Voloshchuk N. І., Orlenko O. B.

STUDY OF CENTRAL AND PERIPHERAL MECHANISMS UNDERLYING THE ANALGESIC EFFECT OF N-(γ-AMINOBUTYRYL)-1-AZA-4,7,10,13 TETRAOXACYCLOPENTADECANE HYDROCHLORIDE IN RATS

---

Show/Download

About the author:

Voloshchuk N. І., Orlenko O. B.

Heading:

CLINICAL AND EXPERIMENTAL MEDICINE

Type of article:

Scientific article

Annotation:

The need to develop analgesic drugs with increased efficacy and a safer safety profile remains relevant today. Macrocyclic derivatives of γ-aminobutyric acid (GABA) are considered a promising direction in the search for new agents with central analgesic activity. Previous studies have demonstrated that a new molecule, N-(γ-aminobutyry lo)-1-aza-4,7,10,13-tetraoxacyclopentadecane hydrochloride (compound C-3), exhibits pronounced analgesic activ ity in various models of pain perception. The aim of the study was to investigate the central and peripheral mech anisms of analgesia of compound C-3 in rats, as well as to evaluate the involvement of the opioid and cannabinoid systems in its realization. The contribution of central analgesic mechanisms was assessed using the formalin test; changes in analgesic activity following administration of pharmacological antagonists were evaluated in the tail-flick model, while anti-inflammatory activity was studied in the carrageenan-induced paw edema model. To elucidate the mechanisms of action, opioid receptor antagonists (naloxone, nor-BNI) and a cannabinoid CB₁ receptor antagonist (AM 251) were used. It was established that administration of compound C-3 (1 mg/kg, intraperitoneally) produced a pronounced analgesic effect, predominantly in the first phase of the formalin test, indicating the predominance of central antinociceptive mechanisms. The anti-inflammatory effect was weak – 17.3% compared with 73% for diclofenac sodium. Pre-administration of naloxone and nor-BNI only partially reduced the effect of the compound, whereas AM 251 almost completely abolished it. Thus, the analgesic action of compound C-3 is mediated predom inantly through CB₁-dependent pathways, with a lesser contribution of the opioid system. The obtained results in dicate that compound C-3 may represent a promising prototype for the development of new non-opioid analgesics with a mechanism of action associated with the endocannabinoid system.

Bibliography:

1. Secondulfo C, Mazzeo F, Pastorino GMG, Vicidomini A, Meccariello R, Operto FF. Opioid and Cannabinoid Systems in Pain: Emerging Molecular Mechanisms and Use in Clinical Practice, Health, and Fitness. Int J Mol Sci. 2024;25(17):9407. DOI: 10.3390/ijms25179407.
2. Ge T, Wu Z, Sha S, Yang X, Liu H, Song L, et al. Directions for analgesic development. J Anesth Transl Med. 2024;3(3):87-95. DOI: 10.1016/j.jatmed.2024.08.003.
3. Yang Y, Li P, Feng H, Zeng R, Li S, Zhang Q. Macrocycle-Based Supramolecular Drug Delivery Systems: A Concise Review. Molecules. 2024;29(16):3828. DOI: 10.3390/molecules29163828.
4. Ullah F, Khan TA, Iltaf J, Anwar S, Khan MFA, Khan MR, et al. Heterocyclic Crown Ethers with Potential Biological and Pharmacological Properties: From Synthesis to Applications. Appl Sci. 2022;12(3):1102. DOI: 10.3390/app12031102.
5. Murai N, Kondo Y, Akuzawa S, Mihara T, Shiraishi N, Kakimoto S, et al. A novel GABAB receptor positive allosteric modulator, ASP8062, exerts analgesic effects in a rat model of fibromyalgia. Eur J Pharmacol. 2019;865:172750. DOI: 10.1016/j.ejphar.2019.172750.
6. Karcz M, Abd-Elsayed A, Chakravarthy K, Aman MM, Strand N, Malinowski MN, et al. Pathophysiology of Pain and Mechanisms of Neuromodulation: A Narrative Review (A Neuron Project). J Pain Res. 2024;17:3757-3790. DOI: 10.2147/JPR.S475351.
7. Voloshchuk NI, Orlenko OB, Petrushenko VV, Basok SS, Larionov VB, Golovenko MYa. Experimental study of N-(γ-aminobutyryl)-1 aza-4,7,10,13-tetraoxacyclopentadecane hydrochloride analgesic activity in pain syndromes of different etiology. Word Biol Med. 2024;1(87):187-191. DOI: 10.26724/2079-8334-2024-1-87-187-191.
8. Council of Europe. European Convention for the Protection of Vertebrate Animals Used for Experimental and Other Scientific Purposes. Strasbourg: Council of Europe; 1986. 52 p.
9. Voloshchuk NI, Orlenko OB, Slyeptsova IV. Investigation of the acute toxicity and analgesic activity of a novel derivative of N-(γ aminobutyryl)-1-aza-4,7,10,13-tetraoxacyclopentadecane hydrochloride. Perspektyvy ta innovatsii nauky (Ser. Pedahohika, Psykholohiia, Medytsyna). 2025;11(57):2775-2786. DOI: 10.52058/2786-4952-2025-11(57)-2775-2786.
10. Oliver VL, Pang DSJ. Pain Recognition in Rodents. Vet Clin North Am Exot Anim Pract. 2023;26(1):121-149. DOI: 10.1016/j. cvex.2022.07.010.
11. Molodan YuO, Larionov VB, Borysiuk IYu, Makarenko OA. Tvarynni modeli in vivo dlya skryninhu potentsiynykh protyzapalnykh ta znebolyuvalnykh zasobiv (ohlyad literatury). Visnyk ONU. Biolohiia. 2023;28(2(53)):113-127. DOI: 10.18524/2077–1746.2023.2(53).293327.
12. Gregory NS, Harris AL, Robinson CR, Dougherty PM, Fuchs PN, Sluka KA. An overview of animal models of pain: disease models and outcome measures. J Pain. 2013;14(11):1255-1269.
13. Vogel HG. Drug Discovery and Evaluation: Pharmacological Assays. Berlin: Springer; 2008. 2068 p.
14. Curatolo M. Central Sensitization and Pain: Pathophysiologic and Clinical Insights. Curr Neuropharmacol. 2024;22(1):15-22. DOI: 10.2174/1570159 X20666221012112725.
15. Modi AD, Parekh A, Pancholi YN. Evaluating pain behaviours: Widely used mechanical and thermal methods in rodents. Behav Brain Res. 2023;446:114417. DOI: 10.1016/j.bbr.2023.114417.
16. Raup-Konsavage WM, Sepulveda DE, Wang J, Dokholyan NV, Vrana KE, Graziane NM. Antinociceptive Effects of Cannabichromene (CBC) in Mice: Insights from von Frey, Tail-Flick, Formalin, and Acetone Tests. Biomedicines. 2023;12(1):83. DOI: 10.3390/biomedicines12010083.
17. Xiang L, Huang Q, Chen T, He Q, Yao H, Gao Y. Ethanol extract of Paridis rhizoma attenuates carrageenan-induced paw swelling in rats by inhibiting the production of inflammatory factors. BMC Complement Med Ther. 2023;23(1):437. DOI: 10.1186/s12906-023-04264-6.
18. Pande LJ, Arnet RE, Piper BJ. An Examination of the Complex Pharmacological Properties of the Non-Selective Opioid Modulator Buprenorphine. Pharmaceuticals (Basel). 2023;16(10):1397. DOI: 10.3390/ph16101397.
19. Che T, Roth BL. Molecular basis of opioid receptor signaling. Cell. 2023;186(24):5203-5219. DOI: 10.1016/j.cell.2023.10.029.
20. Ullah F, Ullah S, Khan MFA, Mustaqeem M, Paracha RN, Rehman MFU, et al. Fluorescent and Phosphorescent Nitrogen-Containing Heterocycles and Crown Ethers: Biological and Pharmaceutical Applications. Molecules. 2022;27(19):6631. DOI: 10.3390/ molecules27196631.
21. Sieghart W, Chiou LC, Ernst M, Fabjan J, Savić MM, Lee MT. α6-Containing GABAA Receptors: Functional Roles and Therapeutic Potentials. Pharmacol Rev. 2022;74(1):238-270. DOI: 10.1124/pharmrev.121.000293.
22. Nieto A, Bailey T, Kaczanowska K, McDonald P. GABAB Receptor Chemistry and Pharmacology: Agonists, Antagonists, and Allosteric Modulators. Curr Top Behav Neurosci. 2022;52:81-118. DOI: 10.1007/7854_2021_232.
23. Pinto M, Sousa M, Lima D, Tavares I. Participation of mu-opioid, GABAB, and NK1 receptors of major pain control medullary areas in pathways targeting the rat spinal cord: implications for descending modulation of nociceptive transmission. J Comp Neurol. 2008;510(2):175 187. DOI: 10.1002/cne.21793.
24. Lowe H, Toyang N, Steele B, Bryant J, Ngwa W. The Endocannabinoid System: A Potential Target for the Treatment of Various Diseases. Int J Mol Sci. 2021;22(17):9472. DOI: 10.3390/ijms22179472.
25. Leo LM, Abood ME. CB1 Cannabinoid Receptor Signaling and Biased Signaling. Molecules. 2021;26(17):5413. DOI: 10.3390/ molecules26175413.

Publication of the article:

«Bulletin of problems biology and medicine», 2026 Issue 1, 180, 203-214 pages, index UDC 615.212:612.821:616 009.7

DOI:

10.29254/2077-4214-2026-1-180-203-214