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Mol Pain. 2011 Mar 30;7:22. doi: 10.1186/1744-8069-7-22.

Ret-dependent and Ret-independent mechanisms of Gfl-induced sensitization.

Author information

1
Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana, 46202, USA. bschmutz@iupui.edu

Abstract

BACKGROUND:

The GDNF family ligands (GFLs) are regulators of neurogenic inflammation and pain. We have previously shown that GFLs increase the release of the sensory neuron neuropeptide, calcitonin gene-related peptide (CGRP) from isolated mouse DRG.

RESULTS:

Inhibitors of the mitogen-activated protein kinase (MAPK) pathway abolished the enhancement of CGRP release by GDNF. Neurturin-induced enhancement in the stimulated release of CGRP, used as an indication of sensory neuronal sensitization, was abolished by inhibition of the phosphatidylinositol-3 kinase (PI-3K) pathway. Reduction in Ret expression abolished the GDNF-induced sensitization, but did not fully inhibit the increase in stimulus-evoked release of CGRP caused by neurturin or artemin, indicating the presence of Ret-independent GFL-induced signaling in sensory neurons. Integrin β-1 and NCAM are involved in a component of Ret-independent GFL signaling in sensory neurons.

CONCLUSIONS:

These data demonstrate the distinct and variable Ret-dependent and Ret-independent signaling mechanisms by which GFLs induce sensitization of sensory neurons. Additionally, there is a clear disconnect between intracellular signaling pathway activation and changes in sensory neuronal function.

PMID:
21450093
PMCID:
PMC3078874
DOI:
10.1186/1744-8069-7-22
[Indexed for MEDLINE]
Free PMC Article

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