Investigating the Effects of Orexin and its Receptors on Inflammatory Processes in Experimental Models: A Review Study

Authors

Fatemeh Sohrabi1, Sadaf Khodaveisi1, Mohammad SheibaniMohammad Sheibani ORCID2, 3,*
1Student Research Committee, Iran University of Medical Sciences, Tehran, Iran
2Department of Pharmacology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
3Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran
*Corresponding Author: Department of Pharmacology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran Email: [email protected]

Koomesh:Vol. 28, issue 1; e160830
Published online:Mar 20, 2026
Article type:Review Article
How to Cite:Sohrabi F, Khodaveisi S, Sheibani M. Investigating the Effects of Orexin and its Receptors on Inflammatory Processes in Experimental Models: A Review Study. koomesh. 2026;28(1):e160830. doi: https://doi.org/10.69107/koomesh-160830

Highlights

References

  • 1.
    Inutsuka A, Yamanaka A. The physiological role of orexin/hypocretin neurons in the regulation of sleep/wakefulness and neuroendocrine functions. Front Endocrinol (Lausanne). 2013;4:18. [PubMed ID:23508038]. [PubMed Central ID:PMC3589707]. https://doi.org/10.3389/fendo.2013.00018.
  • 2.
    Sakurai T. The role of orexin in motivated behaviours. Nat Rev Neurosci. 2014;15(11):719–31. [PubMed ID:25301357]. https://doi.org/10.1038/nrn3837.
  • 3.
    Sheibani M, Shayan M, Khalilzadeh M, Ghasemi M, Dehpour AR. Orexin receptor antagonists in the pathophysiology and treatment of sleep disorders and epilepsy. Neuropeptides. 2023;99:102335. [PubMed ID:37003137]. https://doi.org/10.1016/j.npep.2023.102335.
  • 4.
    Marcus JN, Aschkenasi CJ, Lee CE, Chemelli RM, Saper CB, Yanagisawa M, et al. Differential expression of orexin receptors 1 and 2 in the rat brain. J Comp Neurol. 2001;435(1):6–25. [PubMed ID:11370008]. https://doi.org/10.1002/cne.1190.
  • 5.
    Villano I, La Marra M, Di Maio G, Monda V, Chieffi S, Guatteo E, et al. Physiological Role of Orexinergic System for Health. Int J Environ Res Public Health. 2022;19(14). [PubMed ID:35886210]. [PubMed Central ID:PMC9323672]. https://doi.org/10.3390/ijerph19148353.
  • 6.
    Wei W, Motoike T, Krzeszinski JY, Jin Z, Xie XJ, Dechow PC, et al. Orexin regulates bone remodeling via a dominant positive central action and a subordinate negative peripheral action. Cell Metab. 2014;19(6):927–40. [PubMed ID:24794976]. [PubMed Central ID:PMC4047150]. https://doi.org/10.1016/j.cmet.2014.03.016.
  • 7.
    Heinonen MV, Purhonen AK, Makela KA, Herzig KH. Functions of orexins in peripheral tissues. Acta Physiol (Oxf). 2008;192(4):471–85. [PubMed ID:18294339]. https://doi.org/10.1111/j.1748-1716.2008.01836.x.
  • 8.
    Sheibani M, Ghasemi M, Dehpour AR. Lithium and Erectile Dysfunction: An Overview. Cells. 2022;11(1). [PubMed ID:35011733]. [PubMed Central ID:PMC8750948]. https://doi.org/10.3390/cells11010171.
  • 9.
    Sheibani M, Shayan M, Khalilzadeh M, Soltani ZE, Jafari-Sabet M, Ghasemi M, et al. Kynurenine pathway and its role in neurologic, psychiatric, and inflammatory bowel diseases. Mol Biol Rep. 2023;50(12):10409–25. [PubMed ID:37848760]. https://doi.org/10.1007/s11033-023-08859-7.
  • 10.
    Soya S, Sakurai T. Evolution of Orexin Neuropeptide System: Structure and Function. Front Neurosci. 2020;14:691. [PubMed ID:32754010]. [PubMed Central ID:PMC7365868]. https://doi.org/10.3389/fnins.2020.00691.
  • 11.
    Bentzley BS, Aston-Jones G. Orexin-1 receptor signaling increases motivation for cocaine-associated cues. Eur J Neurosci. 2015;41(9):1149–56. [PubMed ID:25754681]. [PubMed Central ID:PMC4420694]. https://doi.org/10.1111/ejn.12866.
