2005 Fiscal Year Final Research Report Summary
Development of new therapeutics for pain, based on the suppression of tyrosine kinase activity
| Project/Area Number |
16591554
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Anesthesiology/Resuscitation studies
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| Research Institution | Kyoto Prefectural University of Medicine |
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Principal Investigator |
HIROSE Munetaka Kyoto Prefectural University of Medicine, Anesthesiology, Instructor, 医学研究科, 助手 (50275228)
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| Project Period (FY) |
2004 – 2005
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| Keywords | Tyrosine kinase / Local anesthetic / Nerve growth factor / TrkA / Lidocaine / Hyperalgesia / Autophosphorylation / PC12 |
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| Research Abstract |
TrkA and TrkB, which are the receptors of nerve growth factor(NGF) produced in the peripheral tissue and brain-derived neurotrophic factor(BDNF) as a neurotransmitter, reportedly plays a pivotal role for development of pain. NGF binding to extracellular portion of TrkA leads to autophosphorylation of five different tyrosine residues, located in the juxamembrane domain (Y490), in the activation loop of tyrosine kinase domain (Y670, Y674, Y675), and in the C-terminal (Y785). Amino acid sequences of activation loop including these three tyrosine residues (Y670, Y674, Y675) in TrkA reveal homology with those of the insulin receptor, which are the target of the inhibitory effect of lidocaine on the insulin receptor tyrosine kinase activity. I hypothesized that local anesthetics inhibit NGF-stimulated tyrosine kinase activity of TrkA and suppress NGF signaling. The present study investigated the effect of local anesthetics, lidocaine, bupivacaine, and procaine (40 μM, 400 μM and 4000 μM), on NGF signaling using PC 12 cell line derived from rat pheochoromocytoma, which is a useful model for studying NGF signaling and sympathetic sprouting.
Both 400 μM and 4000 μM of lidocaine significantly attenuated NGF-stimulated tyrosine phosphorylation of TrkA in PC 12 cells and also suppressed the increase of neurite bearing cells stimulated by NGF. Over 40 μM of bupivacaine and 4000 μM of procaine suppressed both NGF-stimulated tyrosine phosphorylation of TrkA and the increase of neurite bearing cells stimulated by NGF. Only 4000 μM of lidocaine and bupivacaine had cytotoxic effect on PC 12 cells. idocaine (400 μM) corresponds to the concentration around or in the peripheral nerve after local administration. The inhibition of TrkA activity might be involved in the mechanism of the suppression of chronic pain by local anesthetics.
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