title: Spider peptide Phα1β induces analgesic effect in a model of cancer pain.
abstract: The marine snail peptide ziconotide (ω-conotoxin MVIIA) is used as an analgesic in cancer patients refractory to opioids, but may induce severe adverse effects. Animal venoms represent a rich source of novel drugs, so we investigated the analgesic effects and the side-effects of spider peptide Phα1β in a model of cancer pain in mice with or without tolerance to morphine analgesia. Cancer pain was induced by the inoculation of melanoma B16-F10 cells into the hind paw of C57BL/6 mice. After 14 days, painful hypersensitivity was detected and Phα1β or ω-conotoxin MVIIA (10-100 pmol/site) was intrathecally injected to evaluate the development of antinociception and side-effects in control and morphine-tolerant mice. The treatment with Phα1β or ω-conotoxin MVIIA fully reversed cancer-related painful hypersensitivity, with long-lasting results, at effective doses 50% of 48 (32-72) or 33 (21-53) pmol/site, respectively. Phα1β produced only mild adverse effects, whereas ω-conotoxin MVIIA induced dose-related side-effects in mice at analgesic doses (estimated toxic dose 50% of 30 pmol/site). In addition, we observed that Phα1β was capable of controlling cancer-related pain even in mice tolerant to morphine antinociception (100% of inhibition) and was able to partially restore morphine analgesia in such animals (56 ± 5% of inhibition). In this study, Phα1β was as efficacious as ω-conotoxin MVIIA in inducing analgesia in a model of cancer pain without producing severe adverse effects or losing efficacy in opioid-tolerant mice, indicating that Phα1β has a good profile for the treatment of cancer pain in patients.
authors.affiliation: Graduate Program in Biochemistry and Molecular Pharmacology, Faculty of Medicine, Federal University of Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Flavia Karine
authors.initials: FK
authors.lastname: Rigo
authors.forename: Gabriela
authors.initials: G
authors.lastname: Trevisan
authors.forename: Fernanda
authors.initials: F
authors.lastname: Rosa
authors.forename: Gerusa D
authors.initials: GD
authors.lastname: Dalmolin
authors.forename: Michel Fleith
authors.initials: MF
authors.lastname: Otuki
authors.forename: Ana Paula
authors.initials: AP
authors.lastname: Cueto
authors.forename: Célio José
authors.initials: CJ
authors.lastname: de Castro Junior
authors.forename: Marco Aurelio
authors.initials: MA
authors.lastname: Romano-Silva
authors.forename: Marta do N
authors.initials: Mdo N
authors.lastname: Cordeiro
authors.forename: Michael
authors.initials: M
authors.lastname: Richardson
authors.forename: Juliano
authors.initials: J
authors.lastname: Ferreira
authors.forename: Marcus V
authors.initials: MV
authors.lastname: Gomez
mesh_terms: D000700:Analgesics / Q000009:adverse effects / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D004361:Drug Tolerance; D008297:Male; D008546:Melanoma, Experimental / Q000150:complications / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000009:adverse effects / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy*; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D010455:Peptides / Q000009:adverse effects / Q000494:pharmacology*; D013111:Spider Venoms / Q000494:pharmacology*; D013112:Spiders / Q000378:metabolism*; D020960:omega-Conotoxins / Q000009:adverse effects / Q000494:pharmacology
chemical_list: D000700:Analgesics; D010455:Peptides; C583821:Phalpha1beta toxin, Phoneutria nigriventer; D013111:Spider Venoms; D020960:omega-Conotoxins; D009020:Morphine; C078452:ziconotide