TY - JOUR
T1 - Characterization of antiallodynic actions of ALE-0540, a novel nerve growth factor receptor antagonist, in the rat
AU - Owolabi, Joshua B.
AU - Rizkalla, Geihan
AU - Tehim, Ashok
AU - Ross, Gregory M.
AU - Riopelle, Richard J.
AU - Kamboj, Rajender
AU - Ossipov, Michael
AU - Bian, Di
AU - Wegert, Sandara
AU - Porreca, Frank
AU - Lee, David K.H.
PY - 1999/6
Y1 - 1999/6
N2 - 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.
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 (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.
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M3 - Article
C2 - 10336516
AN - SCOPUS:0033035408
SN - 0022-3565
VL - 289
SP - 1271
EP - 1276
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
IS - 3
ER -