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

Joshua B. Owolabi, Geihan Rizkalla, Ashok Tehim, Gregory M. Ross, Richard J. Riopelle, Rajender Kamboj, Michael Ossipov, Di Bian, Sandara Wegert, Frank Porreca, David K.H. Lee

Research output: Contribution to journalArticlepeer-review

102 Scopus citations

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 μM, 3.72 ± 1.3 μM, 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) μg, respectively. ALE-0540 given i.th., at doses of 30 and 60 μg, 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.

Original languageEnglish (US)
Pages (from-to)1271-1276
Number of pages6
JournalJournal of Pharmacology and Experimental Therapeutics
Volume289
Issue number3
StatePublished - Jun 1 1999

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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