Skip to main content
Log in

Hyperalgesic and edematogenic effects of peptides isolated from the venoms of honeybee (Apis mellifera) and neotropical social wasps (Polybia paulista and Protonectarina sylveirae)

  • Original Article
  • Published:
Amino Acids Aims and scope Submit manuscript

Abstract

Stings by bees and wasps, including Brazilian species, are a severe public health problem. The local reactions observed after the envenoming includes typical inflammatory response and pain. Several studies have been performed to identify the substances, including peptides that are responsible for such phenomena. The aim of the present study is to characterize the possible nociceptive (hyperalgesic) and edematogenic effects of some peptides isolated from the venoms of the honeybee (Apis mellifera) and the social wasps Polybia paulista and Protonectarina sylveirae, in addition to characterize some of the mechanisms involved in these phenomena. For this purpose, different doses of the peptides mellitin (Apis mellifera), Polybia-MP-I, N-2-Polybia-MP-I (Polybia paulista), Protonectarina-MP-NH2 and Protonectarina-MP-OH (Protonectarina sylveirae) were injected into the hind paw of mice. Hyperalgesia and edema were determined after peptide application, by using an electronic von Frey apparatus and a paquimeter. Carrageenin and saline were used as controls. Results showed that melittin, Polybia-MP-I, N-2-Polybia-MP-I, Protonectarina-MP-NH2 and Protonectarina-MP-OH peptides produced a dose- and time-related hyperalgesic and edematogenic responses. Both phenomena are detected 2 h after melittin, Polybia-MP-I, N-2-Polybia-MP-I injection; their effects lasted until 8 h. In order to evaluate the role of prostanoids and the involvement of lipidic mediators in hyperalgesia induced by the peptides, indomethacin and zileuton were used. Results showed that zileuton blocked peptide-induced hyperalgesia and induced a decrease of the edematogenic response. On the other hand, indomethacin did not interfere with these phenomena. These results indicate that melittin, Polybia-MP-I, N-2-Polybia-MP-I, Protonectarina-MP-NH2, and Protonectarina-MP-OH peptides could contribute to inflammation and pain induced by insect venoms.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Ali MF, Soto A, Knoop FC, Conlon JM (2001) Antimicrobial peptides isolated from skin secretions of the diploid frog, Xenopus tropicalis (Pipidae). Biochim Biophys Acta 1550:81–89

    CAS  PubMed  Google Scholar 

  • Antonicelli L, Bilo MB, Bonifazi F (2002) Epidemiology of Hymenoptera allergy. Curr Opin Allergy Clin Immunol 2:341–346

    Article  PubMed  Google Scholar 

  • Berger W, De Chandt MT, Cairns CB (2007) Zileuton: clinical implications of 5-Lipoxygenase inhibition in severe airway disease. Int J Clin Pract 61:663–676

    Article  CAS  PubMed  Google Scholar 

  • Castro FFM, Palma MS (2009) Alergia a venenos de insetos. Manole, Brasil

    Google Scholar 

  • Chacur M, Longo I, Picolo G, Gutierrez JM, Lomonte B, Guerra JL, Teixeira CF, Cury Y (2003) Hyperalgesia induced by Asp49 and Lys49 phospholipases A(2) from Bothrops asper snake venom: pharmacological mediation and molecular determinants. Toxicon 41:667–678

    Article  CAS  PubMed  Google Scholar 

  • Chacur M, Gutiérrez JM, Milligan ED, Wieseler-Frank J, Britto LR, Maier SF, Watkins LR, Cury Y (2004) Snake venom components enhance pain upon subcutaneous injection: an initial examination of spinal cord mediators. Pain 111:65–76

    Article  CAS  PubMed  Google Scholar 

  • Chan WC, White PD (2004) Fmoc solid phase peptide synthesis: a practical approach. Oxford University Press, Cambridge

    Google Scholar 

  • Charpin D, Birnbaum J, Vervloet D (1994) Epidemiology of hymenoptera allergy. Clin Exp Allergy 24:1010–1015

    Article  CAS  PubMed  Google Scholar 

  • Chen C, Cavanaugh JM, Ozaktay AC, Kallakuri S, King AL (1997) Effects of phospholipases A2 on lumbar nerve root structure and function. Spine 22:1057–1064

