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RET-DEPENDENT AND RET-INDEPENDENT MECHANISMS OF GFL-INDUCED ENHANCEMENT IN THE CAPSAICIN STIMULATED-RELEASE OF iCGRP FROM SENSORY NEURONS

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dc.contributor.advisor Hingtgen, Cynthia M en_US
dc.contributor.author Schmutzler, Brian en_US
dc.date.accessioned 2010-06-16T17:50:23Z
dc.date.available 2011-05-14T11:57:17Z
dc.date.issued 2010-06-16T17:50:23Z
dc.date.submitted 2009 en_US
dc.identifier.uri http://hdl.handle.net/2022/8798
dc.description Thesis (Ph.D.) - Indiana University, Pharmacology & Toxicology, 2009 en_US
dc.description.abstract The glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) are peptides implicated in the inflammatory response. They are released in increased amounts during inflammation and induce thermal hyperalgesia. Whether these molecules directly affect the sensitivity of primary nociceptive sensory neurons is unknown. This information could provide a link between increased inflammation-induced release of GFLs and their ability to promote inflammatory hyperalgesia. These molecules bind to one of four GFRα receptor subtypes, and this GFL-GFRα complex often translocates to the receptor tyrosine kinase, Ret. The focus of this dissertation was to determine whether GFLs modulate the stimulated-release of calcitonin gene-related peptide (CGRP). Isolated sensory neurons and freshly dissociated spinal cord tissue were used to examine the enhancement in stimulated-release of CGRP, a measure of sensitization. Exposure of isolated sensory neurons to GDNF, neurturin, and artemin, enhanced the capsaicin stimulated-release of immunoreactive CGRP (iCGRP). Sensitization by GFLs occurred in freshly dissociated spinal cord tissue. Persephin, another member of the GFL family, did not enhance stimulated-release of iCGRP. These results demonstrate that specific GFLs are mediators of neuronal sensitivity. The intracellular signaling pathways responsible for this sensitization were also evaluated. Inhibition of the mitogen activated protein kinase (MAPK)/extracellular signal-related kinase 1/2 (Erk 1/2) pathway selectively abolished the enhancement of CGRP release by GDNF. NTN-induced sensitization was abolished by inhibition of the phosphatidylinositol-3-kinase (PI-3K) pathway. Reduction in Ret abolished the GDNF-induced sensitization, but did not fully inhibit NTN or ART-induced sensitization. Inhibition of other cell surface receptors (neural cell adhesion molecule (NCAM), and Integrin β-1) had distinct effects on the sensitization capability of each of the GFLs. Ret and NCAM inhibition in combination abolished ART-induced sensitization. It was necessary to inhibit Ret, NCAM, and Integrin β-1 to prevent the NTN-induced sensitization. These data demonstrate that the GFLs use distinct signaling mechanisms to induce the sensitization of nociceptive sensory neurons. The work presented in this thesis provides the first evidence for these novel and distinct Ret-independent pathways for GFL-induced actions and provides insight into the mechanism of sensory neuronal sensitization in general. en_US
dc.language.iso EN en_US
dc.publisher [Bloomington, Ind.] : Indiana University en_US
dc.subject artemin en_US
dc.subject CGRP en_US
dc.subject DRG en_US
dc.subject GDNF en_US
dc.subject neurturin en_US
dc.subject sensory neuron en_US
dc.subject.classification Neurobiology en_US
dc.title RET-DEPENDENT AND RET-INDEPENDENT MECHANISMS OF GFL-INDUCED ENHANCEMENT IN THE CAPSAICIN STIMULATED-RELEASE OF iCGRP FROM SENSORY NEURONS en_US
dc.type Doctoral Dissertation en_US


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