Skip to main content

Pain-Modulating Peptides in Spider Venoms: Good and Evil

  • Reference work entry
  • First Online:
Book cover Spider Venoms

Part of the book series: Toxinology ((TOXI))

Abstract

While few spiders are responsible for human envenomations of medical importance, their venom contains a large variety of bio-active molecules, able to modulate neuronal ion channels and receptors. These Neurotoxins involved in the paralysis of prey and toxicity during human envenomation have been extensively studied. Some of them helped to demonstrate the role of ion channels subtypes and receptors in pain processing. In spider venoms, molecules such as biogenic amines, ATP or NGF have a role in the induction of pain. Polyamines, by blocking NMDA channels, induce prey paralysis, but some are also able to modulate TRPV1 and AMPA channels involved in pain transmission. Many peptide toxins, which share a common structure, a compact cysteine knot, activate voltage-gated sodium channels and have a synergistic action to induce pain. More recently isolated peptides have shown analgesic effects by modulating ion channels such as voltage-gated calcium channels, ASICs, P2X3, and SACs. Some of these neurotoxins could be the basis for the development of future analgesics.

An erratum to this chapter can be found at http://dx.doi.org/10.1007/978-94-007-6389-0_24

An erratum to this chapter can be found at http://dx.doi.org/10.1007/978-94-007-6389-0_24

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

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 299.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 329.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Ahmed N, Pinkham M, Warrell DA. Symptom in search of a toxin: muscle spasms following bites by Old World tarantula spiders (Lampropelma nigerrimum, Pterinochilus murinus, Poecilotheria regalis) with review. QJM. 2009;102(12):851–7.

    Article  CAS  PubMed  Google Scholar 

  • Baron A, Diochot S, Salinas M, Deval E, Noel J, Lingueglia E. Venom toxins in the exploration of molecular, physiological and pathophysiological functions of acid-sensing ion channels. Toxicon. 2013;75:187–204.

    Article  CAS  PubMed  Google Scholar 

  • Bohlen CJ, Priel A, Zhou S, King D, Siemens J, Julius D. A bivalent tarantula toxin activates the capsaicin receptor, TRPV1, by targeting the outer pore domain. Cell. 2010;141(5):834–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bucaretchi F, Deus Reinaldo CR, Hyslop S, Madureira PR, De Capitani EM, Vieira RJ. A clinico-epidemiological study of bites by spiders of the genus Phoneutria. Rev Inst Med Trop Sao Paulo. 2000;42(1):17–21.

    Article  CAS  PubMed  Google Scholar 

  • Bush SP, Giem P, Vetter RS. Green lynx spider (Peucetia viridans) envenomation. Am J Emerg Med. 2000;18(1):64–6.

    Article  CAS  PubMed  Google Scholar 

  • Casewell NR, Huttley GA, Wuster W. Dynamic evolution of venom proteins in squamate reptiles. Nat Commun. 2012;3:1066.

    Article  PubMed  Google Scholar 

  • Chen JQ, Zhang YQ, Dai J, Luo ZM, Liang SP. Antinociceptive effects of intrathecally administered huwentoxin-I, a selective N-type calcium channel blocker, in the formalin test in conscious rats. Toxicon. 2005;45(1):15–20.

    Article  CAS  PubMed  Google Scholar 

  • Chizh BA, Illes P. P2X receptors and nociception. Pharmacol Rev. 2001;53(4):553–68.

    CAS  PubMed  Google Scholar 

  • Clark RF, Wethern-Kestner S, Vance MV, Gerkin R. Clinical presentation and treatment of black widow spider envenomation: a review of 163 cases. Ann Emerg Med. 1992;21(7):782–7.

    Article  CAS  PubMed  Google Scholar 

  • Costa SK, Brain SD, Antunes E, De Nucci G, Docherty RJ. Phoneutria nigriventer spider venom activates 5-HT4 receptors in rat-isolated vagus nerve. Br J Pharmacol. 2003;139(1):59–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Costa SK, Starr A, Hyslop S, Gilmore D, Brain SD. How important are NK1 receptors for influencing microvascular inflammation and itch in the skin? Studies using Phoneutria nigriventer venom. Vascul Pharmacol. 2006;45(4):209–14.

    Article  CAS  PubMed  Google Scholar 

  • Dalmolin GD, Silva CR, Rigo FK, Gomes GM, Cordeiro Mdo N, Richardson M, Silva MA, Prado MA, Gomez MV, Ferreira J. Antinociceptive effect of Brazilian armed spider venom toxin Tx3-3 in animal models of neuropathic pain. Pain. 2011;152(10):2224–32.

