Advertisement

Inflammopharmacology

, Volume 27, Issue 1, pp 121–128 | Cite as

Preventive treatment with dizocilpine attenuates oedema in a carrageenan model of inflammation: the interaction of glutamatergic and nitrergic signaling

  • Dragana P. SrebroEmail author
  • Sonja Vučković
  • Aleksandar Milovanović
  • Katarina Savić Vujović
  • Čedomir Vučetić
  • Milica Prostran
Original Article

Abstract

Dizocilpine is a highly selective and potent non-competitive antagonist of the N-methyl-d-aspartate (NMDA) glutamate receptor. It is well known that dizocilpine has different neuroprotective effects in animal models of pain, epilepsy and oedema during trauma. The search for alternative antiinflammatory drugs is ongoing. We investigated the anti-oedematous effects of dizocilpine and the probable mechanism of action in a rat model that mimics local and persistent inflammation without tissue injury or damage. Male Wistar rats were injected with 100 μL of 0.5% carrageenan to the plantar surface of the hind paw. Anti-oedematous activity was assessed in the carrageenan-induced paw inflammatory oedema test with a plethysmometer. To assess possible mechanisms of dizocilpine action, we examined the effects of the selective inhibitor of neuronal [N-ω-propyl-l-arginine hydrochloride (L-NPA)] and inducible [S-methylisothiourea (SMT)] nitric oxide synthase (NOS). Dizocilpine after systemic (0.0005, 0.005 and 0.02 mg/kg, subcutaneous (s.c.)), but not after local peripheral administration, reduced the paw inflammatory oedema. The effect is not dose dependent, and the highest decrease by about 47% at the time of maximally developed oedema was achieved with 0.005 mg/kg. Intraperitoneally (i.p.) administered L-NPA (0.5, 1 and 2 mg/kg) or SMT (0.005, 0.01 and 0.015 mg/kg) before dizocilpine abolished or reduced the anti-oedematous effect of dizocilpine by about 70–85%. An acute single dose of dizocilpine administered before inducing oedema systemically reduced the development of inflammatory oedema. The mechanism of the anti-oedematous effect includes, at least partially, an increase in nitric oxide (NO) production.

Keywords

MK-801 Paw oedema Antiinflammatory Anti-oedematous Preemptive therapy NOS inhibitors 

Notes

Acknowledgements

This work was supported by the Ministry of Education, Science and Technological Development of Serbia (Grant number 175023).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution at which the studies were conducted.

