title: Antinociceptive effect of a novel armed spider peptide Tx3-5 in pathological pain models in mice.
abstract: The venom of the Brazilian armed spider Phoneutria nigriventer is a rich source of biologically active peptides that have potential as analgesic drugs. In this study, we investigated the analgesic and adverse effects of peptide 3-5 (Tx3-5), purified from P. nigriventer venom, in several mouse models of pain. Tx3-5 was administered by intrathecal injection to mice selected as models of postoperative (plantar incision), neuropathic (partial sciatic nerve ligation) and cancer-related pain (inoculation with melanoma cells) in animals that were either sensitive or tolerant to morphine. Intrathecal administration of Tx3-5 (3-300 fmol/site) in mice could either prevent or reverse postoperative nociception, with a 50 % inhibitory dose (ID50) of 16.6 (3.2-87.2) fmol/site and a maximum inhibition of 87 ± 10 % at a dose of 30 fmol/site. Its effect was prevented by the selective activator of L-type calcium channel Bay-K8644 (10 μg/site). Tx3-5 (30 fmol/site) also produced a partial antinociceptive effect in a neuropathic pain model (inhibition of 67 ± 10 %). Additionally, treatment with Tx3-5 (30 fmol/site) nearly abolished cancer-related nociception with similar efficacy in both morphine-sensitive and morphine-tolerant mice (96 ± 7 and 100 % inhibition, respectively). Notably, Tx3-5 did not produce visible adverse effects at doses that produced antinociception and presented a TD50 of 1125 (893-1418) fmol/site. Finally, Tx3-5 did not alter the normal mechanical or thermal sensitivity of the animals or cause immunogenicity. Our results suggest that Tx3-5 is a strong drug candidate for the treatment of painful conditions.
authors.affiliation: Programa de Pós-graduação em Ciências Biológicas: Bioquímica Toxicológica, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil. saramarchesan@hotmail.com.|Departamento de Bioquímica e Biologia Molecular, Universidade Federal de Santa Maria, Avenida Roraima 1000, Cidade Universitária, Santa Maria, RS, 97105-900, Brazil. saramarchesan@hotmail.com.
authors.forename: Sara M
authors.initials: SM
authors.lastname: Oliveira
authors.affiliation: Programa de Pós-graduação em Ciências Biológicas: Bioquímica Toxicológica, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil.
authors.forename: Cássia R
authors.initials: CR
authors.lastname: Silva
authors.affiliation: Programa de Pós-graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Trevisan
authors.affiliation: Programa de Pós-graduação em Ciências Biológicas: Bioquímica Toxicológica, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil.
authors.forename: Jardel G
authors.initials: JG
authors.lastname: Villarinho
authors.affiliation: Fundação Ezequiel Dias, Belo Horizonte, MG, Brazil.
authors.forename: Marta N
authors.initials: MN
authors.lastname: Cordeiro
authors.affiliation: Fundação Ezequiel Dias, Belo Horizonte, MG, Brazil.
authors.forename: Michael
authors.initials: M
authors.lastname: Richardson
authors.affiliation: Fundação Ezequiel Dias, Belo Horizonte, MG, Brazil.
authors.forename: Márcia H
authors.initials: MH
authors.lastname: Borges
authors.affiliation: Programa de Pós-graduação em Farmacologia Bioquímica e Molecular, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.|Nucleo de Pós-graduação, Instituto de Ensino e Pesquisa da Santa Casa de Belo Horizonte, Belo Horizonte, MG, Brazil.
authors.forename: Célio J
authors.initials: CJ
authors.lastname: Castro
authors.affiliation: Programa de Pós-graduação em Farmacologia Bioquímica e Molecular, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.|Nucleo de Pós-graduação, Instituto de Ensino e Pesquisa da Santa Casa de Belo Horizonte, Belo Horizonte, MG, Brazil.
authors.forename: Marcus V
authors.initials: MV
authors.lastname: Gomez
authors.affiliation: Programa de Pós-graduação em Ciências Biológicas: Bioquímica Toxicológica, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil. ferreiraj99@gmail.com.|Programa de Pós-graduação em Farmacologia, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil. ferreiraj99@gmail.com.|Departamento de Farmacologia, Universidade Federal de Santa Catarina, Campus Universitário Reitor João David Ferreira Lima, Bairro Trindade, Florianópolis, SC, 88040-900, Brazil. ferreiraj99@gmail.com.
authors.forename: Juliano
authors.initials: J
authors.lastname: Ferreira
mesh_terms: D000700:Analgesics / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D002120:Calcium Channel Agonists / Q000494:pharmacology; D000072716:Cancer Pain / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009437:Neuralgia / Q000188:drug therapy*; D009479:Neuropeptides / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D009498:Neurotoxins / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D059225:Nociception / Q000187:drug effects; D013111:Spider Venoms / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000700:Analgesics; D002120:Calcium Channel Agonists; D009479:Neuropeptides; D009498:Neurotoxins; D013111:Spider Venoms; C098736:Tx3 neurotoxin
keywords: Cancer-related pain; Hyperalgesia; L-type VSCC blocker; Morphine tolerance; Neuropathic pain; Phoneutria nigriventer; Postoperative pain