Regulatory effect of а synthetic opioid neuropeptid on protein homeostasis under cold stress conditions

  • N. M. Moisieieva Institute of Cryobiology and Cryomedicine of the National Academy of Sciences of Ukraine, 23 Pereyaslavska st, 61016, Kharkiv, Ukraine https://orcid.org/0000-0002-9845-2317
  • V. H. Myrnyi Institute of Cryobiology and Cryomedicine of the National Academy of Sciences of Ukraine, 23 Pereyaslavska st, 61016, Kharkiv, Ukraine https://orcid.org/0009-0001-2393-2295
  • Y. S. Akhatova Institute of Cryobiology and Cryomedicine of the National Academy of Sciences of Ukraine, 23 Pereyaslavska st, 61016, Kharkiv, Ukraine https://orcid.org/0000-0002-1536-6924
  • O. L. Horina Institute of Cryobiology and Cryomedicine of the National Academy of Sciences of Ukraine, 23 Pereyaslavska st, 61016, Kharkiv, Ukraine https://orcid.org/0000-0003-4075-650X
Keywords: cryobiology, low temperatures, hypothermia, cold adaptation, dalargin, opioid receptors, protein metabolism, homeothermic animals, аlbumins, globulins, stress

Abstract

Background: Opioid neuropeptides are capable of regulating metabolic processes through the activation of specific opioid receptors, particularly under stress conditions. However, the mechanisms of their impact on protein metabolism under chronic cold stress (CCS) remain insufficiently studied. Given the importance of maintaining protein homeostasis under extreme conditions, investigating the role of neuropeptides in correcting protein profiles is of practical significance for developing new approaches to pharmacological adaptation.

Objective: To investigate changes in protein metabolism in the serum of guinea pigs under chronic cold stress, assess the protective effects of dalargin, and determine the role of the opioid system in regulating these processes.

Materials and Methods: The study involved guinea pigs exposed to CCS conditions. Changes in protein metabolism were assessed by measuring total protein, albumin, and globulins in the serum using standard biochemical methods. A synthetic leu-enkephalin analog (dalargin) was used as a corrective agent and administered subcutaneously at a dose of 100 µg/kg 30 min before CCS induction.

Results. In animals exposed to CCS, a statistically significant decrease in albumin levels and an increase in globulin levels were observed compared with intact values, which led to a disruption of the albumin–globulin ratio and indicated an imbalance in protein metabolism. Administration of dalargin contributed to normalization of the albumin–globulin ratio by restoring globulin and albumin levels in the blood of experimental animals, indicating stabilization of protein homeostasis and a protective effect of dalargin under conditions of CCS.

In addition, administration of dalargin reduced the accumulation of malondialdehyde (MDA) under conditions of cold stress, demonstrating antioxidant and cytoprotective effects and ensuring the maintenance of structural and functional integrity of tissues.

Conclusions. The study results suggest that dalargin is a promising agent for the pharmacological correction of metabolic disturbances induced by chronic cold stress, as it reduces MDA accumulation, exhibiting antioxidant and cytoprotective effects, and highlight the important role of the opioid neuropeptide system in the regulation of protein metabolism and maintenance of tissue structural integrity under extreme environmental conditions.

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References

Gao R, Shi L, Guo W, Xu Y, Jin X, Yan S, et al. Effects of housing and management systems on the growth, immunity, antioxidation, and related physiological and biochemical indicators of donkeys in cold weather. Animals. 2022;12(18):2405. https://doi.org/10.3390/ani12182405

Gao Y, Liu Y, He J, Zhang Y, Wang T, Wu L, et al. Effects of heat waves and cold spells on blood parameters: a cohort study of blood donors in Tianjin, China. Environ Health Prev Med. 2024;29:25. https://doi.org/10.1265/ehpm.24-00023

Saeki K, Obayashi K, Kurumatani N. Platelet count and indoor cold exposure among elderly people: A cross-sectional analysis of the HEIJO-KYO study. J Epidemiol. 2017;27(12):562–7. https://doi.org/10.1016/j.je.2016.12.018

Moisieieva N, Gulevskyy O, Gorina O. Effect of leu-enkephalin (dalargin) on apoptosis and necrosis of leukocytes after cold stress. Probl Cryobiol Cryomed. 2022;32(1):14–23. https://doi.org/10.15407/cryo32.01.014

Gulevskyy OK, Moisieieva NM, Gorina OL, Sidorenko OS. Preincubation of L929 line fibroblasts with synthetic leu-enkephalin TYR-D-ALA-GLY-PHE-LEU-ARG preserves their proliferative potential under cold stress. Cytol Genet. 2022;56:343–50. https://doi.org/10.3103/S0095452722040053

