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 Sep 17;1021(1):101-11. doi: 10.1016/j.brainres.2004.06.041.


The major local symptom of Phoneutria nigriventer envenomation is an intense pain, which can be controlled by infiltration with local anesthetics or by systemic treatment with opioid analgesics. Previous work showed that intraplantar ( injection of Phoneutria nigriventer venom in rats induces hyperalgesia, mediated peripherally by tachykinin and glutamate receptors. The present study examined the spinal mechanisms involved in pain-enhancing effect of this venom. Intraplantar injection of venom into rat hind paw induced hyperalgesia. This phenomenon was inhibited by intrathecal (i.t.) injection of tachykinin NK1 (GR 82334) or NK2 (GR 94800) receptor antagonists, a calcitonin gene-related peptide (CGRP) receptor antagonist (CGRP8-37) and N-methyl-D-aspartate (NMDA; MK 801 and AP-5), non-NMDA ionotropic (CNQX), or metabotropic (AIDA and MPEP) glutamate receptor antagonists, suggesting the involvement of spinal neurokinins and excitatory amino acids. The role of proinflammatory cytokines, nitric oxide (NO), and prostanoids in spinally mediated pain facilitation was also investigated. Pharmacological blockade of tumour necrosis factor-alpha (TNFalpha) or interleukin-1beta (IL-1beta) reduced the hyperalgesic response to venom. Intrathecal injection of L-N6-(1-iminoethyl)lysine (L-NIL), but not of 7-nitroindazole (7-NI), inhibited hyperalgesia induced by the venom, indicating that NO, generated by the activity of the inducible form of nitric oxide synthase, also mediates this phenomenon. Furthermore, indomethacin, an inhibitor of cyclooxigenases (COX), or celecoxib, a selective inhibitor of COX-2, abolished venom-induced hyperalgesia, suggesting the involvement of spinal prostanoids in this effect. These data indicate that the spinal mechanisms of pain facilitation induced by Phoneutria nigriventer venom involves a plethora of mediators that may cooperate in the genesis of venom-induced central sensitization.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / pharmacology
  • Calcitonin Gene-Related Peptide Receptor Antagonists
  • Celecoxib
  • Citrates / pharmacology
  • Cyclooxygenase Inhibitors / pharmacology
  • Dizocilpine Maleate / pharmacology
  • Enzyme Inhibitors / pharmacology
  • Excitatory Amino Acid Antagonists / pharmacology
  • Hyperalgesia / chemically induced
  • Hyperalgesia / drug therapy
  • Hyperalgesia / immunology*
  • Indazoles / pharmacology
  • Interleukin-1 / antagonists & inhibitors
  • Interleukin-1 / immunology*
  • Lysine / analogs & derivatives*
  • Lysine / pharmacology
  • Male
  • Neurokinin-1 Receptor Antagonists
  • Nitric Oxide Synthase / antagonists & inhibitors
  • Pain / chemically induced
  • Pain / drug therapy
  • Pain / immunology*
  • Physalaemin / analogs & derivatives*
  • Physalaemin / pharmacology
  • Prostaglandins / metabolism
  • Pyrazoles
  • Rats
  • Rats, Wistar
  • Receptors, Calcitonin Gene-Related Peptide / metabolism
  • Receptors, Neurokinin-1 / metabolism
  • Spider Venoms / toxicity*
  • Spinal Cord / immunology*
  • Spinal Cord / metabolism
  • Sulfonamides / pharmacology
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / immunology*


  • Antibodies
  • Calcitonin Gene-Related Peptide Receptor Antagonists
  • Citrates
  • Cyclooxygenase Inhibitors
  • Enzyme Inhibitors
  • Excitatory Amino Acid Antagonists
  • Indazoles
  • Interleukin-1
  • N(6)-(1-iminoethyl)lysine
  • Neurokinin-1 Receptor Antagonists
  • Prostaglandins
  • Pyrazoles
  • Receptors, Calcitonin Gene-Related Peptide
  • Receptors, Neurokinin-1
  • Spider Venoms
  • Sulfonamides
  • Tumor Necrosis Factor-alpha
  • GR 82334
  • Physalaemin
  • fluorocitrate
  • Dizocilpine Maleate
  • Nitric Oxide Synthase
  • Celecoxib
  • Lysine
  • 7-nitroindazole