Skip to main content
SpringerLink
Log in

Antinociceptive effect of a novel armed spider peptide Tx3-5 in pathological pain models in mice

  • Ion channels, receptors and transporters
  • Published:
Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

Abstract

The venom of the Brazilian armed spider Phoneutria nigriventer is a rich source of biologically active peptides that have potential as analgesic drugs. In this study, we investigated the analgesic and adverse effects of peptide 3-5 (Tx3-5), purified from P. nigriventer venom, in several mouse models of pain. Tx3-5 was administered by intrathecal injection to mice selected as models of postoperative (plantar incision), neuropathic (partial sciatic nerve ligation) and cancer-related pain (inoculation with melanoma cells) in animals that were either sensitive or tolerant to morphine. Intrathecal administration of Tx3-5 (3–300 fmol/site) in mice could either prevent or reverse postoperative nociception, with a 50 % inhibitory dose (ID50) of 16.6 (3.2–87.2) fmol/site and a maximum inhibition of 87 ± 10 % at a dose of 30 fmol/site. Its effect was prevented by the selective activator of L-type calcium channel Bay-K8644 (10 μg/site). Tx3-5 (30 fmol/site) also produced a partial antinociceptive effect in a neuropathic pain model (inhibition of 67 ± 10 %). Additionally, treatment with Tx3-5 (30 fmol/site) nearly abolished cancer-related nociception with similar efficacy in both morphine-sensitive and morphine-tolerant mice (96 ± 7 and 100 % inhibition, respectively). Notably, Tx3-5 did not produce visible adverse effects at doses that produced antinociception and presented a TD50 of 1125 (893–1418) fmol/site. Finally, Tx3-5 did not alter the normal mechanical or thermal sensitivity of the animals or cause immunogenicity. Our results suggest that Tx3-5 is a strong drug candidate for the treatment of painful conditions.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

ANOVA:

Analysis of variance

BSA:

Bovine serum albumin

EDTA:

Ethylenediamine tetraacetic acid

ID50 :

Inhibitory dose 50 %

IL-1β:

Interleukin-1 beta

i.p.:

Intraperitoneal

i.pl.:

Intraplantar

i.t.:

Intrathecal

LPS:

Lipopolysaccharide

PBS:

Phosphate-buffered saline

PMSF:

Phenylmethylsulphonyl fluoride

PSNL:

Partial sciatic nerve ligation

s.c.:

Subcutaneous

TD50 :

Toxic dose 50 %

Tx3-5:

Peptide 3-5

VSCC:

Voltage-sensitive calcium channels

References

  1. Antkiewicz-Michaluk L, Michaluk J, Romańska IVJ (1993) Reduction of morphine dependence and potentiation of analgesia by chronic co-administration of nifedipine. Psychopharmacol (Berl) 111:457–64

    Article  CAS  Google Scholar 

  2. Atanassoff PG, Hartmannsgruber MW, Thrasher J, Wermeling D, Longton W, Gaeta R, Singh T, Mayo M, McGuire D, Luther RR (2000) Ziconotide, a new N-type calcium channel blocker, administered intrathecally for acute postoperative pain. Reg Anesth Pain Med 25:274–278. doi:10.1053/xr.2000.5662

    CAS  PubMed  Google Scholar 

  3. Ballantyne JC, Shin NS (2008) Efficacy of opioids for chronic pain: a review of the evidence. Clin J Pain 24:469–478

    Article  PubMed  Google Scholar 

  4. Le Bars D, Gozariu M, Cadden SW (2001) Animal models of nociception. Pharmacol Rev 53:597–652

    PubMed  Google Scholar 

  5. Brenneis C, Coste O, Altenrath K, Angioni C, Schmidt H, Schuh CD, Zhang DD, Henke M, Weigert A, Brüne B, Rubin B, Nusing R, Scholich K, Geisslinger G (2011) Anti-inflammatory role of microsomal prostaglandin E synthase-1 in a model of neuroinflammation. J Biol Chem 286:2331–2342

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL (1994) Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 53:55–63

    Article  CAS  PubMed  Google Scholar 

  7. Coderre TJ, Melzack R (1992) The role of NMDA receptor-operated calcium channels in persistent nociception after formalin-induced tissue injury. J Neurosci 12:3671–5

