Différents modes de gestion

• A administração de antagonistaNMDA por via intraganglionar apresentou efeito analgésico agudo nos primeiros 1 ou 2 dias após lesão do nervo periférico sugerindoa participação de células satélites gliais neste momento.

• A administração de antagonistas NMDA por via intratecal induziu efeito analgésico em praticamente todos os dias testados, sugerindo um papel dos receptores NMDA medulares no processamento da dor ou em sensibilização central.

• Em longo prazo, o efeito da administração intraganglionar de antagonista NMDA d-AP5 foi semelhante àquele obtido pela administração intratecal do mesmo antagonista, indicando a participação de receptores NMDA periféricos, provavelmente em célulassatélites gliais, nodesenvolvimento da dor neuropática. • Cetamina parece ter um efeito melhor que d-AP5, quando administrados por via

intratecal, sobre o desenvolvimento da dor de origemneuropática.

• Antagonistas NMDA de ação preferencialmente periférica podem ser úteis no tratamento de dores de origem neuropática, possivelmente apresentando menos efeitosadversos.

REFERÊNCIAS

AMIR, R.; MICHAELIS, M.; DEVOR, M. Burst Discharge in Primary Sensory Neurons: Triggered by Subthreshold Oscillations, Maintained by Depolarizing Afterpotentials. The Journal of Neuroscience, v.22, n.3, p.1187-1198. 2002.

ARALDI, D, FERRARI, L.F., et al. Peripheral inflammatory hyperalgesia depends on the COX increase in the dorsal root ganglion. Proceedings of the National Academy of Sciences of the United States of America. v.110, n.9 , p.3603-8.2013.

AUSTIN, P. J.; WU, A.;MOALEM-TAYLOR, G.Chronic Constriction of the Sciatic Nerve and Pain HypersensitivityTesting in Rats. Journal of VisualizedExperiments, n. 61, p. 1-6. 2012.

BASBAUM A., JESSELL T. The perception of pain. In: Kandel ER, Schwartz JH, Jessell TM, editors. Principles of Neural Science.4a ed. New York: McGraw-Hill, Health Professions Division;2000.

BENNETT, J.; XIE, Y.A peripheral mononeuropathy in rat that produces disorders of pain sensationlike thoseseen in man. Pain, v. 33, n. 1, p. 87-107, 1988.

BORSOOK, D. et al. Surgically induced neuropathic pain: understanding the perioperative process. Ann Surg,v. 257, n. 3, p. 403-12. 2013.

CHAKRABORTY, A.; MURPHY, S.; COLEMAN, N. The role of NMDA receptors in neural stem cell proliferation and differentiation. Stem Cells and Development, p. scd.2016.0325. 2017.

CHIZH, B. A. Low dose ketamine: a therapeutic and research tool to explore N-methyl-D- aspartate (NMDA) receptor-mediated plasticity in pain pathways. Journal of psychopharmacology(Oxford,England), v. 21, n. 3, p. 259-71. 2007.

CHIZH, B. A. Novel approaches to targeting glutamatereceptors forthe treatment of chronic pain: Review article. Amino Acids, v. 23, n. 1-3, p. 169-176, 2002.

COLLINS, S. et al. Review Article NMDA Receptor Antagonists for the Treatment of Neuropathic Pain. Pain Medicine, p. 1726-1742. 2010.

COLLOCA, L. et al. Neuropathic pain. Nature Reviews Disease Primers, v. 3, p. 17002. 2017.

COSTA, F. A. L.; MOREIRA NETO, F. L. Células gliais satélite de gânglios sensitivos: O seu papel na dor.RevistaBrasileirade Anestesiologia, v. 65, n. 1, p. 73-81. 2015.

DAHL, B.; KEHLET, H. Preventive analgesia. Current Opinion in Anesthesiology, v. 24, n. 3, p. 331-338, 2011.

DEVOR, M. Unexplained peculiarities ofthe dorsal root ganglion. Pain, v. 82, p. S27-S35. 1999.

DWORKIN, R. H.; MCDERMOTT, M. P.; RAJA, S. N. Preventing Chronic Postsurgical Pain. Anesthesiology, v. 112, p. 516-518. 2010.

EIDE, P. K. Wind-up and the NMDA receptor complex from a clinical perspective.

European Journal of Pain, v. 4,n. 1, p. 5-15. 2000.

EISENBERG, E.; PUD, D. Can patients with chronic neuropathic pain be cured by acute administration of the NMDA receptorantagonistamantadine?Pain,v. 74, n. 2-3, p. 337-339.

1998.

FERRARI, L. F. et al.Anovel technique to perform direct intraganglionar injections in rats. Journal ofNeuroscienceMethods, v. 159, n. 2, p. 236-243. 2007.

FERRARI, L. F. et al. Inflammatory sensitization of nociceptors depends on activation of NMDA receptorsin DRG satellite cells. Proceedings of the National Academy of Sciences, v. 111, n. 51, p. 18363-18368. 2014.

