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Effects of Semax in the Rat Models of Acute Stress

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Abstract

Acute stress exposure triggers a cascade of neurochemical reactions, leading, specifically, to behavior changes and increased pain tolerance in humans and animals. ACTH/MSH-like peptides play an important role in regulating the organism’s response to stressful exposures. The aim of the present study was to assess the effects of the heptapeptide Semax, a synthetic ACTH4–10 analog, in various models of acute stress. The effect of intraperitoneal Semax administration at doses of 0.05 and 0.5 mg/kg on changes in behavior and pain sensitivity of Wistar rats was investigated in models of inescapable intermittent footshock stress and forced cold-water swim stress. To assess the involvement of the endogenous opioid system in the effects of stress, there was studied an impact of the preadministration with the opioid receptor antagonist Naloxone (1 mg/kg). The stressors used led to an increase in the pain threshold in the paw-pressure test, which indicates the development of stress-induced analgesia (SIA). In addition, rats exposed to stress showed decreased exploratory behavior and increased anxiety-like behavior in the hole board test. Both Semax and Naloxone attenuated SIA in the model of inescapable footshock stress, but did not affect pain threshold values in the model of forced cold-water swim stress. Both drugs did not affect rat behavior in the above models of acute stress. It can be concluded that Semax attenuates the opioid form of SIA, but does not affect behavior changes in rats exposed to acute stress.

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REFERENCES

  1. Wilder RL (1995) Neuroendocrine–immune system interactions and autoimmunity. Annu Rev Immunol 13: 307–338. https://doi.org/10.1146/annurev.iy.13.040195.001515

    Article  CAS  PubMed  Google Scholar 

  2. Finn DP (2010) Endocannabinoid-mediated modulation of stress responses: physiological and pathophysiological significance. Immunobiology 215(8): 629–646. https://doi.org/10.1016/j.imbio.2009.05.011

    Article  CAS  PubMed  Google Scholar 

  3. Ghasemzadeh Z, Rezayof A (2015) Ventral hippocampal nicotinic acetylcholine receptors mediate stress-induced analgesia in mice. Prog Neuropsychopharmacol Biol Psychiatry 56: 235–242. https://doi.org/10.1016/j.pnpbp.2014.09.008

    Article  CAS  PubMed  Google Scholar 

  4. Cecconello AL, Torres IL, Oliveira C, Zanini P, Niches G, Ribeiro MF (2016) DHEA administration modulates stress-induced analgesia in rats. Physiol Behav 157: 231–236. https://doi.org/10.1016/j.physbeh.2016.02.004

    Article  CAS  PubMed  Google Scholar 

  5. Tillage RP, Foster SL, Lustberg D, Liles LC, McCann KE, Weinshenker D (2021) Co-released norepinephrine and galanin act on different timescales to promote stress-induced anxiety-like behavior. Neuropsychopharmacology 46(8): 1535–1543. https://doi.org/10.1038/s41386-021-01011-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Floriou-Servou A, von Ziegler L, Waag R, Schläppi C, Germain PL, Bohacek J (2021) The Acute Stress Response in the Multiomic Era. Biol Psychiatry 89(12): 1116–1126. https://doi.org/10.1016/j.biopsych.2020.12.031

    Article  CAS  PubMed  Google Scholar 

  7. Gulyaeva NV (2022) Neuroendocrine control of hyperglutamatergic states in brain pathologies: the effects of glucocorticoids. Russ J Physiol 108(9): 1077–1093. https://doi.org/10.31857/S0869813922090102

    Article  Google Scholar 

  8. O’Connor TM, O’Halloran DJ, Shanahan F (2000) The stress response and the hypothalamic-pituitary-adrenal axis: from molecule to melancholia. QJM 93(6): 323–333. https://doi.org/10.1093/qjmed/93.6.323

    Article  PubMed  Google Scholar 

  9. Busnardo C, Crestani CC, Scopinho AA, Packard BA, Resstel LBM, Correa FMA, Herman JP (2019) Nitrergic neurotransmission in the paraventricular nucleus of the hypothalamus modulates autonomic, neuroendocrine and behavioral responses to acute restraint stress in rats. Prog Neuropsychopharmacol Biol Psychiatry 90: 16–27. https://doi.org/10.1016/j.pnpbp.2018.11.001