    CAS  PubMed  Google Scholar 

  8. Corbett AD, Henderson G, Mcknight AT, Paterson SJ (2006) 75 years of opioid research: the exciting but vain quest for the Holy Grail. Br J Pharmacol 1:153–162

    Google Scholar 

  9. Cordeiro Mdo N, de Figueiredo SG, Valentim Ado C, Diniz CR, von Eickstedt VR, Gilroy J, Richardson M (1993) Purification and amino acid sequences of six TX3 type neurotoxins from the venom of the Brazilian “armed” spider Phoneutria nigriventer. Toxicon 31:35–42

    Article  PubMed  Google Scholar 

  10. Dahl JB, Kehlet H (2006) Postoperative pain and its management. In: McMahon SB, Klotzenburg M (eds) Wall and Melzack’s Textbook of pain. Elsevier Churchill Livingstone, Philadelphia, p 635–651

  11. Dalmolin GD, Silva CR, Rigo FK, Gomes GM, Cordeiro MDN, Richardson M, Silva MAR, Prado MAM, Gomez MV, Ferreira J (2011) Antinociceptive effect of Brazilian armed spider venom toxin Tx3-3 in animal models of neuropathic pain. Pain 152:2224–2232. doi:10.1016/j.pain.2011.04.015

    Article  CAS  PubMed  Google Scholar 

  12. Dierssen M, Flórez JHM (1990) Calcium channel modulation by dihydropyridines modifies sufentanil-induced antinociception in acute and tolerant conditions. Naunyn Schmiedebergs Arch Pharmacol 342:559–65

    Article  CAS  PubMed  Google Scholar 

  13. Dixon WJ (1980) Efficient analysis of experimental observations. Annu Rev Pharmacol Toxicol 20:441–462

    Article  CAS  PubMed  Google Scholar 

  14. Dobremez E, Bouali-Benazzouz R, Fossat P, Monteils L, Dulluc J, Nagy FLM (2005) Distribution and regulation of L-type calcium channels in deep dorsal horn neurons after sciatic nerve injury in rats. Eur J Neurosci 21:3321–33

    Article  CAS  PubMed  Google Scholar 

  15. Dworkin RH, O’Connor AB, Backonja M, Farrar JT, Finnerup NB, Jensen TS, Kalso EA, Loeser JD, Miaskowski C, Nurmikko TJ, Portenoy RK, Rice AS, Stacey BR, Treede RD, Turk DC, Wallace MS (2007) Pharmacologic management of neuropathic pain: evidence-based recommendations. Pain 132:237–251

    Article  CAS  PubMed  Google Scholar 

  16. Fajardo O, Meseguer V, Belmonte CVF (2008) TRPA1 channels: novel targets of 1,4-dihydropyridines. Channels (Austin) 2:429–38

    Article  Google Scholar 

  17. Farmer P, Frenk J, Knaul FM, Shulman LN, Alleyne G, Armstrong L, Atun R, Blayney D, Chen L, Feachem R, Gospodarowicz M, Gralow J, Gupta S, Langer A, Lob-Levyt J, Neal C, Mbewu A, Mired D, Piot P, Reddy KS, Sachs JD, Sarhan M, Seffrin JR (2010) Expansion of cancer care and control in countries of low and middle income: a call to action. Lancet 376:1186–1193. doi:10.1016/S0140-6736(10)61152-X

    Article  PubMed  Google Scholar 

  18. Filos KS, Goudas LC, Patroni OTV (1993) Analgesia with epidural nimodipine. Lancet 342:1047

    Article  CAS  PubMed  Google Scholar 

  19. Fossat P, Dobremez E, Bouali-Benazzouz R, Favereaux A, Bertrand SS, Kilk K, Léger C, Cazalets JR, Langel U, Landry M, Nagy F (2010) Knockdown of L calcium channel subtypes: differential effects in neuropathic pain. J Neurosci 30:1073–1085

    Article  CAS  PubMed  Google Scholar 

  20. Gao YJ, Cheng JK, Zeng Q, Xu ZZ, Decosterd I, Xu X, Ji RR (2009) Selective inhibition of JNK with a peptide inhibitor attenuates pain hypersensitivity and tumor growth in a mouse skin cancer pain model. Exp Neurol 219:146–55

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Gomez MV, Kalapothakis E, Guatimosim C, Prado MA (2002) Phoneutria nigriventer venom: a cocktail of toxins that affect ion channels. Cell Mol Neurobiol 22:579–588. doi:10.1023/A:1021836403433

