Big dynorphin

Big dynorphin is an endogenous opioid peptide of the dynorphin family that is composed of both dynorphin A and dynorphin B. ^{[1] [2]} It is derived from the precursor protein prodynorphin, encoded by the PDYN gene. Big dynorphin is notable for its potent activity at opioid receptors and its role in modulating pain, stress, emotion, and neurophysiological functions such as learning and memory. Big dynorphin 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. ^[2] It has nociceptive and anxiolytic-like properties, as well as effects on memory in mice. ^{[3] [4]}

Big dynorphin is a principal endogenous, agonist at the human kappa-opioid receptor. ^{[1] [5]}

Receptor Binding and Activity

Big dynorphin primarily acts as an agonist at κ-opioid receptors, where it exhibits high potency and efficacy, leading to analgesic, dysphoric, and sedative effects ^[6] . Additionally, evidence suggests it may also interact with NMDA (N-methyl-D-aspartate) receptors independently of opioid pathways, contributing to effects on synaptic plasticity and neurotoxicity. ^[7]

Physiological and Behavioral Effects

Research has implicated big dynorphin in a variety of physiological processes:

• Pain modulation: Like other dynorphins, big dynorphin can produce analgesic effects but may also induce hyperalgesia in certain contexts. ^{[8] [6]}
• Emotion and stress: Big dynorphin is involved in the regulation of anxiety-like and depressive-like behaviors, often through its activation of the dynorphin/KOR system. ^[9]
• Memory and learning: It has been shown to impair spatial memory in rodent models, possibly through NMDA receptor modulation. ^[7]

Pathophysiological Roles

Big dynorphin levels are altered in several neuropsychiatric and neurodegenerative conditions:

• Depression and addiction: Alterations in dynorphin signaling, including big dynorphin, are linked to substance use disorders and stress-related mood disorders. ^[9]

See Also

[edit]

• Dynorphin
• κ-Opioid receptor
• Prodynorphin
• Endogenous opioid peptides

References

1. "Big dynorphin: Biological activity". IUPHAR/BPS Guide to PHARMACOLOGY. International Union of Basic and Clinical Pharmacology. Retrieved 20 October 2017. Principal endogenous agonists at κ receptor
2. "Big dynorphin: Structure – Peptide Sequence". IUPHAR/BPS Guide to PHARMACOLOGY. International Union of Basic and Clinical Pharmacology. Retrieved 20 October 2017. 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
3. Kuzmin, Alexander; Madjid, Nather; Terenius, Lars; Ogren, Sven Ove; Bakalkin, Georgy (2005). "Big Dynorphin, a Prodynorphin-Derived Peptide Produces NMDA Receptor-Mediated Effects on Memory, Anxiolytic-Like and Locomotor Behavior in Mice". Neuropsychopharmacology. 31 (9): 1928–1937. doi: 10.1038/sj.npp.1300959 . ISSN   0893-133X. PMID   16292317.
4. Tan-No K, Esashi A, Nakagawasai O, et al. (2002). "Intrathecally administered big dynorphin, a prodynorphin-derived peptide, produces nociceptive behavior through an N-methyl-D-aspartate receptor mechanism". Brain Res. 952 (1): 7–14. doi:10.1016/S0006-8993(02)03180-3. PMID   12363399. S2CID   1734522.
5. Merg F, Filliol D, Usynin I, et al. (2006). "Big dynorphin as a putative endogenous ligand for the kappa-opioid receptor". J. Neurochem. 97 (1): 292–301. doi: 10.1111/j.1471-4159.2006.03732.x . PMID   16515546.
6. Lai, Josephine; Luo, Miaw-Chyi; Chen, Qingmin; Ma, Shouwu; Gardell, Luis R.; Ossipov, Michael H.; Porreca, Frank (1982-01-22). "Dynorphin A activates bradykinin receptors to maintain neuropathic pain". Nature Neuroscience. 9 (12): 1534–1540. doi:10.1038/nn1804. ISSN   1546-1726. PMID   17115041.
7. Kanemitsu, Yoshio; Hosoi, Masako; Zhu, Ping Jun; Weight, Forrest F; Peoples, Robert W; McLaughlin, Joseph S; Zhang, Li (November 2003). "Dynorphin A inhibits NMDA receptors through a pH-dependent mechanism". Molecular and Cellular Neuroscience. 24 (3): 525–537. doi:10.1016/S1044-7431(03)00214-8. PMID   14664805.
8. Vanderah, Todd W.; Gardell, Luis R.; Burgess, Shannon E.; Ibrahim, Mohab; Dogrul, Ahmet; Zhong, Cheng-Min; Zhang, En-Tan; Malan, T. Philip; Ossipov, Michael H.; Lai, Josephine; Porreca, Frank (2000-09-15). "Dynorphin Promotes Abnormal Pain and Spinal Opioid Antinociceptive Tolerance". The Journal of Neuroscience. 20 (18): 7074–7079. doi:10.1523/JNEUROSCI.20-18-07074.2000. ISSN   0270-6474. PMC   6772839 . PMID   10995854.
9. Bruchas, M.R.; Land, B.B.; Chavkin, C. (February 2010). "The dynorphin/kappa opioid system as a modulator of stress-induced and pro-addictive behaviors". Brain Research. 1314: 44–55. doi:10.1016/j.brainres.2009.08.062. PMC   2819621 . PMID   19716811.