GASOTRANSMITTERS AS MODULATORS OF THE NOCICEPTIVE AND ANTINOCICEPTIVE SYSTEMS

Authors:

Abstract:

The article summarizes current data on the roles of nitrogen monoxide, hydrogen sulfide, and carbon monoxide in modulating nociceptive and antinociceptive systems. Currently, gasotransmitters are considered vital endogenous signaling molecules that regulate neuroinflammation, synaptic transmission, and pain sensitivity. For this analysis, contemporary experimental and review studies published in 2021–2026 and indexed in PubMed, Scopus, Web of Science, and Google Scholar were used. It was established that nitrogen monoxide, hydrogen sulfide, and carbon monoxide can exhibit both pronociceptive and antinociceptive effects depending on their concentration, the localization of synthesis, and pathophysiological conditions. Gasotransmitters participate in peripheral and central sensitization, ion channel regulation, glial cell activation, and the development of oxidative stress and inflammatory responses. Concurrently, they can activate endogenous pain-suppression mechanisms via potassium channels, cGMP-dependent signaling pathways, and by restricting neuroinflammation. The accumulated data indicate that pharmacological modulation of gasotransmitter systems is a promising approach for developing novel analgesic agents to manage inflammatory and neuropathic pain syndromes.

Keywords:

gasotransmitters nitrogen monoxide hydrogen sulfide carbon monoxide molecular mechanisms nociception antinociception pain modulation neuroinflammation neuropathic pain inflammatory pain

References:

1. Ali A, Wang Y, Wu L, Yang G. Gasotransmitter signaling in energy homeostasis and metabolic disorders. Free Radic Res. 2021;55:83–105. doi:10.1080/10715762.2020.1862827.
2. Almeida DL, Mendes Ferreira RC, Fonseca FC, Dias Machado DP, Aguiar DD, Guimaraes FS, et al. Cannabidiol induces systemic analgesia through activation of the PI3Kγ/nNOS/NO/KATP signaling pathway in neuropathic mice. A KATP channel S-nitrosylation-dependent mechanism. Nitric Oxide. 2024 May 1;146:1-9. doi: 10.1016/j.niox.2024.02.005.
3. Bakalarz D, Surmiak M, Yang X, Wójcik D, Korbut E, Śliwowski Z, et al. Organic carbon monoxide prodrug BW-CO-111 in protection against chemically-induced gastric mucosal damage. Acta Pharm Sin B. 2021;11:456–475. doi: 10.1016/j.apsb.2020.08.005.
4. Barua S, Sim AY, Kim JY, Shin I, Lee JE. Maintenance of the Neuroprotective Function of the Amino Group Blocked Fluorescence-Agmatine. Neurochem Res. 2021 Aug;46(8):1933-1940. doi: 10.1007/s11064-021-03319-9.
5. Batallé G, Bai X, Pol O. The interaction between carbon monoxide and hydrogen sulfide during chronic joint pain in young female mice. Antioxidants (Basel). 2022;11(7):1271. https://doi.org/10.3390/antiox11071271.
6. Bauer N, Liu D, Nguyen T, Wang B. Unraveling the interplay of dopamine, carbon monoxide, and heme oxygenase in neuromodulation and cognition. ACS Chem Neurosci. 2024;15(3):400–407. https://doi.org/10.1021/acschemneuro.3c00742.
7. Bedair AF, Wahid A, El-Mezayen NS, El-Yazbi AF, Khalil HA, Hassan NW, et al. Nicorandil/ morphine crosstalk accounts for antinociception and hepatoprotection in hepatic fibrosis in rats: Distinct roles of opioid/cGMP and NO/KATP pathways. Biomed Pharmacother. 2023 Sep;165:115068. doi: 10.1016/j.biopha.2023.115068.
8. Benza RL, Grünig E, Sandner P, Stasch JP, Simonneau G. The nitric oxide-soluble guanylate cyclase-cGMP pathway in pulmonary hypertension: from PDE5 to soluble guanylate cyclase. Eur Respir Rev. 2024;33(171):230183. doi: 10.1183/16000617.0183-202.
9. Cazuza RA, Arantes ALF, Pol O, Leite-Panissi CRA. HO-CO pathway activation may be associated with hippocampal μ and δ opioid receptors in inhibiting inflammatory pain aversiveness and nociception in WT but not NOS2-KO mice. Brain Res Bull. 2021;169:8–17. https://doi.org/10.1016/j.brainresbull.2021.01.002.
10. Cazuza RA, Batallé G, Bai X, Leite-Panissi CRA, Pol O. Effects of treatment with a carbon monoxide donor and an activator of heme oxygenase 1 on the nociceptive, apoptotic and/or oxidative alterations induced by persistent inflammatory pain in the central nervous system of mice. Brain Res Bull. 2022;188:169–178. https://doi.org/10.1016/j.brainresbull.2022.08.004.
11. Chao JJ, Hu L, Mi JF, Mao GJ, Xu F, Hu L, et al. Monitoring the level of hydrogen sulfide in arthritis and its treatment with a novel near-infrared fluorescent probe. Anal Chim Acta. 2025 May 15;1351:343898. doi: 10.1016/j.aca.2025.343898.
12. Cirino G, Szabo C, Papapetropoulos A. Physiological roles of hydrogen sulfide in mammalian cells, tissues, and organs. Physiol Rev. 2023;103(1):31–276. https://doi.org/10.1152/physrev.00028.2021.
13. Coavoy-Sanchez SA, Marques LAC, Costa SKP, Muscara MN. Role of gasotransmitters in inflammatory edema. Antioxid Redox Signal. 2024;40(4–6):272–291. https://doi.org/10.1089/ars.2022.0089.
14. Dallazen JL, Santos LG, Teixeira SA, De Nucci G, Muscará MN, Costa SKP. Elucidating the Significance of Endogenous Hydrogen Sulfide as a Novel Candidate for Postoperative Pain Recovery in a Murine Model. Eur J Pain. 2025 Jul;29(6):e70043. doi: 10.1002/ejp.70043.
15. Dichiara M, Artacho-Cordón A, Turnaturi R, Santos-Caballero M, González-Cano R, Pasquinucci L, et al. Dual Sigma-1 receptor antagonists and hydrogen sulfide-releasing compounds for pain treatment: design, synthesis, and pharmacological evaluation. Eur J Med Chem. 2022;230:114091. doi:10.1016/j.ejmech.2021.114091.
16. Duan HZ, Wu CW, Shen SL, Zhang JY, Li L. Neuroprotective effects of early brain injury after subarachnoid hemorrhage in rats by calcium channel mediating hydrogen sulfide. Cell Mol Neurobiol. 2021;41:1707–1714. https://doi.org/10.1016/j.bcp.2020.113931.
