Dados do Trabalho

Título

EFEITO ANTINOCICEPTIVO DA ADMNISTRAÇAO INTRAVENOSA DA FORMA RECOMBINANTE DO PEPTIDEO PHΑ1Β

Fundamentação/Introdução

Bloqueadores de canais para cálcio regulados por voltagem, quando injetados via intratecal (i.t.) tem ação analgésica em diversos modelos de dor animal. A Phα1β recombinante mostrou os mesmos efeitos analgésicos que a toxina nativa (derivada do veneno da aranha Phoneutria Nigriventer), quando injetada i.t.. Porém esta via de administração para drogas analgésicas limita o seu uso clinico em pacientes, sugerindo a busca por uma via parenteral menos invasiva

Objetivos

- Verificar o efeito antinociceptivo da administração do peptídeo recombinante da toxina Phα1β (Phα1βr) por via intravenosa (i.v.), em modelos de dor crônica (induzida por constrição crônica do nervo ciático CCI e paclitaxel PAC) e em um modelo de dor aguda induzida por PAC; Verificar os efeitos colaterais da administração do peptídeo Phα1βr i.v..

Delineamento e Métodos

No estudo experimental foram utilizados 72 ratos Wistar (12 grupos n=6) e 30 camundongos Balb-c (5 grupos n=6) machos. Afim de investigar o possível efeito antinociceptivo da administração do peptideo foram utilizados modelos de dor neuropática (induzida por CCI ou PAC) e dor aguda(induzida por PAC). Os ratos foram tratados com Phα1βr i.v. (0,006-0,6 mg/kg i.v.) ou PBS e avaliados através do teste de Von Frey.
Foram verificados também possíveis efeitos colaterais motores (através do teste de campo aberto), e bioquimicos (CKMB, TGO, TGP, LDH, lactato, creatinina e uréia) para as doses de 0,2-1,8 mg/kg, i.v. em camundongos.

O projeto foi aceito pelo comitê de ética (CEUA) da Universidade do Extremo Sul Catarinense.

Resultados

A Phα1βr (0,2mg/kg iv) reduziu amplamente a hipersensibilidade mecânica (nocicepção neuropática) induzida pela CCI. Os efeitos analgésicos duraram 4 horas, atingindo 67,7% ± 9,1% de inibição para a dose de 0,06 mg/kg (i.v.) e 100% de inibição (Imax = 100%) para a dose de 0,2 mg/kg (iv), com um ED50 de 0,02 (0,01-0,03) mg/kg.
A administração intravenosa de 0,2 mg/kg de Phα1βr inibiu a hiperalgesia mecânica na dor aguda e crônica até 4 horas após administração com 100% de inibição (Imax = 100%).
Não foram observadas mudanças significativas nas funções motoras e nos parâmetros bioquímicos para os efeitos colaterais avaliados. A Phα1βr não causou alterações no limiar mecânico dos grupos controle.

Conclusões/Considerações Finais

Os dados sugerem que a administração i.v da Phα1βr seja possível com antinocicepção induzida sem efeitos colaterais severos em roedores.