    Article  CAS  PubMed  Google Scholar 

  10. Tang W, Zhou D, Wang S, Hao S, Wang X, Helmy M, Zhu J, Wang H (2021) CRH Neurons in the Laterodorsal Tegmentum Mediate Acute Stress-induced Anxiety. Neurosci Bull 37(7): 999–1004. https://doi.org/10.1007/s12264-021-00684-x

    Article  PubMed  PubMed Central  Google Scholar 

  11. Millan MJ, Brocco M (2003) The Vogel conflict test: procedural aspects, gamma-aminobutyric acid, glutamate and monoamines. Eur J Pharmacol 463(1–3): 67–96. https://doi.org/10.1016/s0014-2999(03)01275-5

    Article  CAS  PubMed  Google Scholar 

  12. McCall JG, Al-Hasani R, Siuda ER, Hong DY, Norris AJ, Ford CP, Bruchas MR (2015) CRH Engagement of the Locus Coeruleus Noradrenergic System Mediates Stress-Induced Anxiety. Neuron 87(3): 605–620. https://doi.org/10.1016/j.neuron.2015.07.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. al’Absi M, Nakajima M, Bruehl S (2021) Stress and pain: modality-specific opioid mediation of stress-induced analgesia. J Neural Transm (Vienna) 128(9): 1397–1407. https://doi.org/10.1007/s00702-021-02401-4

  14. Gantz I, Fong TM (2003) The melanocortin system. Am J Physiol Endocrinol Metab 284(3): E468–E474. https://doi.org/10.1152/ajpendo.00434.2002

    Article  CAS  PubMed  Google Scholar 

  15. Yang Y, Harmon CM (2020) Molecular determinants of ACTH receptor for ligand selectivity. Mol Cell Endocrinol 503: 110688. https://doi.org/10.1016/j.mce.2019.110688

    Article  CAS  PubMed  Google Scholar 

  16. Sharfman N, Gilpin NW (2021) The Role of Melanocortin Plasticity in Pain-Related Outcomes After Alcohol Exposure. Front Psychiatry 12: 764720. https://doi.org/10.3389/fpsyt.2021.764720

    Article  PubMed  PubMed Central  Google Scholar 

  17. Fridmanis D, Roga A, Klovins J (2017) ACTH Receptor (MC2R) Specificity: What Do We Know About Underlying Molecular Mechanisms? Front Endocrinol (Lausanne) 8: 13. https://doi.org/10.3389/fendo.2017.00013

  18. Gallo-Payet N, Martinez A, Lacroix A (2017) Editorial: ACTH Action in the Adrenal Cortex: From Molecular Biology to Pathophysiology. Front Endocrinol (Lausanne) 8: 101. https://doi.org/10.3389/fendo.2017.00101

  19. Yamano Y, Yoshioka M, Toda Y, Oshida Y, Chaki S, Hamamoto K, Morishima I (2004) Regulation of CRF, POMC and MC4R gene expression after electrical foot shock stress in the rat amygdala and hypothalamus. J Vet Med Sci 66(11): 1323–1327. https://doi.org/10.1292/jvms.66.1323

    Article  CAS  PubMed  Google Scholar 

  20. Chaki S, Okuyama S (2005) Involvement of melanocortin-4 receptor in anxiety and depression. Peptides 26(10): 1952–1964. https://doi.org/10.1016/j.peptides.2004.11.029

    Article  CAS  PubMed  Google Scholar 

  21. Chaki S, Ogawa S, Toda Y, Funakoshi T, Okuyama S (2003) Involvement of the melanocortin MC4 receptor in stress-related behavior in rodents. Eur J Pharmacol 474(1): 95–101. https://doi.org/10.1016/s0014-2999(03)02033-8

    Article  CAS  PubMed  Google Scholar 

  22. Shimazaki T, Chaki S (2005) Anxiolytic-like effect of a selective and non-peptidergic melanocortin 4 receptor antagonist, MCL0129, in a social interaction test. Pharmacol Biochem Behav 80(3): 395–400. https://doi.org/10.1016/j.pbb.2004.11.014

    Article  CAS  PubMed  Google Scholar 

  23. Ashmarin IP, Nezavibatko VN, Levitskaya NG, Koshelev VB, Kamensky AA (1995) Design and investigation of an ACTH(4-10) analogue lacking D-amino acids and hidrophobic radicals. Neurosci Res Commun 16(2): 105–112.

