title: Antinociceptive effect of Brazilian armed spider venom toxin Tx3-3 in animal models of neuropathic pain.
abstract: Venoms peptides have produced exceptional sources for drug development to treat pain. In this study we examined the antinociceptive and side effects of Tx3-3, a peptide toxin isolated from Phoneutria nigriventer venom, which inhibits high-voltage-dependent calcium channels (VDCC), preferentially P/Q and R-type VDCC. We tested the effects of Tx3-3 in animal models of nociceptive (tail-flick test), neuropathic (partial sciatic nerve ligation and streptozotocin-induced diabetic neuropathy), and inflammatory (intraplantar complete Freund's adjuvant) pain. In the tail-flick test, both intrathecal (i.t.) and intracerebroventricular (i.c.v.) injection of Tx3-3 in mice caused a short-lasting effect (ED(50) and 95% confidence intervals of 8.8 [4.1-18.8] and 3.7 [1.6-8.4] pmol/site for i.t. and i.c.v. injection, respectively), without impairing motor functions, at least at doses 10-30 times higher than the effective dose. By comparison, ω-conotoxin MVIIC, a P/Q and N-type VDCC blocker derived from Conus magus venom, caused significant motor impairment at doses close to efficacious dose in tail flick test. Tx3-3 showed a long-lasting antinociceptive effect in neuropathic pain models. Intrathecal injection of Tx3-3 (30 pmol/site) decreased both mechanical allodynia produced by sciatic nerve injury in mice and streptozotocin-induced allodynia in mice and rats. On the other hand, i.t. injection of Tx3-3 did not alter inflammatory pain. Taken together, our data show that Tx3-3 shows prevalent antinociceptive effects in the neuropathic pain models and does not cause adverse motor effects at antinociceptive efficacious doses, suggesting that this peptide toxin holds promise as a novel therapeutic agent for the control of neuropathic pain. The Brazilian armed spider Tx3-3, a new P/Q and R-type calcium channel blocker, effectively alleviates allodynia in animal neuropathic pain models.
authors.affiliation: Programa de Pós-graduação em Farmacologia Bioquímica e Molecular, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil Programa de Pós-graduação em Ciências Biológicas: Bioquímica Toxicológica, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil Fundação Ezequiel Dias, Belo Horizonte, MG, Brazil Laboratório de Neurociência, Departamento de Saúde Mental, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil Robarts Research Institute, University of Western Ontario, London, Ontario, Canada Núcleo de Pós-graduação, Santa Casa de Belo Horizonte, Brazil.
authors.forename: Gerusa Duarte
authors.initials: GD
authors.lastname: Dalmolin
authors.forename: Cássia Regina
authors.initials: CR
authors.lastname: Silva
authors.forename: Flávia Karine
authors.initials: FK
authors.lastname: Rigo
authors.forename: Guilherme Monteiro
authors.initials: GM
authors.lastname: Gomes
authors.forename: Marta
authors.initials: M
authors.lastname: do Nascimento Cordeiro
authors.forename: Michael
authors.initials: M
authors.lastname: Richardson
authors.forename: Marco Aurélio Romano
authors.initials: MAR
authors.lastname: Silva
authors.forename: Marco Antonio Máximo
authors.initials: MAM
authors.lastname: Prado
authors.forename: Marcus Vinicius
authors.initials: MV
authors.lastname: Gomez
authors.forename: Juliano
authors.initials: J
authors.lastname: Ferreira
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D051379:Mice; D009437:Neuralgia / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D009479:Neuropeptides / Q000494:pharmacology*; D009498:Neurotoxins / Q000494:pharmacology*; D009619:Nociceptors / Q000187:drug effects / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D013111:Spider Venoms / Q000494:pharmacology*
chemical_list: D000700:Analgesics; D009479:Neuropeptides; D009498:Neurotoxins; D013111:Spider Venoms; C098736:Tx3 neurotoxin