    Article  CAS  PubMed  Google Scholar 

  • Chen YN, Li KC, Li Z, Shang GW, Liu DN, Lu ZM, Zhang JW, Ji YH, Gao GD, Chen J (2006a) Effects of bee venom peptidergic components on rat pain-related behaviors and inflammation. Neuroscience 138:631–640

    Article  CAS  PubMed  Google Scholar 

  • Chen ZX, Zhang HL, Gu ZL, Chen BW, Han R, Reid PF, Raymond LN, Qin ZH (2006b) A long-form alpha-neurotoxin from cobra venom produces potent opioid-independent analgesia. Acta Pharmacol Sin 27:402–408

    Article  CAS  PubMed  Google Scholar 

  • Cociancich S, Ghazi A, Hetru C, Hoffmann JA, Letellier L (1993) Insect defensin, an inducible antibacterial peptide, forms voltage-dependent channels in Micrococcus luteus. J Biol Chem 268:19239–19245

    CAS  PubMed  Google Scholar 

  • de Oliveira MR, Palma MS (1998) Polybitoxins: a group of phospholipases A2 from the venom of the neotropical social wasp paulistinha (Polybia paulista). Toxicon 36:189–199

    Article  PubMed  Google Scholar 

  • de Oliveira L, Cunha AO, Mortari MR, Coimbra NC, Dos Santos WF (2006) Cataleptic activity of the denatured venom of the social wasp Agelaia vicina (Hymenoptera, Vespidae) in Rattus norvegicus (Rodentia, Muridae). Prog Neuropsychopharmacol Biol Psychiatry 30:198–203

    Article  PubMed  Google Scholar 

  • de Paula L, Santos WF, Malheiro A, Carlos D, Faccioli LH (2006) Differential modulation of cell recruitment and acute edema in a model of Polybia paulista venom-induced inflammation. Int Immunopharmacol 6:182–189

    Article  PubMed  Google Scholar 

  • de Souza BM, Marques MR, Tomazela DM, Eberlin MN, Mendes MA, Palma MS (2004) Mass spectrometric characterization of two novel inflammatory peptides from the venom of the social wasp Polybia paulista. Rapid Commun Mass Spectrom 18:1095–1102

    Article  PubMed  Google Scholar 

  • de Souza BM, da Silva AV, Resende VM, Arcuri HA, Dos Santos Cabrera MP, Ruggiero Neto J, Palma MS (2009) Characterization of two novel polyfunctional mastoparan peptides from the venom of the social wasp Polybia paulista. Peptides 30:1387–1395

    Article  PubMed  Google Scholar 

  • Dohtsu K, Okumura K, Hagiwara K, Palma MS, Nakajima T (1993) Isolation and sequence analysis of peptides from the venom of Protonectarina sylveirae (Hymenoptera-Vespidae). Nat Toxins 1:271–276

    Article  CAS  PubMed  Google Scholar 

  • Dos Santos Cabrera MP, De Souza BM, Fontana R, Konno K, Palma MS, de Azevedo WF Jr, Neto JR (2004) Conformation and lytic activity of eumenine mastoparan: a new antimicrobial peptide from wasp venom. J Peptide Res 64:95–103

    Article  CAS  Google Scholar 

  • Ellis AK, Day JH (2005) Clinical reactivity to insect stings. Curr Opin Allergy Clin Immunol 5:349–354

    Article  PubMed  Google Scholar 

  • Fernandes CM, Pereira Teixeira Cde F, Leite AC, Gutiérrez JM, Rocha FA (2007) The snake venom metalloproteinase BaP1 induces joint hypernociception through TNF-alpha and PGE2-dependent mechanisms. Br J Pharmacol 151:1254–1261

    Article  CAS  PubMed  Google Scholar 

  • Golden DB (1989) Epidemiology of allergy to insect venoms and stings. Allergy Proc 10:103–107

    Article  CAS  PubMed  Google Scholar 

  • Hartman DA, Tomchek LA, Lugay JR, Lewin AC, Chau TT, Carlson RP (1991) Comparison of antiinflammatory and antiallergic drugs in the melittin- and D49 PLA2-induced mouse paw edema models. Agents Actions 34:84–88

