Walker 256 tumor growth suppression by crotoxin involves formyl peptide receptors and lipoxin a(4)

We investigated the effects of Crotoxin (CTX), the main toxin of South American rattlesnake (Crotalus durissus terrificus) venom, on Walker 256 tumor growth, the pain symptoms associated (hyperalgesia and allodynia), and participation of endogenous lipoxin A(4). Treatment with CTX (s.c.), daily, for 5 days reduced tumor growth at the 5th day after injection of Walker 256 carcinoma cells into the plantar surface of adult rat hind paw. This observation was associated with inhibition of new blood vessel formation and decrease in blood vessel diameter. The treatment with CTX raised plasma concentrations of lipoxin A 4 and its natural analogue 15-epi-LXA(4) 4, an effect mediated by formyl peptide receptors (FPRs). In fact, the treatment with Boc-2, an inhibitor of FPRs, abolished the increase in plasma levels of these mediators triggered by CTX. The blockage of these receptors also abolished the inhibitory action of CTX on tumor growth and blood vessel formation and the decrease in blood vessel diameter. Together, the results herein presented demonstrate that CTX increases plasma concentrations of lipoxin A 4 and 15-epi-LXA 4, which might inhibit both tumor growth and formation of new vessels via FPRs.Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (fellowship-CAPES)PAP (fellowship-Secretaria da Saude do Estado de Sao Paulo)FAPESP [07/52447-8]Guggenheim FoundationSpecial Laboratory of Pain and Signaling, Butantan Institute, Avenida Vital Brazil 1500, 05503-900 São Paulo, SP, BrazilCEIS/Department of Biology, Institute of Biosciences of Rio Claro, São Paulo State University (UNESP), Rio Claro, SP, BrazilLaboratory of Pathophysiology, Butantan Institute, Avenida Vital Brazil 1500, 05503-900 São Paulo, SP, BrazilDepartment of Natural Sciences, Mathematics and Education, Agricultural Sciences Center, Federal University of São Carlos, Rodovia Anhanguera Km 174, 13600-970 Araras, SP, BrazilLaboratory of Inflammation and Vascular Pharmacology, Federal University of São Paulo, Rua São Nicolau 210, 09913-030 Diadema, SP, BrazilDepartment of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, Avenida Professor Lineu Prestes 1524, 05508-900 São Paulo, SP, BrazilDepartment of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, Avenida Professor Lineu Prestes 1524, 05508-900 São Paulo, SP, BrazilLaboratory of Inflammation and Vascular Pharmacology, Federal University of São Paulo, Rua São Nicolau 210, 09913-030 Diadema, SP, BrazilFAPESP: 07/52447-8Web of Scienc

Peripheral kappa and delta opioid receptors are involved in the antinociceptive effect of crotalphine in a rat model of cancer pain

Cancer pain is an important clinical problem and may not respond satisfactorily to the current analgesic therapy. We have characterized a novel and potent analgesic peptide, crotalphine, from the venom of the South American rattlesnake Crotalus durissus terrificus. In the present work, the antinociceptive effect of crotalphine was evaluated in a rat model of cancer pain induced by intraplantar injection of Walker 256 carcinoma cells. Intraplantar injection of tumor cells caused the development of hyperalgesia and allodynia, detected on day 5 after tumor cell inoculation. Crotalphine (6 μg/kg), administered p.o., blocked both phenomena. The antinociceptive effect was detected 1 h after treatment and lasted for up to 48 h. Intraplantar injection of nor-binaltorphimine (50 g/paw), a selective antagonist of κ-opioid receptors, antagonized the antinociceptive effect of the peptide, whereas N,N-diallyl-Tyr-Aib-Phe-Leu (ICI 174,864, 10 μg/paw), a selective antagonist of δ-opioid receptors, partially reversed this effect. On the other hand, D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr amide (CTOP, 20 g/paw), an antagonist of μ-opioid receptors, did not modify crotalphine-induced antinociception. These data indicate that crotalphine induces a potent and long lasting opioid-mediated antinociception in cancer pain. © 2013 Elsevier Inc

Crotoxin: Novel activities for a classic beta-neurotoxin

Crotoxin, the main toxin of South American rattlesnake (Crotalus durissus terrificus) venom, was the first snake venom protein to be purified and crystallized. Crotoxin is a heterodimeric beta-neurotoxin that consists of a weakly toxic basic phospholipase A(2) and a nonenzymatic, non-toxic acidic component (crotapotin). The classic biological activities normally attributed to crotoxin include neurotoxicity, myotoxicity, nephrotoxicity and cardiotoxicity. However, numerous studies in recent years have shown that crotoxin also has immunomodulatory, anti-inflammatory, anti-microbial, anti-tumor and analgesic actions. In this review, we describe the historical background to the discovery of crotoxin and its main toxic activities and then discuss recent structure-function studies and investigations that have led to the identification of novel pharmacological activities for the toxin. (C) 2010 Elsevier Ltd. All rights reserved