Anti-inflammatory and antinociceptive activities of glucagon-like peptides: evaluation of their actions on serotonergic, nitrergic, and opioidergic systems

  • Duygun Altıntaş AykanEmail author
  • Murat Kesim
  • Beyza Ayan
  • Ayşegül Kurt
Original Investigation



Glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) are gut derived hormones. GLP-1 and GLP-2 were shown to have pleiotropic effects in intestinal and pancreatic diseases.


We aimed to investigate the activities of GLP-1 and GLP-2 on nociception and inflammation in mice, involving their actions on serotonergic, nitrergic, and opioidergic systems.


Antinociceptive and anti-inflammatory activities of intraperitoneally injected GLPs were evaluated in hotplate latency test, formalin-induced behavioral, and paw edema tests. Ondansetron, a selective 5-HT3 receptor antagonist; L-NAME, a NOS inhibitor; and naloxone, an opioid antagonist were injected to determine the mechanisms of antinociception and anti-inflammation. We also measured blood glucose levels and performed rotarod test in order to evaluate whether the hypoglycemic effect of GLP compounds or alterations in locomotor activity may affect the latency in hotplate test and activity in formalin test.


GLP-1 (0.2 mg/kg) and GLP-2 (0.05, 0.2 mg/kg) significantly increased pain threshold. GLP-1 (0.2 mg/kg) and GLP-2 (0.05, 0.1, 0.2 mg/kg) significantly decreased formalin-induced licking and shaking behaviors. GLP-1 or GLP-2 showed no significant inhibitory action on formalin-induced swelling in paws of mice. Antinociceptive actions of GLP-1 and GLP-2 were significantly decreased with ondansetron and naloxone, and paw shaking behavior significantly increased with naloxone. GLP-1 and GLP-2 did not impair rotarod performance, and did not cause a significant hypoglycemic effect in our normoglycemic mice after rotarod test.


These finding indicated that the antinociceptive and anti-inflammatory effect of GLP-1 was related to opioidergic system. Antinociceptive effect of GLP-2 was partially related to 5-HT3 serotonergic or opioidergic system in hotplate test. However, the anti-inflammatory effect of GLP-2 was not directly related to 5-HT3, NO or opioids.


Glucagon-like peptide 1 Glucagon-like peptide 2 Inflammation Nociception Pain 


Funding information

This study was supported financially by the Karadeniz Technical University Scientific Research Projects, Turkey.

Compliance with ethical standards

The study was carried out at Karadeniz Technical University Medical Faculty, Medical Pharmacology Department. Local ethics committee approved the study (Ethics Committee File No: 2015/44, Approval date: 15/12/2015).

Conflict of interest

The authors declare that there is no conflict of interest.