  • 12.
    Shen YC, Sun X, Li L, Zhang HY, Huang ZL, Wang YQ. Roles of Neuropeptides in Sleep-Wake Regulation. Int J Mol Sci. 2022;23(9). [PubMed ID:35562990]. [PubMed Central ID:PMC9103574]. https://doi.org/10.3390/ijms23094599.
  • 13.
    Calva CB, Fadel JR. Intranasal administration of orexin peptides: Mechanisms and therapeutic potential for age-related cognitive dysfunction. Brain Res. 2020;1731:145921. [PubMed ID:30148983]. [PubMed Central ID:PMC6387866]. https://doi.org/10.1016/j.brainres.2018.08.024.
  • 14.
    De Luca R, Nardone S, Grace KP, Venner A, Cristofolini M, Bandaru SS, et al. Orexin neurons inhibit sleep to promote arousal. Nat Commun. 2022;13(1):4163. [PubMed ID:35851580]. [PubMed Central ID:PMC9293990]. https://doi.org/10.1038/s41467-022-31591-y.
  • 15.
    Barateau L, Dauvilliers Y. Recent advances in treatment for narcolepsy. Ther Adv Neurol Disord. 2019;12:1756286419875622. [PubMed ID:31632459]. [PubMed Central ID:PMC6767718]. https://doi.org/10.1177/1756286419875622.
  • 16.
    Muthmainah M, Gogos A, Sumithran P, Brown RM. Orexins (hypocretins): The intersection between homeostatic and hedonic feeding. J Neurochem. 2021;157(5):1473–94. [PubMed ID:33608877]. https://doi.org/10.1111/jnc.15328.
  • 17.
    Couvineau A, Voisin T, Nicole P, Gratio V, Abad C, Tan YV. Orexins as Novel Therapeutic Targets in Inflammatory and Neurodegenerative Diseases. Front Endocrinol (Lausanne). 2019;10:709. [PubMed ID:31695678]. [PubMed Central ID:PMC6817618]. https://doi.org/10.3389/fendo.2019.00709.
  • 18.
    Sun M, Wang W, Li Q, Yuan T, Weng W. Orexin A may suppress inflammatory response in fibroblast-like synoviocytes. Biomed Pharmacother. 2018;107:763–8. [PubMed ID:30142537]. https://doi.org/10.1016/j.biopha.2018.07.159.
  • 19.
    Blais A, Lan A, Blachier F, Benamouzig R, Jouet P, Couvineau A. Efficiency of Orexin-A for Inflammatory Flare and Mucosal Healing in Experimental Colitis: Comparison with the Anti-TNF Alpha Infliximab. Int J Mol Sci. 2023;24(11). [PubMed ID:37298505]. [PubMed Central ID:PMC10253642]. https://doi.org/10.3390/ijms24119554.
  • 20.
    Tsujino N, Sakurai T. Role of orexin in modulating arousal, feeding, and motivation. Front Behav Neurosci. 2013;7:28. [PubMed ID:23616752]. [PubMed Central ID:PMC3629303]. https://doi.org/10.3389/fnbeh.2013.00028.
  • 21.
    Matzeu A, Martin-Fardon R. Understanding the Role of Orexin Neuropeptides in Drug Addiction: Preclinical Studies and Translational Value. Front Behav Neurosci. 2021;15:787595. [PubMed ID:35126069]. [PubMed Central ID:PMC8811192]. https://doi.org/10.3389/fnbeh.2021.787595.
  • 22.
    Tannenbaum PL, Tye SJ, Stevens J, Gotter AL, Fox SV, Savitz AT, et al. Inhibition of Orexin Signaling Promotes Sleep Yet Preserves Salient Arousability in Monkeys. Sleep. 2016;39(3):603–12. [PubMed ID:26943466]. [PubMed Central ID:PMC4763356]. https://doi.org/10.5665/sleep.5536.
  • 23.
    Salvadore G, Bonaventure P, Shekhar A, Johnson PL, Lord B, Shireman BT, et al. Translational evaluation of novel selective orexin-1 receptor antagonist JNJ-61393215 in an experimental model for panic in rodents and humans. Transl Psychiatry. 2020;10(1):308. [PubMed ID:32895369]. [PubMed Central ID:PMC7477545]. https://doi.org/10.1038/s41398-020-00937-9.
  • 24.
    Evans R, Kimura H, Alexander R, Davies CH, Faessel H, Hartman DS, et al. Orexin 2 receptor-selective agonist danavorexton improves narcolepsy phenotype in a mouse model and in human patients. Proc Natl Acad Sci U S A. 2022;119(35):e2207531119. [PubMed ID:35994639]. [PubMed Central ID:PMC9436334]. https://doi.org/10.1073/pnas.2207531119.
  • 25.
