Abstract

Recently radiolabeled dihydropyridines (DHP's) such as 3H-nitrendipine have been used to identify voltage sensitive calcium channels (VSCC) in many tissues including the brain. Howver, to date VSCC in the brain have been found to be insensitive to such drugs. Thus, the function of the brain DHP receptor is in question at this time. We have identified several neuronal cell lines that do possess VSCC that are blocked by DHP's. We have utilized these cells to identify novel DHP's and toxins (e.g., maitotoxin) that activate VSCC. We propose to examine the properties of VSCC in primary cultures of authentic neurones from the central and peripheral nervous systems. In order to do this, we have devised a specialized microspectrofluorometer capable of analyzing fluorescent signals from single neurones. When cultured neurones such as dorsal root ganglia cells are loaded with the Ca+2 chelating dye, quin-2 they emit a signal which is proportional to the intracellular free [Ca+2]. Thus, on stimulation of the neurone, the influx of Ca+2 via VSCC can be detected as a fluorescent signal. Using this system, we shall analyze the interaction of drugs with VSCC in authentic neurones. In addition, we shall analyze the ability of opiates to mobilize [Ca+2]in in certain neurones.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH040165-02
Application #
3378203
Study Section
(BPNB)
Project Start
1985-06-01
Project End
1988-05-31
Budget Start
1986-06-01
Budget End
1987-05-31
Support Year
2
Fiscal Year
1986
Total Cost
Indirect Cost

  Institution

Name
University of Chicago
Department
Type
Schools of Medicine
DUNS #
225410919
City
Chicago
State
IL
Country
United States
Zip Code
60637

  Publications

White, Fletcher A; Miller, Richard J (2010) Insights into the regulation of chemokine receptors by molecular signaling pathways: functional roles in neuropathic pain. Brain Behav Immun 24:859-65
Thomas, Ajit G; Bodner, Amos; Ghadge, Ghanashyam et al. (2009) GCP II inhibition rescues neurons from gp120IIIB-induced neurotoxicity. J Neurovirol 15:449-57
Bhangoo, Sonia K; Ripsch, Matthew S; Buchanan, David J et al. (2009) Increased chemokine signaling in a model of HIV1-associated peripheral neuropathy. Mol Pain 5:48
Abbadie, Catherine; Bhangoo, Sonia; De Koninck, Yves et al. (2009) Chemokines and pain mechanisms. Brain Res Rev 60:125-34
White, Fletcher A; Feldman, Polina; Miller, Richard J (2009) Chemokine signaling and the management of neuropathic pain. Mol Interv 9:188-95
Miller, Richard J; Jung, Hosung; Bhangoo, Sonia K et al. (2009) Cytokine and chemokine regulation of sensory neuron function. Handb Exp Pharmacol :417-49
Jung, Hosung; Miller, Richard J (2008) Activation of the nuclear factor of activated T-cells (NFAT) mediates upregulation of CCR2 chemokine receptors in dorsal root ganglion (DRG) neurons: a possible mechanism for activity-dependent transcription in DRG neurons in association with neuropathic Mol Cell Neurosci 37:170-7
Bhangoo, Sonia; Ren, Dongjun; Miller, Richard J et al. (2007) Delayed functional expression of neuronal chemokine receptors following focal nerve demyelination in the rat: a mechanism for the development of chronic sensitization of peripheral nociceptors. Mol Pain 3:38
White, Fletcher A; Jung, Hosung; Miller, Richard J (2007) Chemokines and the pathophysiology of neuropathic pain. Proc Natl Acad Sci U S A 104:20151-8
Tran, Phuong B; Ren, Dongjun; Miller, Richard J (2005) The HIV-1 coat protein gp120 regulates CXCR4-mediated signaling in neural progenitor cells. J Neuroimmunol 160:68-76

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