References

  1. Anderson P, Christy ME, Evans BE (1982) 5-Alkyl or hydroxyalkyl substituted-10,11-imines & anticonvulsant use thereof. Issued 1983-08-16, assigned to MERCK & CO INC. US Patent 4399141Google Scholar
  2. Antošová M, Strapková A (2013) Study of the interaction of glutamatergic and nitrergic signalling in conditions of the experimental airways hyperreactivity. Pharmacol Rep 65:650–657CrossRefGoogle Scholar
  3. Beirith A, Santos AR (2002) Calixto JB (2002) Mechanisms underlying the nociception and paw oedema caused by injection of glutamate into the mouse paw. Brain Res 924(2):219–228CrossRefGoogle Scholar
  4. Carey RJ, Dai H, Gui J (1998) Effects of dizocilpine on motor activity and memory. Psychopharmacology 137:241–246CrossRefGoogle Scholar
  5. Chu YC, Guan Y, Skinner J et al (2005) Effect of genetic knockout or pharmacologic inhibition of neuronal nitric oxide synthase on complete Freund’s adjuvant-induced persistent pain. Pain 119:113–123CrossRefGoogle Scholar
  6. Cuzzocrea S, Sautebin L, Sarro GD et al (1999) Role of IL-6 in the pleurisy and lung injury caused by carrageenan. J Immunol 163:5094–5104Google Scholar
  7. Esposito E, Paterniti I, Mazzon E et al (2011) MK801 attenuates secondary injury in a mouse experimental compression model of spinal cord trauma. BMC Neurosci 12:31.  https://doi.org/10.1186/1471-2202-12-31 CrossRefGoogle Scholar
  8. Fujii E, Irie K, Uchida Y, Tsukahara F, Muraki T (1994) Possible role of nitric oxide in 5-hydroxytryptamine-induced increase in vascular permeability in mouse skin. Naunyn Schmiedebergs Arch Pharmacol 350:361–364CrossRefGoogle Scholar
  9. Hucker HB, Hutt JE, White SD et al (1983) Disposition and metabolism of (+)-5-methyl-10,11-dihydro-5H-dibenzo[a, d] cyclohepten-5,10-imine in rats, dogs, and monkeys. Drug Metabol Disp 11:54Google Scholar
  10. Huettner JE, Bean BP (1988) Block of N-methyl-d-aspartate-activated current by the anticonvulsant MK-801: selective binding to open channels. Proc Natl Acad Sci USA 85:1307–1311CrossRefGoogle Scholar
  11. Im DS, Jeon JW, Lee JS et al (2012) Role of the NMDA receptor and iron on free radical production and brain damage following transient middle cerebral artery occlusion. Brain Res 1455:114–123.  https://doi.org/10.1016/j.brainres.2012.03.025 CrossRefGoogle Scholar
  12. Imer MB, Omay A, Uzunkol T et al (2009) Effect of magnesium, MK-801 and combination of magnesium and MK-801 on blood-brain barrier permeability and brain edema after experimental traumatic diffuse brain injury. Neurol Res 31:977–981CrossRefGoogle Scholar
  13. Infante C, Díaz M, Hernández A et al (2007) Expression of nitric oxide synthase isoforms in the dorsal horn of monoarthritic rats: effects of competitive and uncompetitive N-methyl-d-aspartate antagonists. Arthritis Res Ther 9:R53CrossRefGoogle Scholar
  14. Jarosz M, Szkaradek N, Marona H et al (2017) Evaluation of anti-inflammatory and ulcerogenic potential of zinc-ibuprofen and zinc-naproxen complexes in rats. Inflammopharmacology 25:653–663.  https://doi.org/10.1007/s10787-017-0361-0 CrossRefGoogle Scholar
  15. Kubes P, Kanwar S, Niu NF, Gaboury JP (1993) Nitric oxide synthesis inhibition induces leukocyte adhesion via superoxide and mast cells. FASEB J 7:1293–1299CrossRefGoogle Scholar
  16. Liu CH, Cherng CH, Lin SL et al (2011) N-methyl-d-aspartate receptor antagonist MK-801 suppresses glial pro-inflammatory cytokine expression in morphine-tolerant rats. Pharmacol Biochem Behav 99:371–380.  https://doi.org/10.1016/j.pbb.2011.05.016 CrossRefGoogle Scholar
  17. Masini E, Salvemini D, Pistelli A et al (1991) Rat mast cells synthesize a nitric oxide like-factor which modulates the release of histamine. Agents Actions 33:61–63CrossRefGoogle Scholar
  18. Morris (2003) Carrageenan-induced paw edema in the rat and mouse. Methods Mol Biol 225:115–121Google Scholar
  19. Nathan C (2002) Points of control in inflammation. Nature 420:846–852CrossRefGoogle Scholar
  20. Odabasoglu F, Halici Z, Aygun H et al (2011) α-Lipoic acid has anti-inflammatory and anti-oxidative properties: an experimental study in rats with carrageenan-induced acute and cotton pellet-induced chronic inflammations. Br J Nutr 105:31–43.  https://doi.org/10.1017/S0007114510003107 CrossRefGoogle Scholar
  21. Olney JW, Labruyere J, Price MT (1989) Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs. Science 244:1360–1362CrossRefGoogle Scholar
  22. Otterness IG, Wiseman EH, Gans DJ (1979) A comparison of the carrageenan edema test and ultraviolet light-induced erythema test as predictors of the clinical dose in rheumatoid arthritis. Agents Actions 9:177–183CrossRefGoogle Scholar