    Article  CAS  PubMed  Google Scholar 

  22. Gupta M, Singh J, Sood S, Arora B (2003) Mechanism of antinociceptive effect of nimodipine in experimental diabetic neuropathic pain. Exp Clin Pharmacol 25:49–52

    CAS  Google Scholar 

  23. Hagiwara K, Nakagawasai O, Murata A, Yamadera F, Miyoshi I, Tan-No K, Tadano T, Yanagisawa T, Iijima TMM (2003) Analgesic action of loperamide, an opioid agonist, and its blocking action on voltage-dependent Ca2+ channels. Neurosci Res 46:493–7

    Article  CAS  PubMed  Google Scholar 

  24. Hargreaves K, Dubner R, Brown F, Flores C, Joris J (1988) A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain 32:77–88

    Article  CAS  PubMed  Google Scholar 

  25. Horváth G, Brodacz BH-PU (2001) Role of calcium channels in the spinal transmission of nociceptive information from the mesentery. Pain 93:35–41

    Article  PubMed  Google Scholar 

  26. Hylden JL, Wilcox GL (1980) Intrathecal morphine in mice: a new technique. Eur J Pharmacol 67:313–316

    Article  CAS  PubMed  Google Scholar 

  27. Ishii K, Taira NYT (1985) Differential antagonism by Bay k 8644, a dihydropyridine calcium agonist, of the negative inotropic effects of nifedipine, verapamil, diltiazem and manganese ions in canine ventricular muscle. Br J Pharmacol 84:577–84

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Michaluk J, Karolewicz B, Antkiewicz-Michaluk L, Vetulani J (1998) Effects of various Ca2q channel antagonists on morphine analgesia, tolerance and dependence, and on blood pressure in the rat. Eur J Pharmacol 352:189–197

    Article  CAS  PubMed  Google Scholar 

  29. King NB, Fraser V (2013) Untreated pain, narcotics regulation, and global health ideologies. PLoS Med 10:e1001411. doi:10.1371/journal.pmed.1001411

    Article  PubMed  PubMed Central  Google Scholar 

  30. Kuner R (2010) Central mechanisms of pathological pain. Nat Med 16:1258–1266. doi:10.1038/nm.2231

    Article  CAS  PubMed  Google Scholar 

  31. Leão RM, Cruz JS, Diniz CR, Cordeiro MN, Beirão PS (2000) Inhibition of neuronal high-voltage activated calcium channels by the omega-phoneutria nigriventer Tx3-3 peptide toxin. Neuropharmacology 39:1756–67

    Article  PubMed  Google Scholar 

  32. Leão RM, Cruz JS, Diniz CR, Cordeiro MN, Beirão PLS (1997) Calcium channel blocking toxins in the venom of Phoneutria nigriventer. J Venom Anim Toxins 3:223

    Google Scholar 

  33. Loeser JD, Treede RD (2008) The Kyoto protocol of IASP basic pain terminology. Pain 137:473–477. doi:10.1016/j.pain.2008.04.025

    Article  PubMed  Google Scholar 

  34. Luvisetto S, Marinelli S, Panasiti MS, D’Amato FR, Fletcher CF, Pavone F, Pietrobon D (2006) Pain sensitivity in mice lacking the Cav2.1??1 subunit of P/Q-type Ca2+ channels. Neuroscience 142:823–832. doi:10.1016/j.neuroscience.2006.06.049

    Article  CAS  PubMed  Google Scholar 

  35. Makin MK (2001) Strong opioids for cancer pain. J R Soc Med 94:17–21

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Malmberg AB, Basbaum AI (1998) Partial sciatic nerve injury in the mouse as a model of neuropathic pain: behavioral and neuroanatomical correlates. Pain 76:215–222

    Article  CAS  PubMed  Google Scholar 

  37. Malmberg AB, Yaksh TL (1994) Voltage-sensitive calcium channels in spinal nociceptive processing: blockade of N- and P-type channels inhibits formalin-induced nociception. J Neurosci 14:4882–4890

    CAS  PubMed  Google Scholar 

  38. Mantyh PW, Clohisy DR, Koltzenburg M, Hunt SP (2002) Molecular mechanisms of cancer pain. Nat Rev Cancer 2:201–209

    Article  CAS  PubMed  Google Scholar 

  39. Marshall I, Weinstock M (1971) Quantitative method for assessing one symptom of the withdrawal syndrome in mice after chronic morphine administration. Nature 234:223–224