GABAY, E.; TAL, M. Pain behavior and nerve electrophysiology in the CCI model of neuropathic pain. Pain, v. 110, n. 1-2, p. 354-360. 2004.

GRAPE, S.; TRAMÈR, R. Do we need preemptive analgesia for the treatment of postoperative pain?. Best Practice & Research ClinicalAnaesthesiology, v. 21, n. 1, p. 51­ 63, 2007.

GUILBAUD, G. et al. Time course of degeneration and regeneration of myelinated nerve fibres following chronic loose ligatures ofthe rat sciatic nerve: can nervelesionsbe linked to the abnormal pain-related behaviours? Pain,v. 53, n. 2, p. 147-158. 1993.

HAMA, A.; SAGEN, J. Selective antinociceptiveeffects of a combination of the N-methyl-D- aspartate receptor peptideantagonist [Ser(1)] histogranin and morphine inrat models of pain.

Pharmacology research & perspectives, v. 2, n. 2, p. e00032. 2014.

HANANI, M. Satellite glial cellsin sensory ganglia:From form to function. Brain Research

Reviews, v. 48, n. 3, p. 457-476. 2005.

HANANI, M. et al. Satellite glial cells in dorsal root ganglia are activated in streptozotocin- treated rodents. Journal of Cellular and Molecular Medicine, v. 18, n. 12, p. 2367-2371. 2014.

HIROTA, K.; LAMBERT, D. G. Ketamine: its mechanism(s) of action and unusual clinical uses. British Journalof Anaesthesia, v. 77, n. 4, p. 441 -444. 1996.

KAJANDER, K. C.; POLLOCK, C. H.; BERG, H. Evaluation of hindpaw position in rats during chronic constriction injury (CCI) produced with different suture materials.

Somatosensory& motor research, v. 13,n. 2, p. 95-101. 1996.

KARANIKOLAS, M. et al. Optimized Perioperative Analgesia Reduces Chronic Phantom Limb Pain Intensity, Prevalence, and Frequency A Prospective, Randomized, Clinical Trial. The Journal of the American Society of Anesthesiologists, v. 114, n. 5, p. 1144­

KEHLET, H.; JENSEN, T. S.; WOOLF, C. J. Persistent postsurgical pain: risk factors and prevention. The Lancet, v. 367, n. 9522, p. 1618-1625. 2006.

LI, L. et al. Chloride Homeostasis CriticallyRegulates Synaptic NMDA Receptor Activity in Neuropathic Pain. Cell Reports, v. 15, n. 7, p. 1376-1383. 2016.

LEFÈVRE, Y. et al. Neuropathic pain depends upon d-serine co-activationof spinal NMDA receptors in rats. Neuroscience Letters, v. 603, p. 42-47. 2015.

LIEBERMAN, AR. Sensory ganglia, in: D.N. Landon (Ed.), The Peripheral Nerve, Chapmanand Hall, London, p. 188-278. 1976.

LIU, C. N. et al. Tactile allodynia in the absence of C-fiber activation: Altered firing propertiesof DRG neurons following spinal nerve injury. Pain, v. 85, n. 3, p. 503-521. 2000. LIU, X., ZHOU JL., CHUNG, K., CHUNG, JM. Ion channels associated with the ectopicdischarges generated after segmental spinal nerveinjury in the rat. Brain Res. v. 900, p. 119-127. 2001.

LIU, F. Y. et al. Activation of satellite glial cellsin lumbardorsalroot ganglia contributesto neuropathic pain after spinal nerve ligation. Brain Research, v. 1427, p. 65-77, 2012.

LOESER, J.D., TREEDER.D. The Kyoto protocol of IASP Basic Pain Terminology. Pain, v.137, n.3, p. 473-477. 2008.

MARTINEZ, V. et al. Clinical, histological, and biochemical predictors of postsurgical neuropathic pain. Pain, v. 156, n. 11, p. 2390-2398, 2015.

MAVES,J. et al. Possible chemical contribution fromchromic gut sutures produces disorders of pain sensation like those seeninman. Pain, v. 54, n. 1, p. 57-69, 1993.

MERSKEY, H; BOGDUK, N. Classification of chronic pain. 2nd ed. Seattle: IASP Press. 1994.

MESTRE, C. et al. A method to perform direct transcutaneous intrathecal injection in rats. Journal ofpharmacological and toxicological methods, v. 32,n. 4, p. 197-200, 1994. MORRIS, R. G. M. NMDA receptors and memory encoding. Neuropharmacology, v. 74, p. 32-40. 2013.

NICKEL, F. et al. Mechanisms of neuropathicpain. European Neuropsychopharmacology, v. 22, n. 2, p. 81-91. 2012.

OHARA, PeterT. et al. Gliopathic pain: when satellite glial cells gobad. TheNeuroscientist, v. 15,n. 5,p. 450-463, 2009.

OLIVEIRA, L. M. As Dores. In: Lent, R. Neurociência da Mente e do Comportamento. 1a Edição.Rio de Janeiro: Guanabara Koogan. cap. 8. p. 183-201. 2008.

