = 413–415 | date = January 1982 | doi = 10.1126/science.6120570 | issn = 0036-8075 | pmid = 6120570}}</ref> Big dynorphin immunoreactivity has been detected in regions such as the nucleus accumbens, caudate nucleus, and hippocampus, with significant levels detected in cerebrospinal fluid. The ratio of big dynorphin to dynorphin B in human brain tissue is approximately 1:3.<ref name="pmid16515546" />

== Pharmacology ==

=== Opioid receptors === {| class="wikitable floatleft" style="font-size:small;" |+{{Nowrap|Big dynorphin activities}} !Target !Affinity (Ki, nM) |- |KOR |0.198 (Ki) 0.741 ({{Abbrlink|EC50|half-maximal effective concentration}}) 159% ({{Abbrlink|Emax|maximal efficacy}}) |- |MOR |14 (Ki) 87 ({{Abbr|EC50|half-maximal effective concentration}}) 115% ({{Abbr|Emax|maximal efficacy}}) |- |DOR |43 (Ki) 119 ({{Abbr|EC50|half-maximal effective concentration}}) 100% ({{Abbr|Emax|maximal efficacy}}) |- |NOP |105 |- |ASIC1 |26-211 ({{Abbr|EC50|half-maximal effective concentration}}) |- class="sortbottom" | colspan="2" style="width: 1px; background-color:var(--background-color-notice-subtle,#eaecf0); color:inherit; text-align: center;" |'''Notes:''' The smaller the value, the more avidly the drug interacts with the site. Max. stimulation is shown as percentage of that induced by dyn A1-17 '''Sources:''' <ref name="pmid16515546" /><ref name="Sherwood2009" /><ref name="Leisle2021" /> |} Big dynorphin acts as a potent full agonist at the human κ-opioid receptor (KOR), exhibiting extremely high relative efficacy at this target.<ref name="pmid16515546" /> In one binding assay it demonstrated similar affinity to dynorphin A, but about 14 to 32-fold higher potency to activate G proteins than other dynorphin peptides.<ref name="pmid16515546" /> In contrast, other studies have suggested similar or higher potencies of other dynorphins.<ref name="Hall2016">{{cite journal | vauthors = Hall SM, Lee YS, Hruby VJ | date = 2016 | title = Dynorphin A analogs for the treatment of chronic neuropathic pain | journal = Future Medicinal Chemistry | volume = 8 | issue = 2 | pages = 165–177 | doi = 10.4155/fmc.15.164 | issn = 1756-8919 | pmid = 26824470 | pmc = 4976860}}</ref><ref name="Zangrandi2024">{{cite journal | vauthors = Zangrandi L, Fogli B, Mutti A, Staritzbichler R, Most V, Hildebrand PW, et al | date = October 2024 | title = Structure–function relationship of dynorphin B variants using naturally occurring amino acid substitutions | journal = Frontiers in Pharmacology | language = English | volume = 15 | article-number = 1484730 | doi = 10.3389/fphar.2024.1484730 | doi-access = free | issn = 1663-9812 | pmid = 39539623 | pmc = 11557314}}</ref>

The peptide is also an agonist of other opioid receptors, It is 70-fold selective towards KOR over μ-opioid receptors (MOR) and 200 over δ-opioid receptor (DOR).<ref name="pmid16515546" />

In older guinea-pig ileum bioassay measuring native receptor function, big dynorphin shows approximately 10-20-fold reduced potency relative to dynorphin A, possibly due to conformational constraints of the larger peptide affecting receptor binding in peripheral tissue. This discrepancy suggests that big dynorphin's efficacy in human KOR systems may not translate directly to potency in peripheral tissue.<ref name="James1984">{{cite journal | vauthors = James IF, Fischli W, Goldstein A | date = January 1984 | title = Opioid receptor selectivity of dynorphin gene products. | url = https://linkinghub.elsevier.com/retrieve/pii/S0022356525216093 | journal = The Journal of Pharmacology and Experimental Therapeutics | language = en | volume = 228 | issue = 1 | pages = 88–93 | doi = 10.1016/S0022-3565(25)21609-3 | issn = 0022-3565 | url-access = subscription | archive-url = http://web.archive.org/web/20260106172036/https://linkinghub.elsevier.com/retrieve/pii/S0022356525216093 | archive-date = 2026-01-06 | url-status = live}}</ref>