    Article  CAS  PubMed  Google Scholar 

  • Davletov BA, Meunier FA, Ashton AC, Matsushita H, Hirst WD, Lelianova VG, Wilkin GP, Dolly JO, Ushkaryov YA. Vesicle exocytosis stimulated by alpha-latrotoxin is mediated by latrophilin and requires both external and stored Ca2+. EMBO J. 1998;17(14):3909–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Deval E, Gasull X, Noel J, Salinas M, Baron A, Diochot S, Lingueglia E. Acid-sensing ion channels (ASICs): pharmacology and implication in pain. Pharmacol Ther. 2010;128(3):549–58.

    Article  CAS  PubMed  Google Scholar 

  • Diaz A, Dickenson AH. Blockade of spinal N- and P-type, but not L-type, calcium channels inhibits the excitability of rat dorsal horn neurones produced by subcutaneous formalin inflammation. Pain. 1997;69(1–2):93–100.

    Article  CAS  PubMed  Google Scholar 

  • Duncan AW, Tibballs J, Sutherland SK. Effects of Sydney funnel-web spider envenomation in monkeys, and their clinical implications. Med J Aust. 1980;2(8):429–35.

    CAS  PubMed  Google Scholar 

  • Dutertre S, Lewis RJ. Use of venom peptides to probe ion channel structure and function. J Biol Chem. 2010;285(18):13315–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fukuizumi T, Ohkubo T, Kitamura K. Spinally delivered N-, P/Q- and L-type Ca2+ −channel blockers potentiate morphine analgesia in mice. Life Sci. 2003;73(22):2873–81.

    Article  CAS  PubMed  Google Scholar 

  • Futrell JM. Loxoscelism. Am J Med Sci. 1992;304(4):261–7.

    Article  CAS  PubMed  Google Scholar 

  • Gewehr C, Oliveira SM, Rossato MF, Trevisan G, Dalmolin GD, Rigo FK, de Castro Junior CJ, Cordeiro MN, Ferreira J, Gomez MV. Mechanisms involved in the nociception triggered by the venom of the armed spider Phoneutria nigriventer. PLoS Negl Trop Dis. 2013;7(4):e2198.

    Article  PubMed  PubMed Central  Google Scholar 

  • Gold MS, Gebhart GF. Nociceptor sensitization in pain pathogenesis. Nat Med. 2010;16(11):1248–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Graudins A, Gunja N, Broady KW, Nicholson GM. Clinical and in vitro evidence for the efficacy of Australian red-back spider (Latrodectus hasselti) antivenom in the treatment of envenomation by a Cupboard spider (Steatoda grossa). Toxicon. 2002;40(6):767–75.

    Article  CAS  PubMed  Google Scholar 

  • Grishin EV, Savchenko GA, Vassilevski AA, Korolkova YV, Boychuk YA, Viatchenko-Karpinski VY, Nadezhdin KD, Arseniev AS, Pluzhnikov KA, Kulyk VB, Voitenko NV, Krishtal OO. Novel peptide from spider venom inhibits P2X3 receptors and inflammatory pain. Ann Neurol. 2010;67(5):680–3.

    CAS  PubMed  Google Scholar 

  • Hackel D, Krug SM, Sauer RS, Mousa SA, Bocker A, Pflucke D, Wrede EJ, Kistner K, Hoffmann T, Niedermirtl B, Sommer C, Bloch L, Huber O, Blasig IE, Amasheh S, Reeh PW, Fromm M, Brack A, Rittner HL. Transient opening of the perineurial barrier for analgesic drug delivery. Proc Natl Acad Sci U S A. 2012;109(29):E2018–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Isbister GK, Fan HW. Spider bite. Lancet. 2011;378(9808):2039–47.

    Article  PubMed  Google Scholar 

  • Isbister GK, Gray MR. A prospective study of 750 definite spider bites, with expert spider identification. QJM. 2002;95(11):723–31.

    Article  CAS  PubMed  Google Scholar 

  • Isbister GK, Gray MR. Latrodectism: a prospective cohort study of bites by formally identified redback spiders. Med J Aust. 2003a;179(2):88–91.

    PubMed  Google Scholar 

  • Isbister GK, Gray MR. White-tail spider bite: a prospective study of 130 definite bites by Lampona species. Med J Aust. 2003b;179(4):199–202.