    CAS  Google Scholar 

  24. Asmarin IP, Nezavibat’ko VN, Miasoedov NF, Kamenskii AA, Grivennikov IA, Ponomareva-Stepnaya MA, Andreeva LA, Kaplan AI, Koshelev VB, Riasina TV (1997) A nootropic adrenocorticotropin analog 4-10—semax (l5 years experience in its design and study). Zhurn Vyss Nervn Deiat im IP Pavlova 47: 420–430. (In Russ).

    CAS  Google Scholar 

  25. Vilenskii DA, Levitskaia NG, Andreeva LA, Alfeeva LYu, Kamenskii AA, Miasoedov NF (2007) Effects of chronic Semax administration on exploratory activity and emotional reaction in white rats. Russ J Physiol 93(6): 661–669. (In Russ).

    CAS  Google Scholar 

  26. Yatsenko KA, Glazova NYu, Inozemtseva LS, Andreeva LA, Kamensky AA, Grivennikov IA, Levitskaya NG, Dolotov OV, Myasoedov NF (2013) Heptapeptide Semax Attenuates the Effects of Chronic Unpredictable Stress in Rats. Dokl Biol Sci 453: 353–357. https://doi.org/10.1134/S0012496613060161

    Article  CAS  PubMed  Google Scholar 

  27. Levitskaya NG, Vilenskii DA, Sebentsova EA, Andreeva LA, Kamensky AA, Myasoedov NF (2010) Influence of semax on the emotional state of white rats in the norm and against the background of cholecystokinin-tetrapeptide action. Biol Bull 37(2): 186–192. https://doi.org/10.1134/S1062359010020147

    Article  CAS  Google Scholar 

  28. Glazova NYu, Sebentsova EA, Manchenko DM, Andreeva LA, Dergunova LV, Levitskaya NG, Limborska SA, Myasoedov NF (2018) The Protective Effect of Semax in a Model of Stress-induced Impairment of Memory and Behavior in White Rats. Biol Bull 45(4): 394–399. https://doi.org/10.1134/S1062359018040040

    Article  Google Scholar 

  29. Ivanova DM, Vilenskii DA, Levitskaya NG, Andreeva LA, Alfeeva LY, Kamenskii AA, Miasoedov NF (2006) Effect of Semax on changes in pain sensitivity and behavior of animals induced by forced swimming. Dokl Biol Sci 407: 123–127. https://doi.org/10.1134/s0012496606020037

    Article  CAS  PubMed  Google Scholar 

  30. Atwal N, Winters BL, Vaughan CW (2020) Endogenous cannabinoid modulation of restraint stress-induced analgesia in thermal nociception. J Neurochem 152(1): 92–102. https://doi.org/10.1111/jnc.14884

    Article  CAS  PubMed  Google Scholar 

  31. Lewis JW, Cannon JT, Liebeskind JC (1980) Opioid and nonopioid mechanisms of stress analgesia. Science 208(4444): 623–625. https://doi.org/10.1126/science.7367889

    Article  CAS  PubMed  Google Scholar 

  32. Mogil JS, Sternberg WF, Balian H, Liebeskind JC, Sadowski B (1996) Opioid and nonopioid swim stress-induced analgesia: a parametric analysis in mice. Physiol Behav 59(1): 123–132. https://doi.org/10.1016/0031-9384(95)02073-x

    Article  CAS  PubMed  Google Scholar 

  33. Hohmann AG, Suplita RL, Bolton NM, Neely MH, Fegley D, Mangieri R, Krey JF, Walker JM, Holmes PV, Crystal JD, Duranti A, Tontini A, Mor M, Tarzia G, Piomelli D (2005) An endocannabinoid mechanism for stress-induced analgesia. Nature 435(7045): 1108-1112. https://doi.org/10.1038/nature03658