    Article  CAS  PubMed  Google Scholar 

  • Higashijima T, Burnier J, Ross EM (1990) Regulation of Gi and Go by mastoparan, related amphiphilic peptides, and hydrophobic amines. Mechanism and structural determinants of activity. J Biol Chem 265:14176–14186

    CAS  PubMed  Google Scholar 

  • Hirai Y, Yasuhara T, Yoshida H, Nakajima T, Fujino M, Kitada C (1979) A new mast cell degranulating peptide “mastoparan” in the venom of Vespula lewisii. Chem Pharm Bull (Tokyo) 27:1942–1944

    CAS  Google Scholar 

  • Ho CL, Shih YP, Wang KT, Yu HM (2001a) Enhancing the hypotensive effect and diminishing the cytolytic activity of hornet mastoparan B by d-amino acid substitution. Toxicon 39:1561–1566

    Article  CAS  PubMed  Google Scholar 

  • Ho IC, Arm JP, Bingham CO 3rd, Choi A, Austen KF, Glimcher LH (2001b) A novel group of phospholipase A2 s preferentially expressed in type 2 helper T cells. J Biol Chem 276:18321–18326

    Article  CAS  PubMed  Google Scholar 

  • Hoffman DR, Wood CL, Hudson P (1983) Demonstration of IgE and IgG antibodies against venoms in the blood of victims of fatal sting anaphylaxis. J Allergy Clin Immunol 71:193–196

    Article  CAS  PubMed  Google Scholar 

  • Horizoe T, Nagakura N, Chiba K, Shirota H, Shinoda M, Kobayashi N, Numata H, Okamoto Y, Kobayashi S (1998) ER-34122, a novel dual 5-lipoxygenase/cyclooxygenase inhibitor with potent anti-inflammatory activity in an arachidonic acid-induced ear inflammation model. Inflamm Res 47:375–383

    Article  CAS  PubMed  Google Scholar 

  • Jensen K, Andersen HO, Olesen J, Lindblom U (1986) Pressure-pain threshold in human temporal region. Evaluation of a new pressure algometer. Pain 25:313–323

    Article  CAS  PubMed  Google Scholar 

  • Jones S, Howl J (2006) Biological applications of the receptor mimetic peptide mastoparan. Curr Protein Pept Sci 7:501–508

    Article  CAS  PubMed  Google Scholar 

  • Kane GC, Tollino M, Pollice M, Kim CJ, Cohn J, Murray JJ, Dworski R, Sheller J, Fish JE, Peters SP (1995) Insights into IgE-mediated lung inflammation derived from a study employing a 5-lipoxygenase inhibitor. Prostaglandins 50:1–18

    Article  CAS  PubMed  Google Scholar 

  • Katayama H, Ohira T, Aida K, Nagasawa H (2002) Significance of a carboxyl-terminal amide moiety in the folding and biological activity of crustacean hyperglycemic hormone. Peptides 23:1537–1546

    Article  CAS  PubMed  Google Scholar 

  • Khanapure SP, Garvey DS, Janero DR, Letts LG (2007) Eicosanoids in inflammation: biosynthesis, pharmacology, and therapeutic frontiers. Curr Top Med Chem 7:311–340

    Article  CAS  PubMed  Google Scholar 

  • Konno K, Hisada M, Fontana R, Lorenzi CC, Naoki H, Itagaki Y, Miwa A, Kawai N, Nakata Y, Yasuhara T, Ruggiero Neto J, de Azevedo WF Jr, Palma, Nakajima T (2001) Anoplin, a novel antimicrobial peptide from the venom of the solitary wasp Anoplius samariensis. Biochim Biophys Acta 1550:70–80

    CAS  PubMed  Google Scholar 

  • Koyama N, Hirata K, Hori K, Dan K, Yokota T (2002) Biphasic vasomotor reflex responses of the hand skin following intradermal injection of melittin into the forearm skin. Eur J Pain 6:447–453

