title: Phα1β toxin prevents capsaicin-induced nociceptive behavior and mechanical hypersensitivity without acting on TRPV1 channels.
abstract: Phα1β toxin is a peptide purified from the venom of the armed spider Phoneutria nigriventer, with markedly antinociceptive action in models of acute and persistent pain in rats. Similarly to ziconotide, its analgesic action is related to inhibition of high voltage activated calcium channels with more selectivity for N-type. In this study we evaluated the effect of Phα1β when injected peripherally or intrathecally in a rat model of spontaneous pain induced by capsaicin. We also investigated the effect of Phα1β on Ca²⁺ transients in cultured dorsal root ganglia (DRG) neurons and HEK293 cells expressing the TRPV1 receptor. Intraplantar or intrathecal administered Phα1β reduced both nocifensive behavior and mechanical hypersensitivity induced by capsaicin similarly to that observed with SB366791, a specific TRPV1 antagonist. Peripheral nifedipine and mibefradil did also decrease nociceptive behavior induced by intraplantar capsaicin. In contrast, ω-conotoxin MVIIA (a selective N-type Ca²⁺ channel blocker) was effective only when administered intrathecally. Phα1β, MVIIA and SB366791 inhibited, with similar potency, the capsaicin-induced Ca²⁺ transients in DRG neurons. The simultaneous administration of Phα1β and SB366791 inhibited the capsaicin-induced Ca²⁺ transients that were additive suggesting that they act through different targets. Moreover, Phα1β did not inhibit capsaicin-activated currents in patch-clamp recordings of HEK293 cells that expressed TRPV1 receptors. Our results show that Phα1β may be effective as a therapeutic strategy for pain and this effect is not related to the inhibition of TRPV1 receptors.
authors.affiliation: Instituto de Ensino e Pesquisa da Santa Casa Belo Horizonte, Rua Domingos Vieira 590, Belo Horizonte, MG, Brazil. celiojcjunior@gmail.com
authors.forename: Celio J
authors.initials: CJ
authors.lastname: Castro-Junior
authors.forename: Julie
authors.initials: J
authors.lastname: Milano
authors.forename: Alessandra H
authors.initials: AH
authors.lastname: Souza
authors.forename: Juliana F
authors.initials: JF
authors.lastname: Silva
authors.forename: Flávia K
authors.initials: FK
authors.lastname: Rigo
authors.forename: Geruza
authors.initials: G
authors.lastname: Dalmolin
authors.forename: Marta N
authors.initials: MN
authors.lastname: Cordeiro
authors.forename: Michael
authors.initials: M
authors.lastname: Richardson
authors.forename: Alexandre G A
authors.initials: AG
authors.lastname: Barros
authors.forename: Renato S
authors.initials: RS
authors.lastname: Gomez
authors.forename: Marco A R
authors.initials: MA
authors.lastname: Silva
authors.forename: Christopher
authors.initials: C
authors.lastname: Kushmerick
authors.forename: Juliano
authors.initials: J
authors.lastname: Ferreira
authors.forename: Marcus V
authors.initials: MV
authors.lastname: Gomez
mesh_terms: D018712:Analgesics, Non-Narcotic / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D020013:Calcium Signaling / Q000187:drug effects; D002211:Capsaicin; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D019476:Insect Proteins / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D049990:Membrane Transport Modulators / Q000494:pharmacology / Q000627:therapeutic use*; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009437:Neuralgia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D013111:Spider Venoms / Q000494:pharmacology / Q000627:therapeutic use*; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D018712:Analgesics, Non-Narcotic; D019476:Insect Proteins; D049990:Membrane Transport Modulators; D009419:Nerve Tissue Proteins; D010455:Peptides; C583821:Phalpha1beta toxin, Phoneutria nigriventer; D011994:Recombinant Proteins; D013111:Spider Venoms; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D002211:Capsaicin