PARSONS, C. G. NMDA receptors as targets for drugaction in neuropathicpain. Eur J

Pharmacol, v. 429, n. 1-3, p. 71-8. 2001.

PETRENKO, A. B. et al. The Role ofN-Methyl-d-Aspartate (NMDA) Receptors in Pain: A Review. Anesthesia& Analgesia, p. 1108-1116. 2003.

PURVES, D. et al. Neurociências- Cap. 10. 4 Ed. p. 231-250. 2010.

SHEN, Y. et al. The effects ofan intraperitoneal single low dose ofketamine in attenuating the postoperative skin/muscle incision and retraction-induced pain related to the inhibition of N-methyl-d-aspartate receptors in the spinal cord. Neuroscience Letters, v. 616, p. 211-217. 2016.

SOTGIU, M. L.; BIELLA, G. Differential effects of MK-801, a N-methyl-d-aspartate non­ competitive antagonist, on the dorsal horn neuron hyperactivity and hyperexcitability in neuropathic rats. NeuroscienceLetters, v. 283, n. 2, p. 153-156. 2000.

SUZUKI, R.; MATTHEWS, E. A.; DICKENSON, A. H. Comparison ofthe effects of MK- 801, ketamine and memantine on responses of spinal dorsal horn neuronesin a rat model of mononeuropathy. Pain, v. 91, n. 1, p. 101-109. 2001.

VIVANCOS, G. et al. An electronic pressure-meternociception paw test for rats. Brazilian

Journal of Medical and Biological Research, v. 37, n. 3, p. 391-399,2004.

WOODHAM, P. et al. Satellite cells surrounding axotomised rat dorsal root ganglion cells increase expression ofa GFAP-likeprotein. NeuroscienceLetters, v. 98, n. 1, p. 8-12. 1989. WU, L.; ZHUO, M. Targeting the NMDA receptor subunit NR2B for the treatment of neuropathic pain. Neurotherapeutics: the journal of the American Society for Experimental Neuro Therapeutics, v. 6, n. 4, p.693-702, 2009.

ZHUO, M. Plasticity of NMDA receptor NR2B subunit in memory and chronic pain. Molecular Brain, v. 2,n. 1, p. 4. 2009.

ZHUO, M.; WU, G.; WU, L. Neuronal and microglial mechanisms of neuropathic pain.

Molecular Brain, v. 4,n. 1, p. 31, 2011.

ZIMMERMANN,M. Ethical guidelines for investigations of experimental pain in conscious animals. Pain,v.16, n.2, p.109-10.1983.

Universidade Federal de Uberlândia

- Comissão de Ética na Utilização de Animais - ComissãoUtilização dede Animais Etica na

CEUA

CERTIFICADO

Certificamos que o

projetointitulado “Avaliação do tratamentocom

antagonistas do receptor NMDA

no

desenvolvimento de dor

neuropática pós-operatória”,

protocolo n° 025/16, sob

a

responsabilidade de

Celina Monteiro

da Cruz

Lotufo

-

que

envolve a produção, manutenção e/ou utilização de animais

pertencentes ao filo Chordata, subfilo

Vertebrata, para fins de

pesquisa científica - encontra-se de

acordo com os preceitos da Lei

n° 11.794, de 8 de outubro de 2008, do Decreto n°

6.899, de 15 de

julho de

2009, e com as normas

editadas pelo ConselhoNacional

de Controle da

Experimentação Animal (CONCEA), e foi

APROVADO pela COMISSÃO

DEÉTICA NA UTILIZAÇÃO

DE

ANIMAIS (CEUA) da UNIVERSIDADE FEDERAL DE

UBERLÂNDIA, em

reunião de

20 demaio de 2016.

(We certify that the project entitled "Avaliação do tratamento com antagonistas do receptor NMDA no desenvolvimento de dor neuropática pós-operatória”, protocol 025/16, under the responsibility ofCelina Monteiro daCruz Lotufo - involving the production, maintenance and/or use of animals belonging to the phylum Chordata, subphylum Vertebrata, for purposes of scientific research - is in accordance with the provisions of Law n° 11.794, ofOctober 8th, 2008, of Decree n° 6.899 of July 15th, 2009, and the rules issued by the National Council for Control of Animal Experimentation (CONCEA) and it was approved for ETHICS COMMISSION ON ANIMAL USE (CEUA) from FEDERAL UNIVERSITY OF UBERLÂNDIA, in meeting of May 20th, 2016).

Uberlândia, 25de maio de2016. Vigência do Projeto Início: 01/07/2016 Término: 01/07/2017

Espécie / Linhagem / Grupos Taxonômicos RatosWistar

Número de animais 40 a 80

Peso / Idade 200 g /8 semanas

Sexo Fêmeas

Origem / Local Biotério CBEA/UFU

Número da Autorização SISBIO -

Atividade(s) -

Prof.Dr.César Augusto Garcia Coordenador da CEUA/UFU