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.