    PubMed  Google Scholar 

  • Isbister GK, Hirst D. A prospective study of definite bites by spiders of the family Sparassidae (huntsmen spiders) with identification to species level. Toxicon. 2003;42(2):163–71.

    Article  CAS  PubMed  Google Scholar 

  • Isbister GK, White J. Clinical consequences of spider bites: recent advances in our understanding. Toxicon. 2004;43(5):477–92.

    Article  CAS  PubMed  Google Scholar 

  • Isbister GK, Seymour JE, Gray MR, Raven RJ. Bites by spiders of the family Theraphosidae in humans and canines. Toxicon. 2003;41(4):519–24.

    Article  CAS  PubMed  Google Scholar 

  • Isbister GK, Gray MR, Balit CR, Raven RJ, Stokes BJ, Porges K, Tankel AS, Turner E, White J, Fisher MM. Funnel-web spider bite: a systematic review of recorded clinical cases. Med J Aust. 2005;182(8):407–11.

    PubMed  Google Scholar 

  • King GF, Gentz MC, Escoubas P, Nicholson GM. A rational nomenclature for naming peptide toxins from spiders and other venomous animals. Toxicon. 2008;52(2):264–76.

    Article  CAS  PubMed  Google Scholar 

  • Kitaguchi T, Swartz KJ. An inhibitor of TRPV1 channels isolated from funnel Web spider venom. Biochemistry. 2005;44(47):15544–9.

    Article  CAS  PubMed  Google Scholar 

  • Klint JK, Senff S, Rupasinghe DB, Er SY, Herzig V, Nicholson GM, King GF. Spider-venom peptides that target voltage-gated sodium channels: pharmacological tools and potential therapeutic leads. Toxicon. 2012;60(4):478–91.

    Article  CAS  PubMed  Google Scholar 

  • Lampe RA, Analgesis peptides from venom of Grammostola spatulata and use therof. Patent US5877026. Publication date 02.03.1999.

    Google Scholar 

  • Lucas SM, Da Silva Junior PI, Bertani R, Cardoso JL. Mygalomorph spider bites: a report on 91 cases in the state of Sao Paulo, Brazil. Toxicon. 1994;32(10):1211–5.

    Article  CAS  PubMed  Google Scholar 

  • Mazzuca M, Heurteaux C, Alloui A, Diochot S, Baron A, Voilley N, Blondeau N, Escoubas P, Gelot A, Cupo A, Zimmer A, Zimmer AM, Eschalier A, Lazdunski M. A tarantula peptide against pain via ASIC1a channels and opioid mechanisms. Nat Neurosci. 2007;10(8):943–5.

    Article  CAS  PubMed  Google Scholar 

  • Miller MK, Whyte IM, White J, Keir PM. Clinical features and management of Hadronyche envenomation in man. Toxicon. 2000;38(3):409–27.

    Article  CAS  PubMed  Google Scholar 

  • Muller GJ. Black and brown widow spider bites in South Africa. A series of 45 cases. S Afr Med J. 1993;83(6):399–405.

    CAS  PubMed  Google Scholar 

  • Mylecharane EJ, Spence I, Sheumack DD, Claassens R, Howden ME. Actions of robustoxin, a neurotoxic polypeptide from the venom of the male funnel-web spider (Atrax robustus), in anaesthetized monkeys. Toxicon. 1989;27(4):481–92.

    Article  CAS  PubMed  Google Scholar 

  • Nentwig W, Gnadinger M, Fuchs J, Ceschi A. A two year study of verified spider bites in Switzerland and a review of the European spider bite literature. Toxicon. 2013;73C:104–10.

    Article  Google Scholar 

  • Nicholson GM, Graudins A. Spiders of medical importance in the Asia-Pacific: atracotoxin, latrotoxin and related spider neurotoxins. Clin Exp Pharmacol Physiol. 2002;29(9):785–94.

    Article  CAS  PubMed  Google Scholar 

  • Nicholson GM, Little MJ, Tyler M, Narahashi T. Selective alteration of sodium channel gating by Australian funnel-web spider toxins. Toxicon. 1996;34(11–12):1443–53.

    Article  CAS  PubMed  Google Scholar 

  • Nicholson GM, Graudins A, Wilson HI, Little M, Broady KW. Arachnid toxinology in Australia: from clinical toxicology to potential applications. Toxicon. 2006;48(7):872–98.

