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Characterization of antiallodynic actions of ALE-0540, a novel nerve growth factor receptor antagonist, in the rat.

Abstract
There is growing evidence that nerve growth factor (NGF) may function as a mediator of persistent pain states. We have identified a novel nonpeptidic molecule, ALE-0540, that inhibits the binding of NGF to tyrosine kinase (Trk) A or both p75 and TrkA (IC50 5.88 +/- 1. 87 microM, 3.72 +/- 1.3 microM, respectively), as well as signal transduction and biological responses mediated by TrkA receptors. ALE-0540 was tested in models of neuropathic pain and thermally-induced inflammatory pain, using two routes of administration, a systemic i.p. and a spinal intrathecal (i.th.) route. Morphine was also tested for comparison in the antiallodynia model using mechanical stimuli. We show that either i.p. or i.th. administration of ALE-0540 in rats produced antiallodynia in the L5/L6 ligation model of neuropathic pain. The calculated A50 values (and 95% confidence intervals) for ALE-0540 administered i.p. and i. th. were 38 (17.5-83) mg/kg and 34.6 (17.3-69.4) microgram, respectively. ALE-0540 given i.th., at doses of 30 and 60 microgram, also blocked tactile allodynia in the thermal sensitization model. Although morphine displayed greater potency [A50 value of 7.1 (5.6-8. 8) mg/kg] than ALE-0540 in anti-allodynic effect when given i.p. to L5/L6-ligated rats, it was not active when administered i.th. These data suggest that a blockade of NGF bioactivity using a NGF receptor antagonist is capable of blocking neuropathic and inflammatory pain and further support the hypothesis that NGF is involved in signaling pathways associated with these pain states. ALE-0540 represents a nonpeptidic small molecule which can be used to examine mechanisms leading to the development of agents for the treatment of pain.
AuthorsJ B Owolabi, G Rizkalla, A Tehim, G M Ross, R J Riopelle, R Kamboj, M Ossipov, D Bian, S Wegert, F Porreca, D K Lee
JournalThe Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 289 Issue 3 Pg. 1271-6 (Jun 1999) ISSN: 0022-3565 [Print] United States
PMID10336516 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Analgesics
  • Heterocyclic Compounds, 3-Ring
  • Nerve Growth Factors
  • Proto-Oncogene Proteins
  • Receptors, Nerve Growth Factor
  • ALE 0540
  • Morphine
  • Receptor Protein-Tyrosine Kinases
  • Receptor, trkA
Topics
  • Analgesics (administration & dosage, pharmacology)
  • Animals
  • Cells, Cultured
  • Chick Embryo
  • Dose-Response Relationship, Drug
  • Ganglia, Spinal (cytology, physiology)
  • Heterocyclic Compounds, 3-Ring (administration & dosage, pharmacology)
  • Hot Temperature
  • Inflammation
  • Injections, Intraperitoneal
  • Injections, Spinal
  • Mice
  • Morphine (pharmacology)
  • Nerve Growth Factors (metabolism)
  • Neuralgia (physiopathology, prevention & control)
  • Neurites (drug effects, physiology)
  • Neurons, Afferent (drug effects, physiology)
  • Pain (physiopathology, prevention & control)
  • Phosphorylation
  • Proto-Oncogene Proteins (antagonists & inhibitors, metabolism)
  • Radioligand Assay
  • Rats
  • Receptor Protein-Tyrosine Kinases (antagonists & inhibitors, metabolism)
  • Receptor, trkA
  • Receptors, Nerve Growth Factor (antagonists & inhibitors, metabolism)
  • Spinal Cord (drug effects, physiology)
  • Spinal Nerves (drug effects, physiology)

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