Abstract
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.
Footnotes
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Send reprint requests to: Joshua B. Owolabi, Ph.D., 81 Hinchleywood Grove, Brampton, Ontario, Canada L6V 4B1. E-mailowolabi{at}sprint.ca
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↵1 This work was supported by Allelix Biopharmaceuticals, Inc.
- Abbreviations:
- NGF
- nerve growth factor
- BDNF
- brain-derived growth factor
- Trk
- tyrosine kinase
- ET
- endothelin
- i.th.
- intrathecal
- i.c.v.
- intracerebroventricular
- CGRP
- calcitonin gene-related peptide
- CI
- confidence interval
- PE
- polyethylene tubing
- L5/6
- fifth and sixth lumber nerves
- DRG
- dorsal root ganglia
- 5-HT
- hydroxytryptamine
- Received October 22, 1998.
- Accepted February 17, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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