    Article  CAS  PubMed  Google Scholar 

  40. Matthews EA, Bee LA, Stephens GJ, Dickenson AH (2007) The Cav2.3 calcium channel antagonist SNX-482 reduces dorsal horn neuronal responses in a rat model of chronic neuropathic pain. Eur J Neurosci 25:3561–3569

    Article  PubMed  Google Scholar 

  41. Matthews EA, Dickenson AH (2001) Effects of spinally delivered N- and P-type voltage-dependent calcium channel antagonists on dorsal horn neuronal responses in a rat model of neuropathy. Pain 92:235–246

    Article  CAS  PubMed  Google Scholar 

  42. McGivern JG (2007) Ziconotide: a review of its pharmacology and use in the treatment of pain. Neuropsychiatr Dis Treat 3:69–85

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Miranda HF, Bustamante D, Kramer V, Pelissier T, Saavedra HPC, Fernandez EPG (1992) Antinociceptive effects of Ca2+ channel blockers. Eur J Pharmacol 217:137–141

    Article  CAS  PubMed  Google Scholar 

  44. Nossaman VE, Ramadhyani U, Kadowitz PJ, Nossaman BD (2010) Advances in perioperative pain management: use of medications with dual analgesic mechanisms, tramadol and tapentadol. Anesth Clin 28:647–666

    Article  CAS  Google Scholar 

  45. Oliveira SM, Drewes CC, Silva CR, Trevisan G, Boschen SL, Moreira CG, De Almeida CD, Da Cunha C, Ferreira J (2011) Involvement of mast cells in a mouse model of postoperative pain. Eur J Pharmacol 672:88–95. doi:10.1016/j.ejphar.2011.10.001

    Article  CAS  PubMed  Google Scholar 

  46. Oliveira SM, Silva CR, Wentz AP, Paim GR, Correa MS, Bonacorso HG, Prudente AS, Otuki MF, Ferreira J (2014) Antinociceptive effect of 3-(4-fluorophenyl)-5-trifluoromethyl-1H-1-tosylpyrazole. A Celecoxib structural analog in models of pathological pain. Pharmacol Biochem Behav 124:396–404. doi:10.1016/j.pbb.2014.07.005

    Article  CAS  PubMed  Google Scholar 

  47. Penn RD, Paice JA (2000) Adverse effects associated with the intrathecal administration of ziconotide. Pain 85:291–296. doi:10.1016/S0304-3959(99)00254-7

    Article  CAS  PubMed  Google Scholar 

  48. Pergolizzi J, Böger RH, Budd K, Dahan A, Erdine S, Hans G, Kress HG, Langford R, Likar R, Raffa RB, Sacerdote P (2008) Opioids and the management of chronic severe pain in the elderly: consensus statement of an International Expert Panel with focus on the six clinically most often used World Health Organization Step III opioids (buprenorphine, fentanyl, hydromorphone, met. Pain Pr 8:287–313

    Article  Google Scholar 

  49. Pogatzki-Zahn EM, Zahn PK, Brennan TJ (2007) Postoperative pain—clinical implications of basic research. Best Pr Res Clin Anaesthesiol 21:3–13

    Article  Google Scholar 

  50. Prado WA (2001) Involvement of calcium in pain and antinociception. Brazilian J Med Biol Res 34:449–461. doi:10.1590/S0100-879X2001000400003

    Article  CAS  Google Scholar 

  51. Pud D, Cohen D, Lawental E, Eisenberg E (2006) Opioids and abnormal pain perception: new evidence from a study of chronic opioid addicts and healthy subjects. Drug Alcohol Depend 82:218–223

    Article  CAS  PubMed  Google Scholar 

  52. Quijada L, Germany A, Hernández CE (1992) Effects of calcium channel antagonists and Bay K 8644 on the analgesic response to pentazocine and U 50488H. Gen Pharmacol 23:837–4

    Article  CAS  PubMed  Google Scholar 

  53. Richardson M, Pimenta AM, Bemquerer MP, Santoro MM, Beirao PS, Lima ME, Figueiredo SG, Bloch C Jr, Vasconcelos EA, Campos FA, Gomes PC, Cordeiro MN (2006) Comparison of the partial proteomes of the venoms of Brazilian spiders of the genus Phoneutria. Comp Biochem Physiol - C Toxicol Pharmacol 142:173–187. doi:10.1016/j.cbpc.2005.09.010