Referências

Staats, P.S.; Yearwood, T.; Charapata, S.G.; Presley, R.W.; Wallace, M.S.; Byas-Smith, M.; Fisher, R.; Bryce, D.A.; Mangieri, E.A.; Luther, R.R., et al. Intrathecal ziconotide in the treatment of refractory pain in patients with cancer or aids: A randomized controlled trial. Jama 2004, 291, 63-70.
ALLCHORNE, Andrew J; BROOM, Daniel C; WOOLF, Clifford J. Detection of Cold Pain, Cold Allodynia and Cold Hyperalgesia in Freely Behaving Rats. Molecular Pain, [s.l.], v. 1, p.1744-8069, 17 jan. 2005.
ANGELOTTI, Timothy; HOFMANN, Franz. Tissue-specific expression of splice variants of the mouse voltage-gated calcium channel α2/δ subunit. Febs Letters, [s.l.], v. 397, n. 2-3, p.331-337, 18 nov. 1996. Wiley.
ASHBURN MA, STAATS PS. Management of chronic pain. Lancet.29;353(9167):1865-1869, 1999.
BACKONJA, Misha-miroslav; IRVING, Gordon; ARGOFF, Charles. Rational Multidrug Therapy in the Treatment of Neuropathic Pain. Current Pain And Headache Reports, Madison, v. 10, p.34-38, 2006.
BASBAUM AI, BAUTISTA DM, SCHERRER G, JULIUS D. Cellular and molecular
BASBAUM AI, JESSELL T. The Perception of Pain. In: Kandel ER, Schwartz J,
AWANG, Y.-x. et al. Peripheral versus central potencies of N-type voltage-sensitive calcium channel blockers. Naunyn-schmiedeberg's Archives Of Pharmacology, [s.l.], v. 357, n. 2, p.159-168, 28 jan. 1998. Springer Nature
BENNETT, Michael I. et al. Prevalence and aetiology of neuropathic pain in cancer patients: A systematic review. Pain, [s.l.], v. 153, n. 2, p.359-365, fev. 2012. Ovid Technologies (Wolters Kluwer Health)
BONICA JJ. The Manegement of Pain, Ed 2, Malvern, Lea & Febiger, 1990, 2120p.
BRUST, Paul F. et al. Human neuronal voltage-dependent calcium channels: Studies on subunit structure and role in channel assembly. Neuropharmacology, [s.l.], v. 32, n. 11, p.1089-1102, nov. 1993. Elsevier BV.
Chen L, Huang H, Sharma HS, Zuo H, Sanberg PR. Cell transplantation as a pain therapy targets both analgesia and neural repair. Cell Transplant. 2013; 22 Suppl 1:S11-9.
COSTIGAN M, SCHOLZ J, WOOLF CJ. Neuropathic pain: a maladaptive response of the nervous system to damage. Annu Rev Neurosci. 2009;32:1-32.
34
DIOCHOT, S.; ALLOUI, A.; RODRIGUES, P.; DAUVOIS, M.; FRIEND, V.; AISSOUNI, Y.; ESCHALIER, A.; LINGUEGLIA, E.; BARON, A. Analgesic effects of mambalgin peptide inhibitors of acid-sensing ion channels in inflammatory and neuropathic pain. Pain 2016, 157, 552-559.
DIXON, W J. Efficient Analysis of Experimental Observations. Annual Review Of Pharmacology And Toxicology, [s.l.], v. 20, n. 1, p.441-462, abr. 1980.
DOLPHIN, Annette C.. The α2δ subunits of voltage-gated calcium channels. Biochimica Et Biophysica Acta (bba) - Biomembranes, [s.l.], v. 1828, n. 7, p.1541-1549, jul. 2013. Elsevier BV. http://dx.doi.org/10.1016/j.bbamem.2012.11.019
FINNERUP NB, et al. Algorithm for neuropathic pain treatment: An evidence based proposal. Pain. v. 137, n. 3, p.289 -305, 2005. BACKONJA, Misha-miroslav; IRVING, Gordon; ARGOFF, Charles. Rational Multidrug Therapy in the Treatment of Neuropathic Pain. Current Pain And Headache Reports, Madison, v. 10, p.34-38, 2006.
GOVER, Tony D.; KAO, Joseph P. Y.; WEINREICH, Daniel. Calcium Signaling in Single Peripheral Sensory Nerve Terminals. The Journal Of Neuroscience, [s.l.], v. 23, n. 12, p.4793-4797, 15 jun. 2003. Society for Neuroscience.