    Article  CAS  PubMed  Google Scholar 

  • Orlova EV, Rahman MA, Gowen B, Volynski KE, Ashton AC, Manser C, van Heel M, Ushkaryov YA. Structure of alpha-latrotoxin oligomers reveals that divalent cation-dependent tetramers form membrane pores. Nat Struct Biol. 2000;7(1):48–53.

    Article  CAS  PubMed  Google Scholar 

  • Pallaghy PK, Nielsen KJ, Craik DJ, Norton RS. A common structural motif incorporating a cystine knot and a triple-stranded beta-sheet in toxic and inhibitory polypeptides. Protein Sci. 1994;3(10):1833–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Park SP, Kim BM, Koo JY, Cho H, Lee CH, Kim M, Na HS, Oh U. A tarantula spider toxin, GsMTx4, reduces mechanical and neuropathic pain. Pain. 2008;137(1):208–17.

    Article  CAS  PubMed  Google Scholar 

  • Pogatzki EM, Niemeier JS, Sorkin LS, Brennan TJ. Spinal glutamate receptor antagonists differentiate primary and secondary mechanical hyperalgesia caused by incision. Pain. 2003;105(1–2):97–107.

    Article  CAS  PubMed  Google Scholar 

  • Pommier P, Rollard C, De Haro L. Spider bites: araneidism of medical importance. Presse Med. 2005;34(1):49–56.

    Article  PubMed  Google Scholar 

  • Pommier P, Rollard C, de Haro L. Steatoda spider envenomation in southern France. Presse Med. 2006;35(12 Pt 1):1825–7.

    Article  PubMed  Google Scholar 

  • Priest BT, Blumenthal KM, Smith JJ, Warren VA, Smith MM. ProTx-I and ProTx-II: gating modifiers of voltage-gated sodium channels. Toxicon. 2007;49(2):194–201.

    Article  CAS  PubMed  Google Scholar 

  • Rash LD, King RG, Hodgson WC. Evidence that histamine is the principal pharmacological component of venom from an Australian wolf spider (Lycosa godeffroyi). Toxicon. 1998;36(2):367–75.

    Article  CAS  PubMed  Google Scholar 

  • Rash LD, Birinyi-Strachan LC, Nicholson GM, Hodgson WC. Neurotoxic activity of venom from the Australian eastern mouse spider (Missulena bradleyi) involves modulation of sodium channel gating. Br J Pharmacol. 2000;130(8):1817–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Redaelli E, Cassulini RR, Silva DF, Clement H, Schiavon E, Zamudio FZ, Odell G, Arcangeli A, Clare JJ, Alagon A, de la Vega RC, Possani LD, Wanke E. Target promiscuity and heterogeneous effects of tarantula venom peptides affecting Na + and K+ ion channels. J Biol Chem. 2010;285(6):4130–42.

    Article  CAS  PubMed  Google Scholar 

  • Ribeiro LA, Jorge MT, Piesco RV, Nishioka Sde A. Wolf spider bites in Sao Paulo, Brazil: a clinical and epidemiological study of 515 cases. Toxicon. 1990;28(6):715–7.

    Article  CAS  PubMed  Google Scholar 

  • Rogers JJ, Stanford C, Dart RC. The use of visual analog pain scales in black widow spider envenomation. J Med Toxicol. 2006;2(1):46–7.

    Article  PubMed  PubMed Central  Google Scholar 

  • Schmalhofer WA, Calhoun J, Burrows R, Bailey T, Kohler MG, Weinglass AB, Kaczorowski GJ, Garcia ML, Koltzenburg M, Priest BT. ProTx-II, a selective inhibitor of NaV1.7 sodium channels, blocks action potential propagation in nociceptors. Mol Pharmacol. 2008;74(5):1476–84.

    Article  CAS  PubMed  Google Scholar 

  • Siemens J, Zhou S, Piskorowski R, Nikai T, Lumpkin EA, Basbaum AI, King D, Julius D. Spider toxins activate the capsaicin receptor to produce inflammatory pain. Nature. 2006;444(7116):208–12.

    Article  CAS  PubMed  Google Scholar 

  • Sorkin LS, Yaksh TL, Doom CM. Pain models display differential sensitivity to Ca2+ −permeable non-NMDA glutamate receptor antagonists. Anesthesiology. 2001;95(4):965–73.