Tomé D, Benoit S, Azzout-Marniche D. Protein metabolism and related body function: mechanistic approaches and health consequences. Proc Nutr Soc. 2021;80(2):243–51. https://doi.org/10.1017/S0029665120007880

Liu Y, Liu P, Hu Y, Cao Y, Lu J, Yang Y, et al. Cold-induced RNA-binding protein promotes glucose metabolism and reduces apoptosis by increasing AKT phosphorylation in mouse skeletal muscle under acute cold exposure. Front Mol Biosci. 2021;8:685993. https://doi.org/10.3389/fmolb.2021.685993

Kovaničová Z, Karhánek M, Kurdiová T, Baláž M, Wolfrum C, Ukropcová B, et al. Metabolomic analysis reveals changes in plasma metabolites in response to acute cold stress and their relationships to metabolic health in cold-acclimatized humans. Metabolites. 2021;11(9):619. https://doi.org/10.3390/metabo11090619

Manfredi LH, Zanon NM, Garófalo MA, Navegantes LC, Kettelhut IC. Effect of short-term cold exposure on skeletal muscle protein breakdown in rats. J Appl Physiol. 2013;115(10):1496–505. https://doi.org/10.1152/japplphysiol.00474.2013

Zhang X, Xiao J, Jiang M, Phillips CJC, Shi B. Thermogenesis and energy metabolism in brown adipose tissue in animals experiencing cold stress. Int J Mol Sci. 2025;26(7):3233. https://doi.org/10.3390/ijms26073233

Shi H, Yao R, Lian S, Liu P, Liu Y, Yang YY, et al. Regulating glycolysis, the TLR4 signal pathway and expression of RBM3 in mouse liver in response to acute cold exposure. Stress. 2019;22(3):366–76. https://doi.org/10.1080/10253890.2019.1568987

Teleglow A, Romanovski V, Skowron B, Mucha D, Tota Ł, Rosińczuk J, et al. The effect of extreme cold on complete blood count and biochemical indicators: a case study. Int J Environ Res Public Health. 2021;19(1):424. https://doi.org/10.3390/ijerph19010424

Liu Y, Xue N, Zhang B, Lv H, Li S. Cold stress induced liver injury of mice through activated NLRP3/Caspase-1/GSDMD pyroptosis signaling pathway. Biomolecules. 2022;12(7):927. https://doi.org/10.3390/biom12070927

Indo HP, Yen HC, Nakanishi I, Matsumoto K, Tamura M, Nagano Y, et al. A mitochondrial superoxide theory for oxidative stress diseases and aging. J Clin Biochem Nutr. 2015;56:1–7. https://doi.org/10.3164/jcbn.14-42

Kempermann G, Song H, Gage FH. Neurogenesis in the adult hippocampus. Cold Spring Harb Perspect Biol. 2015;7:a018812. https://doi.org/10.1101/cshperspect.a018812

Aguilar Diaz De Leon J, Borges CR. Evaluation of oxidative stress in biological samples using the thiobarbituric acid reactive substances assay. J Vis Exp. 2020;159:e61122. https://doi.org/10.3791/61122

Owolabi MA, Abass MM, Emeka PM, Jaja SI, Nnoli M, Dosa BO. Biochemical and histologic changes in rats after prolonged administration of the crude aqueous extract of the leaves of Vitex grandifolia. Pharmacognosy Res. 2010;2(5):273–8. https://doi.org/10.4103/0974-8490.72322

Kim N, Fischer AH, Dyring-Andersen B, Rosner B, Okoye GA. Research techniques mode simple: choosing appropriate statistical methods for clinical research. J Invest Dermatol. 2017;137(10):e173–e178. https://doi.org/10.1016/j.jid.2017.08.007

Zhao FQ, Zhang ZW, Qu JP, Yao HD, Li M, Li S, et al. Cold stress induces antioxidants and Hsps in chicken immune organs. Cell Stress Chaperones. 2014;19(5):635–48. https://doi.org/10.1007/s12192-013-0489-9

Rittié L, Monboisse JC, Gorisse MC, Gillery P. Malondialdehyde binding to proteins dramatically alters fibroblast functions. J Cell Physiol. 2002;191(2):227–36. https://doi.org/10.1002/jcp.10093

Korewo-Labelle D, Karnia MJ, Myślińska D, Kaczor JJ. Impact of chronic cold water immersion and vitamin D3 supplementation on the hippocampal metabolism and oxidative stress in rats. Cells. 2025;14(9):641. https://doi.org/10.3390/cells14090641

