Hyperalgesia induced by Asp49 and Lys49 phospholipases A2 from Bothrops asper snake venom:: pharmacological mediation and molecular determinants

被引:81
作者
Chacur, M
Longo, I
Picolo, G
Gutiérrez, JM
Lomonte, B
Guerra, JL
Teixeira, CFP
Cury, Y
机构
[1] Inst Butantan, Lab Fisiopatol, BR-05503900 Sao Paulo, Brazil
[2] Univ Costa Rica, Fac Microbiol, Inst Clodomiro Picado, San Jose, Costa Rica
[3] Univ Sao Paulo, Fac Med Vet & Zootecn, Dept Patol, BR-05340 Sao Paulo, Brazil
基金
巴西圣保罗研究基金会;
关键词
hyperalgesia; phospholipases A(2); biogenic amines; bradykinin; cytokines; prostanoids; sympathomimetic amines;
D O I
10.1016/S0041-0101(03)00007-2
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
The ability of Lys49 and Asp49 phospholipases A(2) (PLA(2)), from Bothrops asper snake venom, to cause hyperalgesia was investigated in rats, using the paw pressure test. Intraplantar injection of both toxins (5-20 mug/paw) caused hyperalgesia, which peaked 1 h after injections. Incubation of both proteins with heparin, prior to their injection, partially reduced this response. Chemical modification of Asp49 PLA(2) with p-bromophenacyl bromide (p-BPB), which abrogates its PLA(2) activity, also abolished hyperalgesia. Intraplantar injection of a synthetic peptide corresponding to the C-terminal sequence 115-129 of Lys49 PLA(2), caused hyperalgesia of similar time course, but varying magnitude, than that induced by the native protein. In contrast, a homologous peptide derived from the Asp49 PLA(2) did not show any nociceptive effect. Hyperalgesia induced by both PLA(2)s was blocked by the histamine and serotonin receptor antagonists promethazine and methysergide, respectively, by the bradykinin B-2 receptor antagonist HOE 140 and by antibodies to tumor necrosis factor alfa (TNFalpha) and interleukin 1 (IL-1). Pretreatment with guanethidine, atenolol, prazosin and yohimbine, inhibitors of sympathomimetic amines, or with indomethacin, inhibitor of the cyclo-oxygenase pathway, reduced Lys49 PLA(2)-induced hyperalgesia without interfering with the nociceptive activity of Asp49 PLA(2). The hyperalgesic response to both myotoxins was not modified by pretreatment with celecoxib, an inhibitor of the cyclo-oxygenase type II, by zileuton, an inhibitor of the lipoxygenase pathway or by N-g-methyl-L-arginine (LNMMA), an inhibitor of nitric oxide synthase. These results suggest that Asp49 and Lys49 PLA(2)s are important hyperalgesic components of B. asper venom, and that Lys49 and Asp49 PLA(2)s exert their algogenic actions through different molecular mechanisms. (C) 2003 Elsevier Science Ltd. All rights reserved.
引用
收藏
页码:667 / 678
页数:12
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