GRACE, Peter M.; ROLAN, Paul E.; HUTCHINSON, Mark R.. Peripheral immune contributions to the maintenance of central glial activation underlying neuropathic pain. Brain, Behavior, And Immunity, [s.l.], v. 25, n. 7, p.1322-1332, out. 2011. Elsevier BV.
HULLIN, Roger et al. Calcium channel beta subunit heterogeneity: functional expression of cloned cDNA from heart, aorta and brain. The Embo Journal, Munich, v. 11, n. 3, p.885-890, 1992.
JESSELL T, editors. Principles of Neuroscience. New York: Appleton and Lange.
JULIUS D, BASBAUM AI. Molecular mechanisms of nociception. Nature.13:413(6852):203-210. Review, 2001.
KLOTZ, U. Ziconotide--a novel neuron-specific calcium channel blocker for the intrathecal treatment of severe chronic pain--a short review. International journal of clinical pharmacology and therapeutics 2006, 44, 478-483.
KOLOSOV, A.; AURINI, L.; WILLIAMS, E.D.; COOKE, I.; GOODCHILD, C.S. Intravenous injection of leconotide, an omega conotoxin: Synergistic antihyperalgesic effects with morphine in a rat model of bone cancer pain. Pain medicine 2011, 12, 923-941.
KOLOSOV, A.; GOODCHILD, C.S.; COOKE, I. Cnsb004 (leconotide) causes antihyperalgesia without side effects when given intravenously: A comparison with ziconotide in a rat model of diabetic neuropathic pain. Pain medicine 2010, 11, 262-273.
35
KRAYCHETE, Durval Campos; GOZZANI, Judymara Lauzi; KRAYCHETE, Angiolina Campos. Dor neuropática: aspectos neuroquímicos. Revista Brasileira de Anestesiologia, [s.l.], v. 58, n. 5, p.492-505, out. 2008. Elsevier BV.
LOESER, John D.; TREEDE. The Kyoto protocol of IASP Basic Pain Terminology. Pain, [s.l.], v. 137, n. 3, p.473-477, jul. 2008. Ovid Technologies (Wolters Kluwer Health).
LONGO, Dan L. et al. Medicina interna de harrison. 18. ed. Porto Alegre: Amgh, 2013. 1972 p. Tradução de: Almir Lourenço da Fonseca.
LOPRINZI, C.L ET AL. Natural history of paclitaxel-associated acute pain syndrome: Prospective cohort study ncctg n08c1. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2011, 29, 1472-1478.
LOPRINZI, C.L ET AL. The paclitaxel acute pain syndrome: Sensitization of nociceptors as the putative mechanism. Cancer journal 2007, 13, 399-403.
LUCAS, Sylvia. Spiders in Brazil. Toxicon, [s.l.], v. 26, n. 9, p.759-772, jan. 1988. Elsevier BV.
LYNCH, Shalini S; CHENG, Christine M; YEE, Jennie L. Formulary Forum: Intrathecal Ziconotide for Refractory Chronic Pain. Annals Of Pharmacotherapy, [s.l.], v. 40, n. 7-8, p.1293-1300, jul. 2006. SAGE Publications.
MALMBERG, Ab; YAKSH, Tl. Voltage-sensitive calcium channels in spinal nociceptive processing: blockade of N- and P-type channels inhibits formalin-induced nociception. The Journal Of Neuroscience, [s.l.], v. 14, n. 8, p.4882-4890, 1 ago. 1994. Society for Neuroscience.
mechanisms of pain. Cell.16;139(2):267-84. Review, 2009.
NORTON, R.S.P., P. K.; BAELL, J.B.; WRIGHT, C.E.; LEW, M.J.; ANGUS, J.A. Polypeptide omega-conotoxin gvia as a basis for new analgesic and neuroprotective agents. Drug Development Research 1999, 46, 206-218.
PERRET, Danielle; LUO, Z. David. Targeting voltage-gated calcium channels for neuropathic pain management. Neurotherapeutics, [s.l.], v. 6, n. 4, p.679-692, out. 2009. Springer Nature. REVIEW