17. Feng HQ, Han XM, Chen HY, Gao WJ, Zhuang T. Hydrogen Sulfide in Analgesia: The Journey from Gas to Hybrids and Beyond. J Med Chem. 2026 Apr 9;69(7):7512-7537. doi: 10.1021/acs.jmedchem.5c03235. PMID: 41906373.
18. Giniatullin R, Nistri A. Role of ATP in migraine mechanisms: focus on P2X3 receptors. J Headache Pain. 2023;24:1.https://doi.org/10.1186/s10194-022-01535-4.
19. He J, Lu Y, Lu Z, Jiang P, Huang D, Luo Y, et al. Mechanisms and therapeutic potential of hydrogen sulfide in traumatic central nervous system injuries. Med Gas Res. 2026;16(2):148–155. https://doi.org/10.4103/mgr.MEDGASRES-D-25-00034.
20. Herrald AL, Ambrogi EK, Mirica KA. Electrochemical detection of gasotransmitters: status and roadmap. ACS Sens. 2024;9:1682–1705. doi:10.1021/acssensors.3c02529.
21. Hopper CP, Zambrana PN, Goebel U, Wollborn J. A brief history of carbon monoxide and its therapeutic origins. Nitric Oxide. 2021 Jun 1;111-112:45-63. doi: 10.1016/j.niox.2021.04.001.
22. Huerta de la Cruz S, Rodríguez-Palma EJ, Santiago-Castañeda CL, Beltrán-Ornelas JH, Sánchez-López A, Rocha L, et al. Exogenous hydrogen sulfide restores CSE and CBS but no 3-MST protein expression in the hypothalamus and brainstem after severe traumatic brain injury. Metab Brain Dis. 2022 Aug;37(6):1863-1874. doi: 10.1007/s11011-022-01033-1.
23. Kang Q, Zhu Z, Liu Z, Li F, He Y, Yang Y, et al. A novel hydrogen sulfide donor reduces neuroinflammation and seizures by activating ATP-sensitive potassium channels. Neurosci Res. 2024;199:21–29. https://doi.org/10.1016/j.neures.2023.07.004.
24. Khir NAM, Noh ASM, Long I, Zakaria R, Ismail CAN. Recent progress on anti-nociceptive effects of carbon monoxide releasing molecule-2 (CORM-2). Mol Cell Biochem. 2024 Mar;479(3):539-552.doi: 10.1007/s11010-023-04749-5.
25. Krukowska K, Magierowski M. Carbon monoxide (CO)/heme oxygenase (HO)-1 in gastrointestinal tumors pathophysiology and pharmacology: possible anti- and pro-cancer activities. Biochem Pharmacol. 2022;201:115058. https://doi.org/10.1016/j.bcp.2022.115058.
26. Nocheva H, Krastev NS, Krastev DS, Mileva M. The Endogenous Cannabinoid and the Nitricoxidergic Systems in the Modulation of Stress Responses. Int J Mol Sci. 2023 Feb 2;24(3):2886. doi: 10.3390/ijms24032886.
27. O’Connor JL, Fountos DM, Firouzan B, Azizi F, Ghasemi R, Kashfi K. The role of gasotransmitters in Parkinson’s disease: interplay of nitric oxide, carbon monoxide, and hydrogen sulfide. Neurotherapeutics. 2025;22(6):e00710. https://doi.org/10.1016/j.neurot.2025.e00710.
28. Pagel PS, Hang D, Freed JK, Crystal GJ. Advances in Cardiovascular Pharmacotherapy: VII. Soluble Guanylate Cyclase Stimulators in Pulmonary Hypertension and Heart Failure. J Cardiothorac Vasc Anesth. 2026;40(6):1806–1827. doi: 10.1053/j.jvca.2026.02.035 NO.
29. Payne FM, Dabb AR, Harrison JC, Sammut IA. Inhibitors of NLRP3 inflammasome formation: a cardioprotective role for the gasotransmitters carbon monoxide, nitric oxide, and hydrogen sulfide in acute myocardial infarction. Int J Mol Sci. 2024;25(17):9247. https://doi.org/10.3390/ijms25179247.
30. Pol O. The role of carbon monoxide, heme oxygenase-1, and the Nrf2 transcription factor in the modulation of chronic pain and their interactions with opioids and cannabinoids. Med Res Rev. 2021;41:136–155. doi: 10.1002/med.21726.
31. Rangel-Galván M, Rangel-Galván V, Rangel-Huerta A. T-type calcium channel modulation by hydrogen sulfide in neuropathic pain conditions. Front Pharmacol. 2023 Jul 17;14:1212800. doi: 10.3389/fphar.2023.1212800.
32. Rasmussen RH, Ernstsen C, Holm A, Lauritzen SP, Obelitz-Ryom K, Kristensen DM, et al. De novo nitric oxide synthesis drives tactile hypersensitivity induced by ATP-sensitive potassium channel opening in mice: relevance to migraine and other headache disorders. Pain. 2026. Epub ahead of print. https://doi.org/10.1097/j.pain.0000000000003955.
33. Rodkin S, Golovin S, Bachurin S, Lisovin A, Vasilieva I, Tolmacheva A, et al. Inorganic, synthetic, natural, and innovative hybrid hydrogen sulfide donors and inhibitors of its biosynthesis in the treatment of central and peripheral nervous system injuries: a systematic analytical review. Int J Mol Sci. 2025;26(24):11842. https://doi.org/10.3390/ijms262411842.