    Amin TU, Emara R, Pal A, Aldawod H, Jiang G, Liang D, et al. Enhancing the Safety and Efficacy of PSMA-Based Small-Molecule Drug Conjugates by Linker Stabilization and Conjugation to Transthyretin Binding Ligand. J Med Chem. 2022;65(22):15473–86. [PubMed ID:36327103]. https://doi.org/10.1021/acs.jmedchem.2c01423.
  • 26.
    Kaufmann P, Ort M, Golor G, Kornberger R, Dingemanse J. First-in-human study with ACT-539313, a novel selective orexin-1 receptor antagonist. Br J Clin Pharmacol. 2020;86(7):1377–86. [PubMed ID:32067262]. [PubMed Central ID:PMC7319015]. https://doi.org/10.1111/bcp.14251.
  • 27.
    Xiong X, White RE, Xu L, Yang L, Sun X, Zou B, et al. Mitigation of murine focal cerebral ischemia by the hypocretin/orexin system is associated with reduced inflammation. Stroke. 2013;44(3):764–70. [PubMed ID:23349191]. [PubMed Central ID:PMC3638929]. https://doi.org/10.1161/STROKEAHA.112.681700.
  • 28.
    Yousefi-Manesh H, Dehpour AR, Nabavi SM, Khayatkashani M, Asgardoon MH, Derakhshan MH, et al. Therapeutic Effects of Hydroalcoholic Extracts from the Ancient Apple Mela Rosa dei Monti Sibillini in Transient Global Ischemia in Rats. Pharmaceuticals (Basel). 2021;14(11). [PubMed ID:34832888]. [PubMed Central ID:PMC8619919]. https://doi.org/10.3390/ph14111106.
  • 29.
    Zhao D, Zeng Z, Mo H, Hu W, Tian S, Hu D, et al. Orexin-A inhibits cerebral ischaemic inflammatory injury mediated by the nuclear factor-kappaB signalling pathway and alleviates stroke-induced immunodepression in mice. Brain Res Bull. 2021;174:296–304. [PubMed ID:34216650]. https://doi.org/10.1016/j.brainresbull.2021.06.021.
  • 30.
    Li T, Xu W, Ouyang J, Lu X, Sherchan P, Lenahan C, et al. Orexin A alleviates neuroinflammation via OXR2/CaMKKbeta/AMPK signaling pathway after ICH in mice. J Neuroinflammation. 2020;17(1):187. [PubMed ID:32539736]. [PubMed Central ID:PMC7294616]. https://doi.org/10.1186/s12974-020-01841-1.
  • 31.
    Messal N, Fernandez N, Dayot S, Gratio V, Nicole P, Prochasson C, et al. Ectopic expression of OX1R in ulcerative colitis mediates anti-inflammatory effect of orexin-A. Biochim Biophys Acta Mol Basis Dis. 2018;1864(11):3618–28. [PubMed ID:30251681]. https://doi.org/10.1016/j.bbadis.2018.08.023.
  • 32.
    Ogawa Y, Shimojo N, Ishii A, Tamaoka A, Kawano S, Inoue Y. Reduced CSF orexin levels in rats and patients with systemic inflammation: a preliminary study. BMC Res Notes. 2022;15(1):221. [PubMed ID:35752867]. [PubMed Central ID:PMC9233848]. https://doi.org/10.1186/s13104-022-06121-0.
  • 33.
    Deli SB, Bonab SI, Khakpay R, Khakpai F, Feyzi MH. An interaction between basolateral amygdala orexinergic and endocannabinoid systems in inducing anti-nociception in the rat formalin test. Psychopharmacology (Berl). 2022;239(10):3171–84. [PubMed ID:35918531]. https://doi.org/10.1007/s00213-022-06199-1.
  • 34.
    Jahangirvand M, Yazdi F, Moradi M, Haghparast A. Intra-accumbal Orexin-1 Receptors are Involved in Antinociception Induced by Stimulation of the Lateral Hypothalamus in the Formalin Test as an Animal Model of Persistent Inflammatory Pain. Iran J Pharm Res. 2016;15(4):851–9. [PubMed ID:28243282]. [PubMed Central ID:PMC5316264].
  • 35.
    Zareie F, Ghalebandi S, Askari K, Mousavi Z, Haghparast A. Orexin receptors in the CA1 region of hippocampus modulate the stress-induced antinociceptive responses in an animal model of persistent inflammatory pain. Peptides. 2022;147:170679. [PubMed ID:34718063]. https://doi.org/10.1016/j.peptides.2021.170679.
  • 36.