    Article  CAS  PubMed  Google Scholar 

  • Levine JD, Lau W, Kwiat G, Goetzl EJ (1984) Leukotriene B4 produces hyperalgesia that is dependent on polymorphonuclear leukocytes. Science 225:743–745

    Article  CAS  PubMed  Google Scholar 

  • Levine JD, Field HL, Basbaum AI (1993) Peptides and the primary afferent nociceptor. J Neurosci 13:2273–2286

    CAS  PubMed  Google Scholar 

  • Li KC, Chen J (2003) Differential roles of spinal protein kinases C and a in development of primary heat and mechanical hypersensitivity induced by subcutaneous bee venom chemical injury in the rat. Neurosignals 12:292–301

    Article  CAS  PubMed  Google Scholar 

  • Madison S, Whitsel EA, Suarez-Roca H, Maixner W (1992) Sensitizing effects of leukotriene B4 on intradental primary afferents. Pain 49:99–104

    Article  CAS  PubMed  Google Scholar 

  • Maguire (1998) Ectoparasite infestations and arthropod bites and stings. In: Fauci AS (ed) Harrison’s principles of internal medicine. McGraw Hill Health Professions Divisions, New York, pp 2548–2554

  • Martin HA (1990) Leukotriene B4 induced decrease in mechanical and thermal thresholds of C-fiber mechanonociceptors in rat hairy skin. Brain Res 509:273–279

    Article  CAS  PubMed  Google Scholar 

  • Martin HA, Basbaum AI, Goetzl EJ, Levine JD (1988) Leukotriene B4 decreases the mechanical and thermal thresholds of C-fiber nociceptors in the hairy skin of the rat. J Neurophysiol 60:438–445

    CAS  PubMed  Google Scholar 

  • Mendes MA, de Souza BM, Marques MR, Palma MS (2004) Structural and biological characterization of two novel peptides from the venom of the neotropical social wasp Agelaia pallipes pallipes. Toxicon 44:67–74

    Article  CAS  PubMed  Google Scholar 

  • Mendes MA, Souza BM, Palma MS (2005) Structural and biological of three novel mastoparan peptides from the venom of the neotropical social wasp Protopolybia exigua (Saussure). Toxicon 45:101–106

    Article  CAS  PubMed  Google Scholar 

  • Merrifield B (1986) Solid-phase synthesis. Science 232:341–376

    Article  CAS  PubMed  Google Scholar 

  • Murata K, Shinada T, Ohfune Y, Hisada M, Yasuda A, Naoki H, Nakajima T (2009) Novel mastoparan and protonectin analogs isolated from a solitary wasp, Orancistrocerus drewseni drewseni. Amino Acids 37:389–394

    Article  CAS  PubMed  Google Scholar 

  • Mustafa FB, Ng FS, Nguyen TH, Lim LH (2008) Honeybee venom secretory phospholipase A2 induces leukotriene production but not histamine release from human basophils. Clin Exp Immunol 151:94–100

    Article  CAS  PubMed  Google Scholar 

  • Nakajima T (1986) Pharmacological biochemistry of vespid venoms. In: Piek T (ed) Venom of Hymenoptera Academic Press, London, pp 309–327

  • Nakajima T, Uzu S, Wakamatsu K, Saito K, Miyazawa T, Yasuhara T, Tsukamoto Y, Fujino M (1986) Amphiphilic peptides in wasp venom. Biopolymers 25(Suppl):S115–S121

    CAS  PubMed  Google Scholar 

  • Nicolas JP, Lin Y, Lambeau G, Ghomashchi F, Lazdunski M, Gelb MH (1997) Localization of structural elements of bee venom phospholipase A2 involved in N-type receptor binding and neurotoxicity. J Biol Chem 272:7173–7181

    Article  CAS  PubMed  Google Scholar 

  • Parrish HM (1963) Analysis of 460 fatalities from venomous animals in the United States. Am J Med Sci 245:129–141

    Article  CAS  PubMed  Google Scholar 

  • Picolo G, Hisada M, Moura AB, Machado MF, Sciani JM, Conceição IM, Melo RL, Oliveira V, Lima-Landman MT, Cury Y, Konno K, Hayashi MA (2010) Bradykinin-related peptides in the venom of the solitary wasp Cyphononyx fulvognathus. Biochem Pharmacol 79:478–486