Shcheniavskyi ІJ. Cardioprotective effect of enkephalins under immobilization stress. Biotechnol Acta. 2022;15(1):52–60. https://doi.org/10.15407/biotech15.01.052

Zhang J, Wang T, Fang Y, Wang M, Liu W, Zhao J, et al. Clinical significance of serum albumin/globulin ratio in patients with pyogenic liver abscess. Front Surg. 2021;8:677799. https://doi.org/10.3389/fsurg.2021.677799

Martinić R, Sošić H, Turčić P, Konjevoda P, Fučić A, Stojković R, et al. Hepatoprotective effects of Met-enkephalin on acetaminophen-induced liver lesions in male CBA mice. Molecules. 2014;19(8):11833–45. https://doi.org/10.3390/molecules190811833

Duque-Díaz E, Alvarez-Ojeda O, Coveñas R. Enkephalins and ACTH in the mammalian nervous system. Vitam Horm. 2019;111:147–93. https://doi.org/10.1016/bs.vh.2019.05.001

Myrnyi VH, Moisieieva NM. Modulation of nitrogen metabolism under chronic cold stress in guinea pigs: the role of dalargin and naloxone in mediating a protective effect. Bulletin of Problems Biology and Medicine. 2025;3(178):122–8. https://doi.org/10.29254/2077-4214-2025-3-178-122-128

Stein C, Machelska H, Binder W, Schäfer M. Peripheral opioid analgesia. Curr Opin Pharmacol. 2001;1(1):62–5. https://doi.org/10.1016/s1471-4892(01)00005-4

Owczarek D, Cibor D, Mach T, Cieśla A, Pierzchała-Koziec K, Sałapa K, et al. Met-enkephalins in patients with inflammatory bowel diseases. Adv Med Sci. 2011;56(2):158–64. https://doi.org/10.2478/v10039-011-0051-x

Wilenska B, Tymecka D, Włodarczyk M, Sobolewska-Włodarczyk A, Wiśniewska-Jarosińska M, Dyniewicz J, et al. Enkephalin degradation in serum of patients with inflammatory bowel diseases. Pharmacol Rep. 2019;71(1):42–7. https://doi.org/10.1016/j.pharep.2018.08.001

Luo P, Li X, Gao Y, Chen Z, Zhang Q, Wang Z, et al. Central administration of human opiorphin alleviates dextran sodium sulfate-induced colitis in mice through activation of the endogenous opioid system. Front Pharmacol. 2022;13:904926. https://doi.org/10.3389/fphar.2022.904926

Moisieieva N, Gorina O, Akhatova Yu. Effect of dalargin on apoptosis of L929 fibroblasts during cold stress. CryoLetters. 2023;44(6):352–9. https://doi.org/10.54680/fr23610110212

Mann A, Liebetrau S, Klima M, Dasgupta P, Massotte D, Schulz S. Agonist-induced phosphorylation bar code and differential post-activation signaling of the delta opioid receptor revealed by phosphosite-specific antibodies. Sci Rep. 2020;10(1):8585. https://doi.org/10.1038/s41598-020-65589-7

Palkovits M, Baffi JS, Pacak K. Changes in central and peripheral opioid peptide systems during cold stress. Neuroendocrinology. 1988;48(5):514–21.

Myrnyi V, Akhatova Y, Gorina O, Moisieieva N. Correction of hormonal disorders induced by chronic cold stress using synthetic neuropeptide. In: Collection of Scientific Papers «ΛΌГOΣ» [Internet]; 2024 May 24; Zurich, Switzerland; p. 121–3. Available from: https://doi.org/10.36074/logos-24.05.2024.027

Friedman JM. Leptin and the endocrine control of energy balance. Nat Metab. 2019;1(8):754–64. https://doi.org/10.1038/s42255-019-0095-y

Holmes D. Leptin attenuates HPA-axis activation and stress responses. Nat Rev Endocrinol. 2015;11:255. https://doi.org/10.1038/nrendo.2015.34

Yoshikawa M. Bioactive peptides derived from natural proteins with respect to diversity of their receptors and physiological effects. Peptides. 2015;72:208–25. https://doi.org/10.1016/j.peptides.2015.07.013

Published
2026-06-25
Cited
How to Cite
Moisieieva, N. M., Myrnyi , V. H., Akhatova, Y. S., & Horina, O. L. (2026). Regulatory effect of а synthetic opioid neuropeptid on protein homeostasis under cold stress conditions. Biophysical Bulletin, (55), 44-52. https://doi.org/10.26565/2075-3810-2026-55-04
Section
Action of physical agents on biological objects