34. Rodkin S, Nwosu C, Sannikov A, Raevskaya M, Tushev A, Vasilieva I, et al. The role of hydrogen sulfide in regulation of cell death following neurotrauma and related neurodegenerative and psychiatric diseases. Int J Mol Sci. 2023;24(13):10742. https://doi.org/10.3390/ijms241310742.
35. Rose P, Zhu YZ, Moore PK. Hydrogen sulfide and the immune system. Adv Exp Med Biol. 2021;1315:99–128. doi:10.1007/978-981-16-0991-6_5.
36. Ryter SW. Heme oxygenase-1: an anti-inflammatory effector in cardiovascular, lung, and related metabolic disorders. Antioxidants. 2022;11(3):555. https://doi.org/10.3390/antiox11030555.
37. Sarkar S, Kumar R, Matson JB. Hydrogels for gasotransmitter delivery: nitric oxide, carbon monoxide, and hydrogen sulfide. Macromol Biosci. 2024;24(1):e2300138. https://doi.org/10.1002/mabi.202300138.
38. Scammahorn JJ, Nguyen IT, Bos EM, Van Goor H, Joles JA. Fighting oxidative stress with sulfur: hydrogen sulfide in the renal and cardiovascular systems. Antioxidants (Basel). 2021;10:373. doi: 10.3390/antiox10030373.
39. Sekiguchi F, Koike N, Shimada Y, Sugimoto K, Masuda H, Nakamura T, et al. A hydrolysate of poly-trans-[(2-carboxyethyl)germasesquioxane] (Ge-132) suppresses Ca(v)3.2-dependent pain by sequestering exogenous and endogenous sulfide. Redox Biol. 2023 Feb;59:102579. doi: 10.1016/j.redox.2022.102579.
40. Shao S, Xu CB, Chen CJ, Shi GN, Guo QL, Zhou Y, et al. Divanillyl sulfone suppresses NLRP3 inflammasome activation via inducing mitophagy to ameliorate chronic neuropathic pain in mice. J Neuroinflammation. 2021;18:142. doi: 10.1186/s12974-021-02178-z.
41. Shnayder NA, Petrova MM, Popova TE, Davidova TK, Bobrova OP, Trefilova VV, et al. Prospects for the Personalized Multimodal Therapy Approach to Pain Management via Action on NO and NOS. Molecules. 2021 Apr 22;26(9):2431. doi: 10.3390/molecules26092431.
42. Simão S, Santos DF, Teixeira M, Agostinho RR, Rodrigues J, Vitorino M, et al. Unraveling the potential of gasotransmitters as neurogenic and neuroprotective molecules: focus on Alzheimer's and Parkinson's diseases. Redox Rep. 2026;31(1):2592413. https://doi.org/10.1080/13510002.2025.2592413.
43. Song Y, Wu S, Zhang R, et al. Therapeutic potential of hydrogen sulfide in osteoarthritis development. Front Pharmacol. 2024;15:1336693. doi: 10.3389/fphar.2024.1336693.
44. Spiers JG, Steinert JR. Nitrergic modulation of ion channel function in regulating neuronal excitability. Channels (Austin). 2021 Dec;15(1):666-679. doi: 10.1080/19336950.2021.2002594.
45. Suárez-Rojas I, Pérez-Fernández M, Bai X, Martínez-Martel I, Intagliata S, Pittalà V, et al. The inhibition of neuropathic pain incited by nerve injury and accompanying mood disorders by new heme oxygenase-1 inducers: mechanisms implicated. Antioxidants (Basel). 2023;12(10):1859. https://doi.org/10.3390/antiox12101859.
46. Wu YH, Hsieh HL. Roles of heme oxygenase-1 in neuroinflammation and brain disorders. Antioxidants. 2022;11(5):923. doi:10.3390/antiox11050923.
47. Xu OW, Wang J, Alston TA. James Watt, of Steam Engine Fame, Offered Inhaled Carbon Monoxide for Putative Therapeutic Action. Anesth Analg. 2025 Jan 1;140(1):197-201. doi: 10.1213/ANE.0000000000006955.
48. Yang KL, Li WH, Liu YJ, Wei YJ, Ren YK, Mai CD, et al. Hydrogen sulfide attenuates neuroinflammation by inhibiting the NLRP3/Caspase-1/GSDMD pathway in retina or brain neuron following rat ischemia/reperfusion. Brain Sci. 2022;12:1245. doi:10.3390/brainsci12091245.
49. Yuan Z, De La Cruz LK, Yang X, Wang B. Carbon monoxide signaling: examining its engagement with various molecular targets in the context of binding affinity, concentration, and biologic response. Pharmacol Rev. 2022;74(3):825–875. doi:10.1124/pharmrev.121.000564.
50. Zheng ZY, Jin YM, Jin SY, Ke BW. [Carbon Monoxide and Pain Regulation: A Review]. Sichuan Da Xue Xue Bao Yi Xue Ban. 2021 May;52(3):396-401. doi: 10.12182/20210560102.

Publication:

«World of Medicine and Biology» Vol. 22 No. 96 (2026) , с. 201-210
УДК 616-009.7:577.175.1:577.164

DOI:

https://doi.org/10.26724/2079-8334-2026-2-96-201-210