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

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 (Tr k) A or both p75 and TrkA (IC50 5.88 +/- 1.87 mu M, 3.72 +/- 1.3 mu M, resp ectively), as well as signal transduction and biological responses mediated by TrkA receptors. ALE-0540 was tested in models of neuropathic pain and t hermally-induced inflammatory pain, using two routes of administration, a s ystemic i.p. and a spinal intrathecal (i.th.) route. Morphine was also test ed for comparison in the antiallodynia model using mechanical stimuli. We s how that either i.p. or i.th. administration of ALE-0540 in rats produced a ntiallodynia in the L5/L6 ligation model of neuropathic pain. The calculate d A(50) values land 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) mu g, respectively . ALE-0540 given i.th., at doses of 30 and 60 mu g, also blocked tactile al lodynia in the thermal sensitization model. Although morphine displayed gre ater potency [A(50) value of 7.1 (5.6-8.8) mg/kg] than ALE-0540 in anti-all odynic 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 u sing a NGF receptor antagonist is capable of blocking neuropathic and infla mmatory pain and further support the hypothesis that NGF is involved in sig naling pathways associated with these pain states. ALE-0540 represents a no npeptidic small molecule which can be used to examine mechanisms leading to the development of agents for the treatment of pain.