    Article  CAS  PubMed  Google Scholar 

  • Pouny Y, Rapaport D, Mor A, Nicolas P, Shai Y (1992) Interaction of antimicrobial dermaseptin and its fluorescently labeled analogues with phospholipid membranes. Biochemistry 31:12416–12423

    Article  CAS  PubMed  Google Scholar 

  • Rackham A, Ford-Hutchinson AW (1983) Inflammation and pain sensitivity: effects of leukotrienes D4, B4 and prostaglandin E1 in the rat paw. Prostaglandins 25:193–203

    Article  CAS  PubMed  Google Scholar 

  • Rotem S, Radzishevsky I, Inouye RT, Samore M, Mor A (2006) Identification of antimicrobial peptide regions derived from genomic sequences of phage lysins. Peptides 27:8–26

    Article  Google Scholar 

  • Shin HK, Kim JH (2004) Melittin selectively activates capsaicin-sensitive primary afferent fibers. Neuroreport 15:1745–1749

    Article  CAS  PubMed  Google Scholar 

  • Son DJ, Kang J, Kim TJ, Song HS, Sung KJ, Yun do Y, Hong JT (2007) Melittin, a major bioactive component of bee venom toxin, inhibits PDGF receptor beta-tyrosine phosphorylation and downstream intracellular signal transduction in rat aortic vascular smooth muscle cells. J Toxicol Environ Health A 70:1350–1355

    Article  CAS  PubMed  Google Scholar 

  • Song DL, Chang GD, Ho CL, Chang CH (1993) Structural requirements of mastoparan for activation of membrane-bound guanylate cyclase. Eur J Pharmacol 247:283–288

    Article  CAS  PubMed  Google Scholar 

  • Steen CJ, Janniger CK, Schutzer SE, Schwartz RA (2005) Insect sting reactions to bees, wasps, and ants. Int J Dermatol 44:91–94

    Article  PubMed  Google Scholar 

  • Steiner H, Andreu D, Merrifield RB (1988) Binding and action of cecropin and cecropin analogues: antibacterial peptides from insects. Biochim Biophys Acta 939:260–266

    Article  CAS  PubMed  Google Scholar 

  • Sumikura H, Andersen OK, Drewes AM, Arendt-Nielsen L (2006) Secondary heat hyperalgesia induced by melittin in humans. Eur J Pain 10:121–125

    Article  CAS  PubMed  Google Scholar 

  • Tossi A, Sandri L, Giangaspero A (2000) Amphipathic, alpha-helical antimicrobial peptides. Biopolymers 55:4–30

    Article  CAS  PubMed  Google Scholar 

  • Vivancos GG, Verri WA Jr, Cunha TM, Schivo IR, Parada CA, Cunha FQ, Ferreira SH (2004) An electronic pressure-meter nociception paw test for rats. Braz J Med Biol Res 37:391–399

    Article  CAS  PubMed  Google Scholar 

  • Yu YQ, Chen J (2005) Activation of spinal extracellular signaling-regulated kinases by intraplantar melittin injection. Neurosci Lett 381:194–198

    Article  CAS  PubMed  Google Scholar 

  • Zimmermann M (1983) Ethical guidelines for investigations of experimental pain in conscious animals. Pain 16:109–110

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This research is supported by grants from FAPESP (BIOprospecTA Proc. 04/07942-2, 06/57122-6), CNPq, Instituto Nacional de Ciência e Tecnologia em Imunologia (INCT/CNPq-MCT) and Coordenação de Aperfeiçoamento de Nível Superior—Projeto NanoBiotec (CAPES). MSP and YC are researchers for the Brazilian Council for Scientific and Technological Development (CNPq).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Mario Sérgio Palma.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Brigatte, P., Cury, Y., de Souza, B.M. et al. Hyperalgesic and edematogenic effects of peptides isolated from the venoms of honeybee (Apis mellifera) and neotropical social wasps (Polybia paulista and Protonectarina sylveirae). Amino Acids 40, 101–111 (2011). https://doi.org/10.1007/s00726-010-0512-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00726-010-0512-8

Keywords

Navigation