Big dynorphin could theoretically produce some of the classical pharmacological effects associated with KOR agonism such as dysphoria, dissociation, and sedation, but this has not been directly evaluated.<ref name="pmid16515546" /><ref name="Luo1982">{{cite journal | vauthors = Luo MC, Chen Q, Ma S, Gardell LR, Ossipov MH, Porreca F | date = January 1982 | title = Dynorphin A activates bradykinin receptors to maintain neuropathic pain | url = https://www.nature.com/articles/nn1804 | journal = Nature Neuroscience | language = en | volume = 9 | issue = 12 | pages = 1534–1540 | doi = 10.1038/nn1804 | issn = 1097-6256 | pmid = 17115041 | url-access = subscription | archive-url = http://web.archive.org/web/20230213223258/https://www.nature.com/articles/nn1804 | archive-date = 2023-02-13 | url-status = live}}</ref> Similarly biased signaling of big dynorphin at KOR has not yet been assessed.<ref name="Gomes2020">{{cite journal | vauthors = Gomes I, Sierra S, Lueptow L, Gupta A, Gouty S, Margolis EB, et al | date = May 2020 | title = Biased signaling by endogenous opioid peptides | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 117 | issue = 21 | pages = 11820–11828 | doi = 10.1073/pnas.2000712117 | doi-access = free | issn = 0027-8424 | pmid = 32393639 | pmc = 7261131 | bibcode = 2020PNAS..11711820G}}</ref>

=== GPR139 receptor ===

Big dynorphin is one of the activators of the GPR139, a G protein-coupled receptor (GPCR), recently deorphanized as a dynorphin receptor. In a wide neuropeptide library screen it exhibited one of the highest efficacies among prodynorphin-derived peptides.<ref name="LiWintersPandey2025" />

At low concentrations, dynorphins predominantly activate canonical opioid receptors (KOR, MOR, DOR), while at higher concentrations, they additionally recruit GPR139. This receptor couples to Gq/11 G protein-mediated signaling, which is mechanistically opposite to the Gi/o inhibitory signaling of classical opioid receptors. This permits GPR139 to function as a molecular homeostatic brake: when dynorphin reaches high concentrations during intense stress or pain, simultaneous GPR139 activation counteracts excessive opioid receptor signaling through excitatory signaling pathways, preventing pathological over-inhibition of neuronal activity.<ref name="LiWintersPandey2025" />

=== NMDA receptor ===

NMDA receptors are modulated by big dynorphin, producing effects that are antagonist-insensitive to opioid receptor blockade.<ref name="KuzminMadjid2005" /> Intracerebroventricular injection of big dynorphin produced memory enhancement in passive avoidance tests, enhanced locomotor activity in the open field test''',''' and anxiolytic-like effects that were blocked by the NMDA receptor antagonist MK-801 but resistant to nor-BNI, a selective KOR antagonist.<ref name="KuzminMadjid2005" />

In contrast, dynorphin A and dynorphin B at similar doses produced analgesia (mediated by opioid receptors) but did not produce the NMDA-dependent memory enhancement, anxiolysis, or locomotor stimulation.<ref name="KuzminMadjid2005" />

Suggested mechanisms are interaction with the polyamine binding site or the NR2B subunit.<ref name="KuzminMadjid2005" /> The molecular basis for this atypical activity may involve the extended C-terminal region unique to big dynorphin, which contains multiple basic residues (arginine and lysine).<ref name="Kanemitsu2003">{{cite journal | vauthors = Kanemitsu Y, Hosoi M, Zhu PJ, Weight FF, Peoples RW, McLaughlin JS, Zhang L | date = November 2003 | title = Dynorphin A inhibits NMDA receptors through a pH-dependent mechanism | journal = Molecular and Cellular Neuroscience | volume = 24 | issue = 3 | pages = 525–537 | doi = 10.1016/S1044-7431(03)00214-8 | issn = 1044-7431 | pmid = 14664805}}</ref>

=== ASIC1a channel ===

Big dynorphin is a potent endogenous modulator of the acid-sensing ion channel 1a (ASIC1a) and current rescue following steady-state desensitization.<ref name="Sherwood2009" /><ref name="Leisle2021">{{cite journal | vauthors = Leisle L, Margreiter M, Ortega-Ramírez A, Cleuvers E, Bachmann M, Rossetti G, et al | date = September 2021 | title = Dynorphin Neuropeptides Decrease Apparent Proton Affinity of ASIC1a by Occluding the Acidic Pocket | url = https://doi.org/10.1021/acs.jmedchem.1c00447 | journal = Journal of Medicinal Chemistry | volume = 64 | issue = 18 | pages = 13299–13311 | doi = 10.1021/acs.jmedchem.1c00447 | issn = 0022-2623 | pmid = 34461722}}</ref> In comparison, dynorphin A exhibits a approximately 1000-fold lower potency than big dynorphin at this target.<ref name="Sherwood2009" />

