title: Characterization of the antinociceptive effect of PhTx3-4, a toxin from Phoneutria nigriventer, in models of thermal, chemical and incisional pain in mice.
abstract: Venom-derived peptides constitute a unique source of drug prototypes for the pain management. Many of them can modulate voltage-gated calcium channels that are central in the processing of pain sensation. PhTx3-4 is a peptide isolated from Phoneutria nigriventer venom, which blocks high voltage-activated calcium channels with low specificity, thereby leading to neuroprotection in models of ischemia in vitro. The aim of the present work was evaluating the potential of intrathecal PhTx3-4 in the reversal of different nociceptive states in mice, furthermore assessing the potential of PhTx3-4 in triggering motor side effects. We found that bellow 100 pmol/site, PhTx3-4 did not cause major motor side effects. By comparison, ω-conotoxin MVIIA and ω-conotoxin MVIIC triggered motor side effects at the doses of 10 and 100 pmol/site, respectively. Also, PhTx3-4 (30 pmol/site) caused no significant alterations in the forced locomotor activity test (rotarod) and in the exploratory activity test (versamax). In a model of inflammatory persistent pain (formalin test), PhTx3-4 reversed nociceptive behavior both pre or post-administered, although this effect was observed only at the inflammatory phase of the test and not at the neurogenic phase. Comparatively, ω-conotoxin MVIIC was effective only when post-administered in the formalin test. Nonetheless, PhTx3-4 treatment was devoid of action in acute nociceptive thermal model (hotplate test), whereas morphine showed efficacy in this test. Efficacy of PhTx3-4 in the formalin test was associated with inhibition of formalin-induced glutamate release in the cerebrospinal fluid. PhTx3-4, but not ω-conotoxin MVIIC, reversed NMDA-induced nociceptive behavior indicating a putative role of PhTx3-4 at ionotropic glutamate receptors. Finally, we observed efficacy of PhTx3-4 in ameliorating mechanical hypersensitivity induced by paw incision, a post-operative and more clinically relevant pain model. Taken together, our data show that PhTx3-4 possesses antinociceptive effect in different models of pain in mice, suggesting that this toxin may serve as drug prototype for pain control.
authors.affiliation: Department of Neurotransmitters, Institute of Education and Research, Santa Casa, Belo Horizonte, Minas Gerais, 30150-240, Brazil.
authors.forename: Juliana Figueira
authors.initials: JF
authors.lastname: da Silva
authors.affiliation: Department of Neurotransmitters, Institute of Education and Research, Santa Casa, Belo Horizonte, Minas Gerais, 30150-240, Brazil. Electronic address: celiojcjunior@gmail.com.
authors.forename: Célio José
authors.initials: CJ
authors.lastname: Castro-Junior
authors.affiliation: Department of Biochemistry and Molecular Biology, Federal University of Santa Maria, Santa Maria, Rio Grande do Sul, 97105-900, Brazil.
authors.forename: Sara Marchesan
authors.initials: SM
authors.lastname: Oliveira
authors.affiliation: Department of Pharmacology, Biological Sciences Center, Federal University of Santa Catarina, Florianópolis, Santa Catarina, 80040-900, Brazil.
authors.forename: Gerusa Duarte
authors.initials: GD
authors.lastname: Dalmolin
authors.affiliation: Faculty of Medicine, University of São Paulo, Ribeirão Preto, São Paulo, 14049-900, Brazil.
authors.forename: Cássia Regina
authors.initials: CR
authors.lastname: Silva
authors.affiliation: Department of Pharmacology, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, 30170-901, Brazil.
authors.forename: Luciene Bruno
authors.initials: LB
authors.lastname: Vieira
authors.affiliation: Department of Neurotransmitters, Institute of Education and Research, Santa Casa, Belo Horizonte, Minas Gerais, 30150-240, Brazil.
authors.forename: Danuza Montijo
authors.initials: DM
authors.lastname: Diniz
authors.affiliation: Department of Biochemistry, Ezequiel Dias Foundation, Belo Horizonte, Minas Gerais, 30510-010, Brazil.
authors.forename: Marta do Nascimento
authors.initials: Mdo N
authors.lastname: Cordeiro
authors.affiliation: Department of Pharmacology, Biological Sciences Center, Federal University of Santa Catarina, Florianópolis, Santa Catarina, 80040-900, Brazil.
authors.forename: Juliano
authors.initials: J
authors.lastname: Ferreira
authors.affiliation: Lutheran University of Brazil, Porto Alegre, Rio Grande do Sul, 92425-900, Brazil.
authors.forename: Alessandra Hubner
authors.initials: AH
authors.lastname: Souza
authors.affiliation: Department of Neurotransmitters, Institute of Education and Research, Santa Casa, Belo Horizonte, Minas Gerais, 30150-240, Brazil.
authors.forename: Marcus Vinícius
authors.initials: MV
authors.lastname: Gomez
mesh_terms: D000700:Analgesics / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D008297:Male; D051379:Mice; D009479:Neuropeptides / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D009498:Neurotoxins / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D010146:Pain / Q000188:drug therapy* / Q000517:prevention & control; D013111:Spider Venoms / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D013112:Spiders / Q000737:chemistry
chemical_list: D000700:Analgesics; D009479:Neuropeptides; D009498:Neurotoxins; D013111:Spider Venoms; C098736:Tx3 neurotoxin
keywords: Anti-Nociceptive; Intrathecal; Mice; NMDA receptors; PhTx3-4; Side-effects