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Molecular mechanisms of phenotypic change in intact nociceptors

Soneji, Deepak Jyotindra (2012) Molecular mechanisms of phenotypic change in intact nociceptors. Doctoral Dissertation, University of Pittsburgh.

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Abstract

We have previously shown that regenerated cutaneous afferents exhibit sensitization. These changes were correlated with increased expression of neurotrophic factors in the affected skin, and receptors and ion channels in the dorsal root ganglia (DRG). Here we found that saphenous nerve injury resulted in similar alterations in gene expression in the skin innervated by the uninjured contralateral saphenous nerve. Several Nerve Growth Factor (NGF) and GDNF ligands were upregulated in the dorsal hindpaw hairy skin 7-21 days following contralateral saphenous nerve axotomy. This increase in expression was correlated with upregulation of several receptors and ion channels in the L2,3 DRGs, including GFRα1, nucleotide receptors P2X3, P2Y1, and P2Y2, heat transducing channel TRPV1, and acid-sensing ion channels 1 (ASIC1) and 3 (ASIC3). Characterization of intact saphenous afferent fibers revealed that 4-5 weeks after contralateral injury, C-polymodal population had significantly reduced heat thresholds. There was also a significant increase in the proportion of mechanically insensitive-heat sensitive (CH) neurons. These findings provide evidence of peripheral mechanisms that may be involved in the development of mirror-image pain, a clinical phenomenon in which patients experience pain in the healthy region of the body contralateral to the injury site. The changes in the response properties of intact afferents at 4-5 weeks following contralateral injury were correlated with upregulation of P2Y1 and TRPV1 in the DRGs at 28d post-injury, and we investigated the role of these two targets in the functional plasticity observed by utilizing an in vivo small interfering RNA (siRNA)-mediated knockdown strategy to target the upregulation of P2Y1 and TRPV1 in the L2,3 DRGs at 28 days following contralateral injury. We found that blocking P2Y1 upregulation prevented the heat threshold reduction in C-polymodal afferents and conclude that P2Y1 plays a critical role in the heat sensitivity of these fibers. We then found that blocking the upregulation of TRPV1 blocked the recruitment of C-heat fibers. Taken together, our findings suggest that chronic exposure of intact cutaneous sensory neurons to increased endogenous levels of neurotrophic factors results in upregulation of target receptors and ion channels in the DRG and sensitization and phenotypic changes in intact sensory neurons.


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Details

Item Type: University of Pittsburgh ETD
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Soneji, Deepak Jyotindradjs54@pitt.eduDJS54
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorKoerber, H Richardrkoerber@pitt.eduRKOERBER
Committee ChairDavis, Brian Mbmd1@pitt.eduBMD1
Committee MemberAlbers, Kathryn Mkaa2@pitt.eduKAA2
Committee MemberCard, J Patrickcard@pitt.eduCARD
Committee MemberKolber, Benedict Jkolberb@duq.edu
Committee MemberMolliver, Derek Cdcm12@pitt.eduDCM12
Date: 17 December 2012
Date Type: Publication
Defense Date: 3 December 2012
Approval Date: 17 December 2012
Submission Date: 13 December 2012
Release Date: 17 December 2012
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 126
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Neurobiology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: neurotrophic factor; neurotrophin; nociceptor; pain; siRNA; RNA interference; mirror image pain; dorsal root ganglion; sensory neuron; purinergic; P2Y1; TRPV1
Date Deposited: 17 Dec 2012 17:28
Last Modified: 15 Nov 2016 14:08
URI: http://d-scholarship.pitt.edu/id/eprint/16905

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