  1. Adzu B, Amos S, Kapu SD, Gamaniel KS (2003) Anti-inflammatory and antinociceptive effects of Sphaeranthus senegalensis. J Ethnopharmacol 84(2–3):169–173CrossRefGoogle Scholar
  2. Austin K, Imam NA, Pintar JE, Brubaker PL (2015) IGF binding protein-4 is required for the growth effects of glucagon-like peptide-2 in murine intestine. Endocrinology 156(2):429–436CrossRefGoogle Scholar
  3. Avila-Rojas SH, Velázquez-Lagunas I, Salinas-Abarca AB, Barragán-Iglesias P, Pineda-Farias JB, Granados-Soto V (2015) Role of spinal 5-HT5A, and 5-HT1A/1B/1D, receptors in neuropathic pain induced by spinal nerve ligation in rats. Brain Res 1622:377–385CrossRefGoogle Scholar
  4. Baggio LL, Drucker DJ (2007) Biology of incretins: GLP -1 and GIP. Gastroenterology 132(6):2131–2157CrossRefGoogle Scholar
  5. Barrot M (2012) Tests and models of nociception and pain in rodents. Neuroscience 211:39–50. CrossRefPubMedGoogle Scholar
  6. Brady LS, Holtzman SG (1982) Analgesic effects of intraventricular morphine and enkephalins in nondependent and morphine-dependent rats. J Pharmacol Exp Ther 222(1):190–197PubMedGoogle Scholar
  7. Bulut K, Meier JJ, Ansorge N, Felderbauer P, Schmitz F, Hoffmann P, Schmidt WE, Gallwitz B (2004) Glucagon-like peptide 2 improves intestinal wound healing through induction of epithelial cell migration in vitro-evidence for a TGF--beta-mediated effect. Regul Pept 121(1–3):137–143CrossRefGoogle Scholar
  8. Bulut K, Pennartz C, Felderbauer P, Meier JJ, Banasch M, Bulut D, Schmitz F, Schmidt WE, Hoffmann P (2008) Glucagon like peptide-2 induces intestinal restitution through VEGF release from subepithelial myofibroblasts. Eur J Pharmacol 578(2–3):279–285CrossRefGoogle Scholar
  9. Fan H, Gong N, Li TF, Ma AN, Wu XY, Wang MW, Wang YX (2015) The non-peptide GLP-1 receptor agonist WB4-24 blocks inflammatory nociception by stimulating β-endorphin release from spinal microglia. Br J Pharmacol 172(1):64–79CrossRefGoogle Scholar
  10. Gong N, Xiao Q, Zhu B, Zhang CY, Wang YC, Fan H, Ma AN, Wang YX (2014) Activation of spinal glucagon-like peptide-1 receptors specifically suppresses pain hypersensitivity. J Neurosci 34(15):5322–5334. CrossRefPubMedGoogle Scholar
  11. Hajhashemi V, Sajjadi SE, Heshmati M (2009) Anti-inflammatory and analgesic properties of Heracleum persicum essential oil and hydroalcoholic extract in animal models. J Ethnopharmacol 124(3):475–480CrossRefGoogle Scholar
  12. Insuela DBR, Carvalho VF (2017) Glucagon and glucagon-like peptide-1 as novel anti-inflammatory and immunomodulatory compounds. Eur J Pharmacol 812:64–72. CrossRefPubMedGoogle Scholar
  13. Ismail NI, Ming-Tatt L, Lajis N, Akhtar MN, Akira A, Perimal EK, Israf DA, Sulaiman MR (2016) Antinociceptive effect of 3-(2,3-dimethoxyphenyl)-1-(5-methylfuran-2-yl)prop-2-en-1-one in mice models of induced nociception. Molecules 21(8). doi:
  14. Iwai T, Hayashi Y, Narita S, Kasuya Y, Jin K, Tsugane M, Oka J (2009) Antidepressant-like effects of glucagon-like peptide-2 in mice occur via monoamine pathways. Behav Brain Res 204(1):235–240CrossRefGoogle Scholar
  15. Kagal UA, Angadi NB, Matule SM (2017) Effect of dipeptidyl peptidase 4 inhibitors on acute and subacute models of inflammation in male Wistar rats: an experimental study. Int J Appl Basic Med Res 7(1):26–31CrossRefGoogle Scholar
  16. Kawabata A, Manabe S, Manabe Y, Takagi H (1994) Effect of topical injection of L-arginine on formalin-induced nosiception in the mouse: a dual role of peripherally formed NO in pain modulation. Br J Pharmacol 112(2):547–550CrossRefGoogle Scholar
  17. Macpherson LJ, Xiao B, Kwan KY, Petrus MJ, Dubin AE, Hwang S, Cravatt B, Corey DP, Patapoutian A (2007) An ion channel essential for sensing chemical damage. J Neurosci 27:11412–11415CrossRefGoogle Scholar
  18. Miranda A, Peles S, McLean PG, Sengupta JN (2006) Effects of the 5-HT3 receptor antagonist, alosetron, in a rat model of somatic and visceral hyperalgesia. Pain 126(1–3):54–63CrossRefGoogle Scholar
  19. Nerup N, Ambrus R, Lindhe J, Achiam MP, Jeppesen PB, Svendsen LB (2017) The effect of glucagon-like peptide-1 and glucagon-like peptide-2 on microcirculation: a systematic review. Microcirculation.
  20. Palleria C, Leo A, Andreozzi F, Citraro R, Iannone M, Spiga R, Sesti G, Constanti A, De Sarro G, Arturi F, Russo E (2017) Liraglutide prevents cognitive decline in a rat model of streptozotocin-induced diabetes independently from its peripheral metabolic effects. Behav Brain Res 321:157–169. CrossRefPubMedGoogle Scholar
  21. Shajib MS, Baranov A, Khan WI (2017) Diverse effects of gut-derived serotonin in intestinal inflammation. ACS Chem Neurosci 8(5):920–931CrossRefGoogle Scholar
  22. Shibata M, Ohkubo T, Takahashi H, Inoki R (1989) Modified formalin test: characteristic biphasic pain response. Pain 38(3):347–352CrossRefGoogle Scholar
  23. Sigalet DL, Wallace LE, Holst JJ, Martin GR, Kaji T, Tanaka H, Sharkey KA (2007) Enteric neural pathways mediate the anti-inflammatory actions of glucagon-like peptide 2. Am J Physiol Gastrointest Liver Physiol 293(1):G211–G221CrossRefGoogle Scholar
  24. Sommer C (2006) Is serotonin hyperalgesic or analgesic? Curr Pain Headache Rep 10(2):101–106 ReviewCrossRefGoogle Scholar
  25. Tjølsen A, Berge OG, Hunskaar S, Rosland JH, Hole K (1992) The formalin test: an evaluation of the method. Pain 51(1):5–17CrossRefGoogle Scholar
  26. Trefts E, Williams AS, Wasserman DH (2015) Exercise and the regulation of hepatic metabolism. Prog Mol Biol Transl Sci 135:203–225. ReviewCrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Pharmacology, Faculty of MedicineKahramanmaras Sutcu Imam UniversityKahramanmaraşTurkey
  2. 2.Department of Pharmacology, Faculty of MedicineKaradeniz Technical UniversityTrabzonTurkey
  3. 3.Department of Histology and Embryology, Faculty of MedicineKaradeniz Technical UniversityTrabzonTurkey
  4. 4.Department of Physiology, Faculty of MedicineKaradeniz Technical UniversityTrabzonTurkey

Personalised recommendations