    Article  CAS  PubMed  Google Scholar 

  34. Lafrance M, Roussy G, Belleville K, Maeno H, Beaudet N, Wada K, Sarret P (2010) Involvement of NTS2 receptors in stress-induced analgesia. Neuroscience 166(2): 639–652. https://doi.org/10.1016/j.neuroscience.2009.12.042

    Article  CAS  PubMed  Google Scholar 

  35. Terman GW, Shavit Y, Lewis JW, Cannon JT, Liebeskind JC (1984) Intrinsic mechanisms of pain inhibition: activation by stress. Science 226(4680): 1270–1277. https://doi.org/10.1126/science.6505691

    Article  CAS  PubMed  Google Scholar 

  36. Terman GW, Morgan MJ, Liebeskind JC (1986) Opioid and non-opioid stress analgesia from cold water swim: importance of stress severity. Brain Res 372(1): 167–171. https://doi.org/10.1016/0006-8993(86)91472-1

    Article  CAS  PubMed  Google Scholar 

  37. Sadowski B, Konarzewski M (1999) Analgesia in selectively bred mice exposed to cold in helium/oxygen atmosphere. Physiol Behav 66(1): 145–151. https://doi.org/10.1016/s0031-9384(98)00282-0

    Article  CAS  PubMed  Google Scholar 

  38. Łapo IB, Konarzewski M, Sadowski B (2003) Analgesia induced by swim stress: interaction between analgesic and thermoregulatory mechanisms. Pflugers Arch 446(4): 463–469. https://doi.org/10.1007/s00424-003-1060-9

    Article  CAS  PubMed  Google Scholar 

  39. Takeda H, Tsuji M, Matsumiya T (1998) Changes in head-dipping behavior in the hole-board test reflect the anxiogenic and/or anxiolytic state in mice. Eur J Pharmacol 350(1): 21–29. https://doi.org/10.1016/s0014-2999(98)00223-4

    Article  CAS  PubMed  Google Scholar 

  40. Abbasi-Habashi S, Ghasemzadeh Z, Rezayof A (2020) Morphine improved stress-induced amnesia and anxiety through interacting with the ventral hippocampal endocannabinoid system in rats. Brain Res Bull 164: 407–414. https://doi.org/10.1016/j.brainresbull.2020.09.002

    Article  CAS  PubMed  Google Scholar 

  41. Farzamfard P, Rezayof A, Alijanpour S (2022) Ventral hippocampal NMDA receptors mediate the effects of nicotine on stress-induced anxiety/exploratory behaviors in rats. Neurosci Lett 780: 136649. https://doi.org/10.1016/j.neulet.2022.136649

    Article  CAS  PubMed  Google Scholar 

  42. Bershad AK, Miller MA, Norman GJ, de Wit H (2018) Effects of opioid- and non-opioid analgesics on responses to psychosocial stress in humans. Horm Behav 102: 41–47. https://doi.org/10.1016/j.yhbeh.2018.04.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Smock T, Fields HL (1981) ACTH1-24 blocks opiate-induced analgesia in the rat. Brain Res 212(1): 202–206. https://doi.org/10.1016/0006-8993(81)90052-4

    Article  CAS  PubMed  Google Scholar 

  44. Contreras PC, Takemori AE (1984) Antagonism of morphine-induced analgesia, tolerance and dependence by alpha-melanocyte-stimulating hormone. J Pharmacol Exp Ther 229(1): 21–26.

    CAS  PubMed  Google Scholar 

  45. Ercil NE, Galici R, Kesterson RA (2005) HS014, a selective melanocortin-4 (MC4) receptor antagonist, modulates the behavioral effects of morphine in mice. Psychopharmacology (Berl) 180(2): 279–285. https://doi.org/10.1007/s00213-005-2166-x

  46. Han DJ, He ZG, Yang H (2018) Melanocortin-4 receptor in subthalamic nucleus is involved in the modulation of nociception. Am J Clin Exp Immunol 7(4): 76–80.