    Article  CAS  PubMed  Google Scholar 

  54. Rigo FK, Dalmolin GD, Trevisan G, Tonello R, Silva MA, Rossato MF, Klafke JZ, Cordeiro MDN, Castro Junior CJ, Montijo D, Gomez MV, Ferreira J (2013) Effect of ω-conotoxin MVIIA and Phα1β on paclitaxel-induced acute and chronic pain. Pharmacol Biochem Behav 114-115:16–22. doi:10.1016/j.pbb.2013.10.014

    Article  CAS  PubMed  Google Scholar 

  55. Rigo FK, Trevisan G, Rosa F, Dalmolin GD, Otuki MF, Cueto AP, de Castro Junior CJ, Romano-Silva MA, Cordeiro MDN, Richardson M, Ferreira J, Gomez MV (2013) Spider peptide Phα1β induces analgesic effect in a model of cancer pain. Cancer Sci 104:1226–1230. doi:10.1111/cas.12209

    Article  CAS  PubMed  Google Scholar 

  56. Rosa F, Trevisan G, Rigo FK, Tonello R, Andrade EL, Cordeiro Mdo N, Calixto JB, Gomez MVFJ (2014) Phα1β, a peptide from the venom of the spider Phoneutria nigriventer shows antinociceptive effects after continuous infusion in a neuropathic pain model in rats. Anesth Analg 119:196–202

    Article  CAS  PubMed  Google Scholar 

  57. Sanford M (2013) Intrathecal ziconotide: a review of its use in patients with chronic pain refractory to other systemic or intrathecal analgesics. CNS Drugs 27:989–1002

    Article  CAS  PubMed  Google Scholar 

  58. Santillán R, Maestre JM, Hurle MAFJ (1994) Enhancement of opiate analgesia by nimodipine in cancer patients chronically treated with morphine: a preliminary report. Pain 58:129–132

    Article  PubMed  Google Scholar 

  59. Santillán R, Hurlé MA, Armijo JA, de los Mozos R, Flórez J (1998) Nimodipine‐enhanced opiate analgesia in cancer patients requiring morphine dose escalation: a double‐blind, placebo‐controlled study. Pain 76:17–26

    Article  PubMed  Google Scholar 

  60. Sasamura T, Nakamura S, Iida Y, Fujii H, Murata J, Saiki I, Nojima H, Kuraishi Y (2002) Morphine analgesia suppresses tumor growth and metastasis in a mouse model of cancer pain produced by orthotopic tumor inoculation. Eur J Pharmacol 441:185–191

    Article  CAS  PubMed  Google Scholar 

  61. Saulino M (2007) Successful reduction of neuropathic pain associated with spinal cord injury via of a combination of intrathecal hydromorphone and ziconotide: a case report. Spinal Cord 45:749–752

    Article  CAS  PubMed  Google Scholar 

  62. Scherrer G, Imamachi N, Cao Y-Q, Contet C, Mennicken F, O’Donnell D, Kieffer BL, Basbaum AI (2009) Dissociation of the opioid receptor mechanisms that control mechanical and heat pain. Cell 137:1148–1159. doi:10.1016/j.cell.2009.04.019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Schmidtko A, Lötsch J, Freynhagen R, Geisslinger G (2010) Ziconotide for treatment of severe chronic pain. Lancet 375:1569–1577. doi:10.1016/S0140-6736(10)60354-6

    Article  CAS  PubMed  Google Scholar 

  64. Scott DA, Wright CEAJ (2002) Actions of intrathecal x- conotoxins CVID, GVIA, MVIIA, and morphine in acute and neuropathic pain in the rat. Eur J Pharmacol 451:279–286

    Article  CAS  PubMed  Google Scholar 

  65. Da Silva JF, Castro-Junior CJ, Oliveira SM, Dalmolin GD, Silva CR, Vieira LB, Diniz DM, Cordeiro MDN, Ferreira J, Souza AH, Gomez MV (2015) Characterization of the antinociceptive effect of PhTx3-4, a toxin from Phoneutria nigriventer, in models of thermal, chemical and incisional pain in mice. Toxicon 108:53–61. doi:10.1016/j.toxicon.2015.09.043