POLOMANO, R.C ET AL. A painful peripheral neuropathy in the rat produced by the chemotherapeutic drug, paclitaxel. Pain 2001, 94, 293-304.
POLOMANO, R.C.; BENNETT, G.J. Chemotherapy-evoked painful peripheral neuropathy. Pain medicine 2001, 2, 8-14.
PORRECA, F. Chronic pain and medullary descending facilitation. Trends In Neurosciences, [s.l.], v. 25, n. 6, p.319-325, 1 jun. 2002. Elsevier BV.
36
RAUCK, R.L.; WALLACE, M.S.; BURTON, A.W.; KAPURAL, L.; NORTH, J.M. Intrathecal ziconotide for neuropathic pain: A review. Pain practice : the official journal of World Institute of Pain 2009, 9, 327-337.
REEVES, B.N ET AL. Further data supporting that paclitaxel-associated acue pain syndrome is associated with development of peripheral neuropathy: North central cancer treatment group trial n08c1. Cancer 2012, 118, 5171-5178.
RIGO, F.K.; DALMOLIN, G.D.; TREVISAN, G.; TONELLO, R.; SILVA, M.A.; ROSSATO, M.F.; KLAFKE, J.Z.; Cordeiro Mdo, N.; Castro Junior, C.J.; Montijo, D., et al.Effect of omega-conotoxin mviia and phalpha1beta on paclitaxel-induced acute and chronic pain. Pharmacology, biochemistry, and behavior 2013, 114-115, 16-22.
RIGO, F.K.; TREVISAN, G.; DE PRA, S.D.; CORDEIRO, M.N.; BORGES, M.H.; SILVA, J.F.; SANTA CECILIA, F.V.; DE SOUZA, A.H.; DE OLIVEIRA ADAMANTE, G.; MILIOLI, A.M., ET AL. The spider toxin phalpha1beta recombinant possesses strong analgesic activity. Toxicon : official journal of the International Society on Toxinology 2017, 133, 145-152.
RIGO, F.K.; TREVISAN, G.; ROSA, F.; DALMOLIN, G.D.; OTUKI, M.F.; CUETO, A.P.; DE CASTRO JUNIOR, C.J.; ROMANO-SILVA, M.A.; CORDEIRO MDO, N.; RICHARDSON, M., ET AL. Spider peptide phalpha1beta induces analgesic effect in a model of cancer pain. Cancer science 2013, 104, 1226-1230. B
SALT, T.e.. The possible involvement of excitatory amino acids and NMDA receptors in thalamic pain mechanisms and central pain syndromes. Aps Journal, [s.l.], v. 1, n. 1, p.52-54, mar. 1992.
SCHMIDTKO, A.; LOTSCH, J.; FREYNHAGEN, R.; GEISSLINGER, G. Ziconotide for treatment of severe chronic pain. Lancet 2010, 375, 1569-1577.
SCHOLZ, Joachim; WOOLF, Clifford J.. Can we conquer pain? Nature Neuroscience, [s.l.], v. 5, n.p.1062-1067, nov. 2002. Springer Nature.
Scott, D.A.; Wright, C.E.; Angus, J.A. Actions of intrathecal omega-conotoxins cvid, gvia, mviia, and morphine in acute and neuropathic pain in the rat. European journal of pharmacology 2002, 451, 279-286.
SMITH, Maree T. et al. The novel N-type calcium channel blocker, AM336, produces potent dose-dependent antinociception after intrathecal dosing in rats and inhibits substance P release in rat spinal cord slices. Pain, [s.l.], v. 96, n. 1, p.119-127, mar. 2002. Ovid Technologies (Wolters Kluwer Health)
SOUZA JÚNIOR, Tarcísio Liberato de. Prospecção das toxinas do veneno da aranha Phoneutria nigriventer. 2013. 110 f. Dissertação (Mestrado) - Curso de Programa de Pós-graduação em Toxicologia, Instituto Butantan, São Paulo, 2013
37
SOUZA, A.H.; FERREIRA, J.; CORDEIRO MDO, N.; VIEIRA, L.B.; DE CASTRO, C.J.; TREVISAN, G.; REIS, H.; SOUZA, I.A.; RICHARDSON, M.; PRADO, M.A., et al. Analgesic effect in rodents of native and recombinant ph alpha 1beta toxin, a high-voltage-activated calcium channel blocker isolated from armed spider venom. Pain 2008, 140, 115-126.