    Shahsavari F, Abbasnejad M, Esmaeili-Mahani S, Raoof M. The ability of orexin-A to modify pain-induced cyclooxygenase-2 and brain-derived neurotrophic factor expression is associated with its ability to inhibit capsaicin-induced pulpal nociception in rats. Korean J Pain. 2022;35(3):261–70. [PubMed ID:35768981]. [PubMed Central ID:PMC9251390]. https://doi.org/10.3344/kjp.2022.35.3.261.
  • 37.
    Kooshki R, Abbasnejad M, Esmaeili-Mahani S, Raoof M. The effect of CA1 administration of orexin-A on hippocampal expression of COX-2 and BDNF in a rat model of orofacial pain. Arq Neuropsiquiatr. 2018;76(9):603–8. [PubMed ID:30365624]. https://doi.org/10.1590/0004-282X20180099.
  • 38.
    Rasouli B, Rashvand M, Mousavi Z, Haghparast A. Role of orexin receptors within the dentate gyrus in antinociception induced by chemical stimulation of the lateral hypothalamus in an animal model of inflammatory pain. Peptides. 2020;134:170401. [PubMed ID:32891686]. https://doi.org/10.1016/j.peptides.2020.170401.
  • 39.
    Moteshakereh SM, Nikoohemmat M, Farmani D, Khosrowabadi E, Salehi S, Haghparast A. The stress-induced antinociceptive responses to the persistent inflammatory pain involve the orexin receptors in the nucleus accumbens. Neuropeptides. 2023;98:102323. [PubMed ID:36736068]. https://doi.org/10.1016/j.npep.2023.102323.
  • 40.
    Yousefi-Manesh H, Shirooie S, Noori T, Sheibani M, Tavangar SM, Hemmati S, et al. Spermidine reduced neuropathic pain in chronic constriction injury-induced peripheral neuropathy in rats. Fundam Clin Pharmacol. 2023;37(4):779–85. [PubMed ID:36799067]. https://doi.org/10.1111/fcp.12880.
  • 41.
    Yamaguchi M, Ishikawa M, Aono Y, Saigusa T. OX(2) receptors mediate the inhibitory effects of orexin-A on potassium chloride-induced increases in intracellular calcium ion levels in neurons derived from rat dorsal root ganglion in a chronic pain model. Neuropsychopharmacol Rep. 2020;40(1):30–8. [PubMed ID:31845549]. [PubMed Central ID:PMC7292216]. https://doi.org/10.1002/npr2.12094.
  • 42.
    Ye W, Yan Y, Tang Y, Dong X, Chen G, Kang J, et al. Orexin-A Attenuates Inflammatory Responses in Lipopolysaccharide-Induced Neural Stem Cells by Regulating NF-KB and Phosphorylation of MAPK/P38/Erk Pathways. J Inflamm Res. 2021;14:2007–17. [PubMed ID:34040413]. [PubMed Central ID:PMC8140926]. https://doi.org/10.2147/JIR.S308078.
  • 43.
    Wang L, He T, Wan B, Wang X, Zhang L. Orexin A ameliorates HBV X protein-induced cytotoxicity and inflammatory response in human hepatocytes. Artif Cells Nanomed Biotechnol. 2019;47(1):2003–9. [PubMed ID:31106596]. https://doi.org/10.1080/21691401.2019.1614014.
  • 44.
    Becquet L, Abad C, Leclercq M, Miel C, Jean L, Riou G, et al. Systemic administration of orexin A ameliorates established experimental autoimmune encephalomyelitis by diminishing neuroinflammation. J Neuroinflammation. 2019;16(1):64. [PubMed ID:30894198]. [PubMed Central ID:PMC6425555]. https://doi.org/10.1186/s12974-019-1447-y.
  • 45.
    Li C, Tao T, Tang Y, Lu H, Zhang H, Li H, et al. The association of psychological stress with metabolic syndrome and its components: cross-sectional and bidirectional two-sample Mendelian randomization analyses. Front Endocrinol (Lausanne). 2023;14:1212647. [PubMed ID:38144566]. [PubMed Central ID:PMC10749192]. https://doi.org/10.3389/fendo.2023.1212647.
  • 46.
    Grafe LA, Cornfeld A, Luz S, Valentino R, Bhatnagar S. Orexins Mediate Sex Differences in the Stress Response and in Cognitive Flexibility. Biol Psychiatry. 2017;81(8):683–92. [PubMed ID:27955897]. [PubMed Central ID:PMC5359079]. https://doi.org/10.1016/j.biopsych.2016.10.013.
  • 47.
    Mohammad Jafari R, Sheibani M, Nezamoleslami S, Shayesteh S, Jand Y, Dehpour AR. Drug Repositioning: A Review. Journal of Iranian Medical Council. 2018;1(1):7–10.