    Article  CAS  PubMed  Google Scholar 

  • Souza AH, Ferreira J, Cordeiro MN,Vieira LB, De Castro CJ, Trevisan G, Reis H, Souza IA, Richardson M, Prado MAM, Prado VF, Gomez MV. Analgesic effect in rodents of native and recombinant Ph alpha1beta toxin, a high -voltage-activated calcium channel blocker isolated from armed spider venom. Pain. 2008; 140(1):115–26

    Google Scholar 

  • Sousa SR, Vetter I, Lewis RJ. Venom peptides as a rich source of cav2.2 channel blockers. Toxins (Basel). 2013;5(2):286–314.

    Article  CAS  Google Scholar 

  • Suchyna TM, Johnson JH, Hamer K, Leykam JF, Gage DA, Clemo HF, Baumgarten CM, Sachs F. Identification of a peptide toxin from Grammostola spatulata spider venom that blocks cation-selective stretch-activated channels. J Gen Physiol. 2000;115(5):583–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sutherland SK. Antivenom use in Australia. Premedication, adverse reactions and the use of venom detection kits. Med J Aust. 1992;157(11–12):734–9.

    CAS  PubMed  Google Scholar 

  • Swanson DL, Vetter RS. Loxoscelism. Clin Dermatol. 2006;24(3):213–21.

    Article  PubMed  Google Scholar 

  • Vassilevski AA, Kozlov SA, Grishin EV. Molecular diversity of spider venom. Biochemistry (Mosc). 2009;74(13):1505–34.

    Article  CAS  Google Scholar 

  • Venkatachalam K, Montell C. TRP channels. Annu Rev Biochem. 2007;76:387–417.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vetter RS. Envenomation by a spider, Agelenopsis aperta (family: Agelenidae) previously considered harmless. Ann Emerg Med. 1998;32(6):739–41.

    Article  CAS  PubMed  Google Scholar 

  • Vetter RS. Envenomation by spiders of the genus Hololena (Araneae: Agelenidae). Toxicon. 2012;60(3):312–4.

    Article  CAS  PubMed  Google Scholar 

  • Vetter RS, Isbister GK. Do hobo spider bites cause dermonecrotic injuries? Ann Emerg Med. 2004;44(6):605–7.

    Article  PubMed  Google Scholar 

  • Vetter RS, Isbister GK. Verified bites by the woodlouse spider, Dysdera crocata. Toxicon. 2006;47(7):826–9.

    Article  CAS  PubMed  Google Scholar 

  • Vetter RS, Isbister GK. Medical aspects of spider bites. Annu Rev Entomol. 2008;53:409–29.

    Article  CAS  PubMed  Google Scholar 

  • Vetter RS, Isbister GK, Bush SP, Boutin LJ. Verified bites by yellow sac spiders (genus Cheiracanthium) in the United States and Australia: where is the necrosis? Am J Trop Med Hyg. 2006;74(6):1043–8.

    PubMed  Google Scholar 

  • Wang M, Rong M, Xiao Y, Liang S. The effects of huwentoxin-I on the voltage-gated sodium channels of rat hippocampal and cockroach dorsal unpaired median neurons. Peptides. 2012;34(1):19–25.

    Article  PubMed  Google Scholar 

  • Warrell DA, Shaheen J, Hillyard PD, Jones D. Neurotoxic envenoming by an immigrant spider (Steatoda nobilis) in southern England. Toxicon. 1991;29(10):1263–5.

    Article  CAS  PubMed  Google Scholar 

  • Zanchet EM, Cury Y. Peripheral tackykinin and excitatory amino acid receptors mediate hyperalgesia induced by Phoneutria nigriventer venom. Eur J Pharmacol. 2003;467(1–3):111–8.

    Article  CAS  PubMed  Google Scholar 

  • Zanchet EM, Longo I, Cury Y. Involvement of spinal neurokinins, excitatory amino acids, proinflammatory cytokines, nitric oxide and prostanoids in pain facilitation induced by Phoneutria nigriventer spider venom. Brain Res. 2004;1021(1):101–11.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Sylvie Diochot .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer Science+Business Media Dordrecht

About this entry

Cite this entry

Diochot, S. (2016). Pain-Modulating Peptides in Spider Venoms: Good and Evil. In: Gopalakrishnakone, P., Corzo, G., de Lima, M., Diego-García, E. (eds) Spider Venoms. Toxinology. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-6389-0_18

Download citation

Publish with us

Policies and ethics