    Article  PubMed  Google Scholar 

  66. Silverman SM (2009) Opioid induced hyperalgesia: clinical implications for the pain practitioner. Pain Physician 12:679–684

    PubMed  Google Scholar 

  67. Skov MJ, Beck JC, De Kater AW, Shopp GM (2007) Nonclinical safety of ziconotide: an intrathecal analgesic of a new pharmaceutical class. Int J Toxicol 26:411–421. doi:10.1080/10915810701582970

    Article  CAS  PubMed  Google Scholar 

  68. Smith HS, Deer TR (2009) Safety and efficacy of intrathecal ziconotide in the management of severe chronic pain. Ther Clin Risk Manag 5:521–34

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Song MJ, Wang YQ, Wu GC (2007) Lipopolysaccharide-induced protein kinase D activation mediated by interleukin-1beta and protein kinase C. Brain Res 11:19–27

    Article  Google Scholar 

  70. de Souza AH, Lima MC, Drewes CC, da Silva JF, Torres KC, Pereira EM, de Castro Junior CJ, Vieira LB, Cordeiro MN, Richardson M, Gomez RS, Romano-Silva MA, Ferreira J, Gomez MV (2011) Antiallodynic effect and side effects of Phα1β, a neurotoxin from the spider Phoneutria nigriventer: comparison with ω-conotoxin MVIIA and morphine. Toxicon 58:626–633. doi:10.1016/j.toxicon.2011.09.008

    Article  PubMed  Google Scholar 

  71. De Souza AH, Castro CJ, Rigo FK, De Oliveira SM, Gomez RS, Diniz DM, Borges MH, Cordeiro MN, Silva MAR, Ferreira J, Gomez MV (2013) An evaluation of the antinociceptive effects of Phα1β, a neurotoxin from the spider phoneutria nigriventer, and ω-conotoxin MVIIA, a cone snail Conus magus toxin, in rat model of inflammatory and neuropathic pain. Cell Mol Neurobiol 33:59–67. doi:10.1007/s10571-012-9871-x

    Article  CAS  PubMed  Google Scholar 

  72. Souza AH, Ferreira J, Cordeiro MDN, Vieira LB, De Castro CJ, Trevisan G, Reis H, Souza IA, Richardson M, Prado MA, Prado VF, Gomez MV (2008) Analgesic effect in rodents of native and recombinant Ph alpha 1beta toxin, a high-voltage-activated calcium channel blocker isolated from armed spider venom. Pain 140:115–26. doi:10.1016/j.pain.2008.07.014

    Article  CAS  PubMed  Google Scholar 

  73. Staats PS, Yearwood T, Charapata SG, Presley RW, Wallace MS, Byas-Smith M, Fisher R, Bryce DA, Mangieri EA, Luther RR, Mayo M, McGuire D, Ellis D (2004) Intrathecal ziconotide in the treatment of refractory pain in patients with cancer or AIDS: a randomized controlled trial. Jama 291:63–70

    Article  CAS  PubMed  Google Scholar 

  74. Tonello R, Rigo F, Gewehr C, Trevisan G, Pereira EMR, Gomez MV, Ferreira J (2014) Action of Phα1β, a peptide from the venom of the spider Phoneutria nigriventer, on the analgesic and adverse effects caused by morphine in mice. J Pain 15:619–631. doi:10.1016/j.jpain.2014.02.007

    Article  CAS  PubMed  Google Scholar 

  75. Trevisan G, Rossato MF, Walker CIB, Klafke JZ, Rosa F, Oliveira SM, Tonello R, Guerra GP, Boligon AA, Zanon RB, Athayde ML, Ferreira J (2012) Identification of the plant steroid α-spinasterol as a novel transient receptor potential vanilloid 1 antagonist with antinociceptive properties. J Pharmacol Exp Ther 343:258–69. doi:10.1124/jpet.112.195909

    Article  CAS  PubMed  Google Scholar 

  76. Verma V, Mediratta PKSK (2001) Potentiation of analgesia and reversal of tolerance to morphine by calcium channel blockers. Indian J Exp Biol 39:636–42

    CAS  PubMed  Google Scholar 

  77. Vieira LB, Kushmerick C, Hildebrand ME, Garcia E, Stea A, Cordeiro MN, Richardson M, Gomez MV, Snutch TP (2005) Inhibition of high voltage-activated calcium channels by spider toxin PnTx3-6. J Pharmacol Exp Ther 314:1370–1377