Copyright

© 2026, Author(s). This open-access article is available under the Creative Commons Attribution 4.0 (CC BY 4.0) International License (https://creativecommons.org/licenses/by/4.0/), which allows for unrestricted use, distribution, and reproduction in any medium, provided that the original work is properly cited.

Similar Articles

28
Apr
2014

Orexin (hypocretin): A multi-functional hypothalamic peptide

Mohammad Shabani,
Mohammad Mohammad-Zadeh,
hassan Azhdari Zarmehri

Shabani M, Mohammad-Zadeh M, Azhdari Zarmehri H. Orexin (hypocretin): A multi-functional hypothalamic peptide. koomesh. 2014;15(3):e152644. doi:

30
Sep
2014

Effects of endogenous opioidergic system interaction with orexin on eating in rats

H Azhdari Zarmehri,
mohammad sofiabadi

Azhdari Zarmehri H, sofiabadi M. Effects of endogenous opioidergic system interaction with orexin on eating in rats. J Inflamm Dis. 2024;18(2):e155829. doi:

30
Jun
2013

Effect of Orexin receptor-1 antagonist in acute food deprivation on formalin test

E Ghasemi,
B Salehi,
H Nakhost,
M Sofiabdi,
E Erami,
H Azhdari Zarmehri

Ghasemi E, Salehi B, Nakhost H, Sofiabdi M, Erami E, et al. Effect of Orexin receptor-1 antagonist in acute food deprivation on formalin test. J Inflamm Dis. 2024;17(1):e155740. doi:

31
Oct
2016

Intra-accumbal Orexin-1 Receptors are Involved in Antinociception Induced by Stimulation of the Lateral Hypothalamus in the Formalin Test as an Animal Model of Persistent Inflammatory Pain

Mahboubeh Jahangirvand,
Fatemeh Yazdi,
Marzieh Moradi,
Abbas Haghparast

Jahangirvand M, Yazdi F, Moradi M, Haghparast A. Intra-accumbal Orexin-1 Receptors are Involved in Antinociception Induced by Stimulation of the Lateral Hypothalamus in the Formalin Test as an Animal Model of Persistent Inflammatory Pain. Iran J Pharm Res. 2016;15(4):e125233. doi: https://doi.org/10.22037/ijpr.2016.1921

28
May
2014

Role of orexinergic system in the effects of morphine on food and water intake in male rat

Mohammad SofiAbadi,
Samad Nazemi,
Elaheh Erami,
hassan Azhdari Zarmehri

SofiAbadi M, Nazemi S, Erami E, Azhdari Zarmehri H. Role of orexinergic system in the effects of morphine on food and water intake in male rat. koomesh. 2014;15(3):e153881. doi:

More by these authors

Fatemeh SohrabiPubMedScholar
Sadaf KhodaveisiPubMedScholar
Mohammad SheibaniPubMedScholar
Share
Cited by
Metrics