Peptide potentiates ASIC1a current through a mechanism independent of both opioid and bradykinin receptor signaling.<ref name="Sherwood2009" /> The potency correlates with big dynorphin's features, particularly its high net positive charge (9+) and abundance of arginine residues (6 total), with residues Arg6, Arg7. Big dynorphin rescues proton-gated currents and promotes acidosis-induced neuronal cell death in cultured cortical neurons, implicating it in pathological conditions involving cellular acidification and excitotoxicity.<ref name="Borg2020">{{cite journal | vauthors = Borg CB, Braun N, Heusser SA, Bay Y, Weis D, Galleano I, et al | last13 = Andersen | first13 = Jacob | last14 = Pless | first14 = Stephan A. | date = February 2020 | title = Mechanism and Binding Site of the ASIC1A-Big Dynorphin Interaction | url = https://linkinghub.elsevier.com/retrieve/pii/S0006349519340913 | journal = Biophysical Journal | language = en | volume = 118 | issue = 3 | pages = 582a | doi = 10.1016/j.bpj.2019.11.3158 | bibcode = 2020BpJ...118..582B | issn = 0006-3495 | archive-url = http://web.archive.org/web/20260106071110/https://linkinghub.elsevier.com/retrieve/pii/S0006349519340913 | archive-date = 2026-01-06 | url-status = live}}</ref>

== Functions and effects ==

=== Pain modulation ===

Like other dynorphin peptides, big dynorphin can produce analgesic effects through κ-opioid receptor (KOR) activation at spinal nociceptive sites.<ref name="Luo1982" /> However, at supraspinal levels through non-opioid mechanisms involving NMDA receptor modulation and ASIC1a activation, big dynorphin can produce pro-nociceptive effects, enhancing pain sensitivity in both acute and chronic pain states.<ref name="pmid12363399" />

=== Memory and learning ===

It has been shown that big dynorphin enhances learning in rodent models through NMDA receptor modulation.<ref name="KuzminMadjid2005" /> This contrasts with the amnestic effects typically associated with opioid receptor agonists and other dynorphins. The mechanism may involve modulation of the NR2B subunit, a modulator of cortical synaptic plasticity and long-term potentiation (LTP).<ref name="KuzminMadjid2005" />

== Clinical significance ==

=== Neurodegeneration and chronic pain ===

Big dynorphin is upregulated in spinal cord injury and chronic pain states, where excessive big dynorphin production through both opioid and non-opioid receptor mechanisms contribute to neuronal death, neuroinflammation, and pain chronification.<ref name="Sherwood2009" />

=== Alzheimer's Disease === In contrary, big dynorphin exhibits neuroprotective properties against amyloid-β (Aβ) accumulation in Alzheimer's disease. It reduces the hydrophobicity and slows the aggregation kinetics of Aβ40, the most abundant amyloid species, resulting in around 2-fold reduction in amyloid aggregation compared to Aβ alone.<ref name="Gallego-Villarejo2022">{{cite journal | vauthors = Gallego-Villarejo L, Wallin C, Król S, Enrich-Bengoa J, Suades A, Aguilella-Arzo M, et al | date = 2022 | title = Big dynorphin is a neuroprotector scaffold against amyloid β-peptide aggregation and cell toxicity | journal = Computational and Structural Biotechnology Journal | volume = 20 | pages = 5672–5679 | doi = 10.1016/j.csbj.2022.10.014 | issn = 2001-0370 | pmid = 36284704 | pmc = 9582793 | doi-access = free}}</ref> In human neuroblastoma cell cultures, big dynorphin pre-incubated with Aβ40 significantly increased cell viability to compared to Aβ40 alone.<ref name="Gallego-Villarejo2022" /> The neuroprotective mechanism involves big dynorphin's cationic amino acid residues stabilizing negatively charged regions of Aβ, preventing the β-sheet transition and maintaining Aβ in an α-helical conformation.<ref name="Gallego-Villarejo2022" /> These findings suggest therapeutic potential for big dynorphin-derived peptides in Alzheimer's disease treatment.

==References== {{Reflist|2}}

Category:Neuropeptides Category:Kappa-opioid receptor agonists Category:Opioid peptides