    PubMed  PubMed Central  Google Scholar 

  47. Kovalitskaya YA, Zolotarev YA, Kolobov AA, Sadovnikov VB, Yurovsky VV, Navolotskaya EV (2007) Interaction of ACTH synthetic fragments with rat adrenal cortex membranes. J Pept Sci 13(8): 513–518. https://doi.org/10.1002/psc.873

    Article  CAS  PubMed  Google Scholar 

  48. Manchenko DM, Glazova NYu, Sebentsova EA, Andreeva LA, Dolotov OV, Kamensky AA, Myasoedov NF, Levitskaya NG (2022) Effects of fragment ACTH15-18 and its analog ACTH15-18-PGP on the consequences of the acute stress exposure. Zh Vyss Nervn Deiatelnosti im IP Pavlova 72: 561–575. https://doi.org/10.31857/S0044467722040074

    Article  Google Scholar 

  49. Musazzi L, Tornese P, Sala N, Popoli M (2018) What Acute Stress Protocols Can Tell Us About PTSD and Stress-Related Neuropsychiatric Disorders. Front Pharmacol 9: 758. https://doi.org/10.3389/fphar.2018.00758

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Chakraborty P, Chattarji S (2019) Interventions after acute stress prevent its delayed effects on the amygdala. Neurobiol Stress 10: 100168. https://doi.org/10.1016/j.ynstr.2019.100168

    Article  PubMed  PubMed Central  Google Scholar 

  51. Filippenkov IB, Stavchansky VV, Glazova NY, Sebentsova EA, Remizova JA, Valieva LV, Levitskaya NG, Myasoedov NF, Limborska SA, Dergunova LV (2021) Antistress action of melanocortin derivatives associated with correction of gene expression patterns in the hippocampus of male rats following acute stress. Int J Mol Sci 22 (18): 10054. https://doi.org/10.3390/ijms221810054

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

The work was funded by the Russian Science Foundation (RSF), Grant no. 19-14-00268, https://rscf.ru/project/22-14-35023/.

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Authors and Affiliations

  1. Lomonosov Moscow State University, Faculty of Biology, Moscow, Russia

    N. Yu. Glazova, D. M. Manchenko, E. A. Sebentsova, A. A. Kamensky & N. G. Levitskaya

  2. Institute of Molecular Genetics, National Research Center “Kurchatov Institute”, Moscow, Russia

    N. Yu. Glazova, E. A. Sebentsova, L. A. Andreeva, A. A. Kamensky, L. V. Dergunova, S. A. Limborska, N. F. Myasoedov & N. G. Levitskaya

  3. Lomonosov Moscow State University, Faculty of Bioengineering and Bioinformatics, Moscow, Russia

    D. A. Vilensky

Authors
  1. N. Yu. Glazova
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  2. D. M. Manchenko
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  3. D. A. Vilensky
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  4. E. A. Sebentsova
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  7. L. V. Dergunova
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  9. N. F. Myasoedov
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  10. N. G. Levitskaya
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Contributions

Conceptualization and design of the experiments (N.G.L., A.A.K., L.V.D., S.A.L., N.F.M.); data collection (N.Yu.G., D.M.M., D.A.V., E.A.S., L.A.A.); data processing (N.Yu.G., D.M.M., D.A.V., E.A.S., N.G.L.); writing and editing the manuscript (N.G.L., N.Yu.G., D.M.M., E.A.S.).

Corresponding author

Correspondence to N. G. Levitskaya.

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COMPLIANCE WITH ETHICAL STANDARDS

The study was carried out in compliance with bioethical standards for the treatment of experimental animals stated in the Rules of Good Laboratory Practice (Order of the Ministry of Health of the Russian Federation no. 199 of 01.04.2016), as well as the requirements of Directive 2010/63/EU of the European Parliament of 22.09.2010.

CONFLICT OF INTEREST

The authors declare that they have no conflict of interest.

Additional information

Translated by A. Polyanovsky

Russian Text © The Author(s), 2023, published in Rossiiskii Fiziologicheskii Zhurnal imeni I.M. Sechenova, 2023, Vol. 109, No. 1, pp. 119–135https://doi.org/10.31857/S0869813923010053.

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Glazova, N.Y., Manchenko, D.M., Vilensky, D.A. et al. Effects of Semax in the Rat Models of Acute Stress. J Evol Biochem Phys 59, 200–212 (2023). https://doi.org/10.1134/S0022093023010179

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