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 (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.
Owolabi
J B
JB
Allelix Biopharmaceuticals Inc., Mississauga, Canada. owalabi@sprint.ca
Rizkalla
G
G
Tehim
A
A
Ross
G M
GM
Riopelle
R J
RJ
Kamboj
R
R
Ossipov
M
M
Bian
D
D
Wegert
S
S
Porreca
F
F
Lee
D K
DK
D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D002642:Chick Embryo; D004305:Dose-Response Relationship, Drug; D005727:Ganglia, Spinal / Q000166:cytology / Q000502:physiology; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage / Q000494:pharmacology*; D006358:Hot Temperature; D007249:Inflammation; D007274:Injections, Intraperitoneal; D007278:Injections, Spinal; D051379:Mice; D009020:Morphine / Q000494:pharmacology; D009414:Nerve Growth Factors / Q000378:metabolism; D009437:Neuralgia / Q000503:physiopathology* / Q000517:prevention & control; D016501:Neurites / Q000187:drug effects / Q000502:physiology; D009475:Neurons, Afferent / Q000187:drug effects / Q000502:physiology*; D010146:Pain / Q000503:physiopathology* / Q000517:prevention & control; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020917:Receptor, trkA; D017475:Receptors, Nerve Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000502:physiology; D013127:Spinal Nerves / Q000187:drug effects / Q000502:physiology
D000700:Analgesics; D006575:Heterocyclic Compounds, 3-Ring; D009414:Nerve Growth Factors; D011518:Proto-Oncogene Proteins; D017475:Receptors, Nerve Growth Factor; C119320:ALE 0540; D009020:Morphine; D020794:Receptor Protein-Tyrosine Kinases; D020917:Receptor, trkA