RT Journal Article
SR Electronic
T1 Characterization of Antiallodynic Actions of ALE-0540, a Novel Nerve Growth Factor Receptor Antagonist, in the Rat
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 1271
OP 1276
VO 289
IS 3
A1 Joshua B. Owolabi
A1 Geihan Rizkalla
A1 Ashok Tehim
A1 Gregory M. Ross
A1 Richard J. Riopelle
A1 Rajender Kamboj
A1 Michael Ossipov
A1 Di Bian
A1 Sandara Wegert
A1 Frank Porreca
A1 David K. H. Lee
YR 1999
UL http://jpet.aspetjournals.org/content/289/3/1271.abstract
AB 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 (IC505.88 ± 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 A50values (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. The American Society for Pharmacology and Experimental Therapeutics