TEIXEIRA, Manoel Jacobsen; FIQUEIRÓ, João Augusto Bertuol. DOR: epidemiologia, fisiopatologia, avaliação, sindromes dolorosas e tratamento. São Paulo: Grupo Editorial Moreira Jr, 2001. 406 p.
TONELLO, R.; FUSI, C.; MATERAZZI, S.; MARONE, I.M.; DE LOGU, F.; BENEMEI, S.; GONCALVES, M.C.; COPPI, E.; CASTRO-JUNIOR, C.J.; GOMEZ, M.V., ET AL. The peptide phalpha1beta, from spider venom, acts as a trpa1 channel antagonist with antinociceptive effects in mice. British journal of pharmacology 2017, 174, 57-69
TONELLO, Raquel et al. Action of Phα1β, a Peptide From the Venom of the Spider Phoneutria nigriventer, on the Analgesic and Adverse Effects Caused by Morphine in Mice. The Journal Of Pain, [s.l.], v. 15, n. 6, p.619-631, jun. 2014. Elsevier BV. A
TREEDE, R. -d. et al. Neuropathic pain: Redefinition and a grading system for clinical and research purposes. Neurology, [s.l.], v. 70, n. 18, p.1630-1635, 14 nov. 2007. Ovid Technologies (Wolters Kluwer Health).
VIEIRA, L.B.; KUSHMERICK, C.; HILDEBRAND, M.E.; GARCIA, E.; STEA, A.; CORDEIRO, M.N.; RICHARDSON, M.; GOMEZ, M.V.; SNUTCH, T.P. Inhibition of high voltage-activated calcium channels by spider toxin pntx3-6. The Journal of pharmacology and experimental therapeutics, 2005, 314, 1370-1377.
WANG, Yong-xiang et al. Effects of intrathecal administration of ziconotide, a selective neuronal N-type calcium channel blocker, on mechanical allodynia and heat hyperalgesia in a rat model of postoperative pain. Pain, [s.l.], v. 84, n. 2, p.151-158, fev. 2000. Ovid Technologies (Wolters Kluwer Health)
WANG, Yong-xiang et al. Interactions of intrathecally administered ziconotide, a selective blocker of neuronal N-type voltage-sensitive calcium channels, with morphine on nociception in rats. Pain, [s.l.], v. 84, n. 2, p.271-281, fev. 2000. Ovid Technologies (Wolters Kluwer Health).
WEBSTER, K e. Somaesthetic pathways. British Medical Bulletin, [s.l.], v. 33, n. 2, p.113-120, maio 1977. Oxford University Press (OUP).
WOOLF, C.J.; MA, Q. Nociceptors--noxious stimulus detectors.Neuron, 2007, 55(3), 353-364.
WOOLF, Clifford J.; MA, Qiufu. Nociceptors—Noxious Stimulus Detectors. Neuron, [s.l.], v. 55, n. 3, p.353-364, ago. 2007. Elsevier BV.
38
XIAO, W.; BOROUJERDI, A.; BENNETT, G.J.; LUO, Z.D. Chemotherapy-evoked painful peripheral neuropathy: Analgesic effects of gabapentin and effects on expression of the alpha-2-delta type-1 calcium channel subunit. Neuroscience 2007, 144, 714-720.
YAKSH, T.L. Calcium channels as therapeutic targets in neuropathic pain. The journal of pain : official journal of the American Pain Society 2006, 7, S13-30.
ZAMPONI GW, LEWIS RJ, TODOROVIC SM, ARNERIC SP, SNUTCH TP. Role of
ZHANG, Ruixin et al. Mechanisms of Acupuncture–Electroacupuncture on Persistent Pain. Anesthesiology, [s.l.], v. 120, n. 2, p.482-503, fev. 2014. Ovid Technologies (Wolters Kluwer Health).
ZHANG, Yu-qiu et al. Excitatory amino acid receptor antagonists and electroacupuncture synergetically inhibit carrageenan-induced behavioral hyperalgesia and spinal fos expression in rats. Pain, [s.l.], v. 99, n. 3, p.525-535, out. 2002.

Palavras-chave

Phα1β, admnistração intravenosa, antinocicepção, dor neuropática, lesão por constrição crônica, paclitaxel.