    Article  CAS  PubMed  Google Scholar 

  78. Villarinho JG, Oliveira SM, Silva CR, Cabreira TN, Ferreira J (2012) Involvement of monoamine oxidase B on models of postoperative and neuropathic pain in mice. Eur J Pharmacol 690:107–114. doi:10.1016/j.ejphar.2012.06.042

    Article  CAS  PubMed  Google Scholar 

  79. Wang Y-X, Pettus M, Gao D, Phillips C, Scott Bowersox S (2000) Effects of intrathecal administration of ziconotide, a selective neuronal N-type calcium channel blocker, on mechanical allodynia and heat hyperalgesia in a rat model of postoperative pain. Pain 84:151–158. doi:10.1016/S0304-3959(99)00197-9

    Article  CAS  PubMed  Google Scholar 

  80. Wang W, Gu J, Li YQ, Tao YX (2011) Are voltage-gated sodium channels on the dorsal root ganglion involved in the development of neuropathic pain? Mol Pain 7:16

    Article  PubMed  PubMed Central  Google Scholar 

  81. Woolf CJ, Mannion RJ (1999) Neuropathic pain: aetiology, symptoms, mechanisms, and management. Lancet 353:1959–1964

    Article  CAS  PubMed  Google Scholar 

  82. Zamponi GW, Striessnig J, DA Koschak A (2015) The physiology, pathology, and pharmacology of voltage-gated calcium channels and their future therapeutic potential. Pharmacol Rev 67:821–70

    Article  PubMed  PubMed Central  Google Scholar 

  83. 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 study was supported by the Instituto Nacional de Ciência e Tecnologia em Medicina Molecular MCT/CNPq, Coordenação de Aperfeiçoamento de Pessoal de Ensino Superior (CAPES), PRONEX and FAPEMIG. We also acknowledge the receipt of fellowships from CNPq, CAPES and FAPEMIG.

Author information

Authors and Affiliations

  1. Programa de Pós-graduação em Ciências Biológicas: Bioquímica Toxicológica, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil

    Sara M. Oliveira, Cássia R. Silva, Jardel G. Villarinho & Juliano Ferreira

  2. Departamento de Bioquímica e Biologia Molecular, Universidade Federal de Santa Maria, Avenida Roraima 1000, Cidade Universitária, Santa Maria, RS, 97105-900, Brazil

    Sara M. Oliveira

  3. Programa de Pós-graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil

    Gabriela Trevisan

  4. Fundação Ezequiel Dias, Belo Horizonte, MG, Brazil

    Marta N. Cordeiro, Michael Richardson & Márcia H. Borges

  5. Programa de Pós-graduação em Farmacologia Bioquímica e Molecular, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil

    Célio J. Castro Jr. & Marcus V. Gomez

  6. Nucleo de Pós-graduação, Instituto de Ensino e Pesquisa da Santa Casa de Belo Horizonte, Belo Horizonte, MG, Brazil

    Célio J. Castro Jr. & Marcus V. Gomez

  7. Programa de Pós-graduação em Farmacologia, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil

    Juliano Ferreira

  8. Departamento de Farmacologia, Universidade Federal de Santa Catarina, Campus Universitário Reitor João David Ferreira Lima, Bairro Trindade, Florianópolis, SC, 88040-900, Brazil

    Juliano Ferreira

Authors
  1. Sara M. Oliveira
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cássia R. Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gabriela Trevisan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jardel G. Villarinho
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Marta N. Cordeiro
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michael Richardson
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Márcia H. Borges
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Célio J. Castro Jr.
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Marcus V. Gomez
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Juliano Ferreira
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Sara M. Oliveira or Juliano Ferreira.

Ethics declarations

The experiments were performed with the approval of the Ethics Committee of the Federal University of Santa Maria (process number 11/2010), and were carried out in accordance with the current guidelines for the care of laboratory animals.

Conflict of interest

The authors declare that they have no conflicts of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Oliveira, S.M., Silva, C.R., Trevisan, G. et al. Antinociceptive effect of a novel armed spider peptide Tx3-5 in pathological pain models in mice. Pflugers Arch - Eur J Physiol 468, 881–894 (2016). https://doi.org/10.1007/s00424-016-1801-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00424-016-1801-1

Keywords

Search

Navigation