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THE IMPACT OF INFLAMMATION ON THE REGULATION OF INTRACELLULAR CALCIUM IN CUTANEOUS NOCICEPTIVE NEURONS

Scheff, Nicole (2014) THE IMPACT OF INFLAMMATION ON THE REGULATION OF INTRACELLULAR CALCIUM IN CUTANEOUS NOCICEPTIVE NEURONS. Doctoral Dissertation, University of Pittsburgh.

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Abstract

The most effective way to treat clinical pain is to target the subpopulation of primary afferent neurons responsible. However, clinical pain is heterogeneous, reflecting, in part, differences in the relative contribution of different subpopulations of afferents. The functional heterogeneity of primary afferents is reflected in the heterogeneous regulation of intracellular Ca2+ ([Ca2+]i). Because the regulation of [Ca2+]i contributes to neuronal function, injury-induced changes in neuronal function may be due to dysregulation in the regulation of [Ca2+]i. Thus, the persistent inflammation-induced increase in the magnitude and duration of depolarization-evoked Ca2+ transient in a subset of putative nociceptive cutaneous DRG neurons served as the focus of this thesis. I first ruled out the contribution of Ca2+-induced Ca2+ release to the inflammation-induced increase in the evoked Ca2+ transient. Results of these experiments also indicated the presence of tightly segregated Ca2+ regulatory domains where Ca2+ transients evoked via Ca2+ influx and release from intracellular stores are functionally isolated. Parametric analysis demonstrated that inflammation-induced changes in evoked Ca2+ had a high threshold for activation, thus I focused on low affinity Ca2+ extrusion mechanism, Na+/Ca2+ exchanger (NCX). I demonstrated that NCX regulates the decay of the evoked transient in the same subset of putative nociceptive afferents modified by inflammation, and can influence axonal [Ca2+]i levels, resting membrane potential, and nociceptive threshold. Finally, I confirmed a role for NCX in response to persistent inflammation, such that the increase in the duration of the evoked transient is due to a loss of NCX in the cell body due to an increase in unidirectional NCX3 trafficking to the peripheral terminals. These observations serve as the basis for my current working hypothesis that the inflammation-induced changes in trafficking of NCX3, underlie three major aspects of the inflammatory response: an increase in transmitter release from the central terminal to contribute to inflammatory hyperalgesia, a change in gene expression secondary to altered Ca2+ transients in the cell body, and a decrease in the neurogenic inflammatory response in the periphery secondary to a decrease in transmitter release. Increasing NCX function may be a potentially novel therapeutic strategy for treatment of inflammatory pain.


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Details

Item Type: University of Pittsburgh ETD
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Scheff, Nicolenns6@pitt.eduNNS6
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorGold, Michaelmsg22@pitt.eduMSG22
Committee ChairGebhart, Geraldgebhartgf@upmc.edu
Committee MemberDavis, Brian Mbmd1@pitt.eduBMD1
Committee MemberMeriney, Stevemeriney@pitt.eduMERINEY
Committee Memberde Groat, William Cwcd2@pitt.eduWCD2
Committee MemberUsachev, Yuriyyuriy-usachev@uiowa.edu
Date: 7 August 2014
Date Type: Publication
Defense Date: 26 June 2014
Approval Date: 7 August 2014
Submission Date: 7 August 2014
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Number of Pages: 189
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Neurobiology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Pain, Nociceptor, Na+/Ca2+ exchanger, Heterogeneity, Calcium, Inflammation
Date Deposited: 07 Aug 2014 17:29
Last Modified: 15 Nov 2016 14:23
URI: http://d-scholarship.pitt.edu/id/eprint/22647

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