  23. Paul-Clark MJ, Gilroy DW, Willis D et al (2001) Nitric oxide synthase inhibitors have opposite effects on acute inflammation depending on their route of administration. J Immunol 166:1169–1177CrossRefGoogle Scholar
  24. Ren K, Dubner R (1993) NMDA receptor antagonists attenuate mechanical hyperalgesia in rats with unilateral inflammation of the hindpaw. Neurosci Lett 163:22–26CrossRefGoogle Scholar
  25. Sakhaee E, Ostadhadi S, Khan MI et al (2017) The role of NMDA receptor and nitric oxide/cyclic guanosine monophosphate pathway in the antidepressant-like effect of dextromethorphan in mice forced swimming test and tail suspension test. Biomed Pharmacother 85:627–634.  https://doi.org/10.1016/j.biopha.2016.11.073 CrossRefGoogle Scholar
  26. Salvemini D, Wang ZQ, Wyatt PS et al (1996) Nitric oxide: a key mediator in the early and late phase of carrageenan-induced rat paw inflammation. Br J Pharmacol 118:829–838CrossRefGoogle Scholar
  27. Sawynok J, Reid A (2002) Modulation of formalin-induced behaviors and edema by local and systemic administration of dextromethorphan, memantine and ketamine. Eur J Pharmacol 450:153–162CrossRefGoogle Scholar
  28. Srebro DP, Vucković SM, Savic Vujovic KR, Prostran MS (2014) Nitric oxide synthase modulates the antihyperalgesic effect of the NMDA receptor antagonist MK-801 on Carrageenan-induced inflammatory pain in rats. Tohoku J Exp Med 234:287–293CrossRefGoogle Scholar
  29. Srebro D, Vučković S, Prostran M (2016) Inhibition of neuronal and inducible nitric oxide synthase does not affect the analgesic effects of NMDA antagonists in visceral inflammatory pain. Acta Neurobiol Exp (Wars) 76:110–116Google Scholar
  30. Srebro DP, Vučković SM, Dožić IS et al (2018) Magnesium sulfate reduces formalin-induced orofacial pain in rats with normal magnesium serum levels. Pharmacol Rep 70:81–86.  https://doi.org/10.1016/j.pharep.2017.08.005 CrossRefGoogle Scholar
  31. Suetake-Koga S, Shimazaki T, Takamori K et al (2006) In vitro and antinociceptive profile of HON0001, an orally active NMDA receptor NR2B subunit antagonist. Pharmacol Biochem Behav 84:134–141CrossRefGoogle Scholar
  32. Tao F, Tao YX, Zhao C et al (2004) Differential roles of neuronal and endothelial nitric oxide synthases during carrageenan-induced inflammatory hyperalgesia. Neuroscience 128:421–430CrossRefGoogle Scholar
  33. Tomić M, Popović V, Petrović S et al (2014) Antihyperalgesic and antiedematous activities of bisabolol-oxides-rich matricaria oil in a rat model of inflammation. Phytother Res 28:759–766.  https://doi.org/10.1002/ptr.5057 CrossRefGoogle Scholar
  34. Vazquez E, Navarro M, Salazar Y (2015) Systemic changes following carrageenan-induced paw inflammation in rats. Inflamm Res 64:333–342.  https://doi.org/10.1007/s00011-015-0814-0 CrossRefGoogle Scholar
  35. Vezzani A, Serafini R, Stasi MA et al (1989) Kinetics of MK-801 and its effect on quinolinic acid-induced seizures and neurotoxicity in rats. J Pharmacol Exp Ther 249:278–283Google Scholar
  36. Vuckovic S, Srebro D, Savic Vujovic K, Prostran M (2015) The antinociceptive effects of magnesium sulfate and MK-801 in visceral inflammatory pain model: the role of NO/cGMP/K(+)ATP pathway. Pharm Biol 53:1621–1627.  https://doi.org/10.3109/13880209.2014.996821 CrossRefGoogle Scholar
  37. Wang Q, Li J, Wei X et al (2014) Alterations of NMDA receptor binding in various brain regions among 6-hydroxydopamine-induced Parkinsonian rats. Int J Neurosci 124:457–465.  https://doi.org/10.3109/00207454.2013.853058 CrossRefGoogle Scholar
  38. Winter CA, Risley EA, Nuss GW (1962) Carrageenin-induced edema in hind paw of the rat as an assay for antiiflammatory drugs. Proc Soc Exp Biol Med 111:544–547CrossRefGoogle Scholar
  39. Yonehara N, Amano K, Kamisaki Y (2002) Involvement of the NMDA-nitric oxide pathway in the development of hypersensitivity to tactile stimulation in dental injured rats. Jpn J Pharmacol 90:145–155CrossRefGoogle Scholar
  40. Zanchet EM, Cury Y (2003) Peripheral tackykinin and excitatory amino acid receptors mediate hyperalgesia induced by Phoneutria nigriventer venom. Eur J Pharmacol 467:111–118CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Department of Pharmacology, Clinical Pharmacology and Toxicology, Faculty of MedicineUniversity of BelgradeBelgradeSerbia
  2. 2.Department of Pharmacology, Clinical Pharmacology and Toxicology, Faculty of MedicineUniversity of BelgradeBelgradeSerbia
  3. 3.Institute of Occupational Health “Dr Dragomir Karajovic”, Faculty of MedicineUniversity of BelgradeBelgradeSerbia
  4. 4.Clinic of Orthopedic Surgery and Traumatology, Clinical Center of Serbia, Faculty of MedicineUniversity of BelgradeBelgradeSerbia

Personalised recommendations