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Modulation of Multiple Modalities of Somatosensory Information by Peripheral Kappa Opioid Receptors

Snyder, Lindsey (2017) Modulation of Multiple Modalities of Somatosensory Information by Peripheral Kappa Opioid Receptors. Doctoral Dissertation, University of Pittsburgh.

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Abstract

Peripherally-restricted kappa opioid receptor (KOR) agonists are emerging as a novel treatment for pain and itch conditions and have shown efficacy in several recent clinical trials. One primary site of action is thought to be at KORs on primary afferent nerves that innervate the body. Yet, the subtypes of primary afferent somatosensory neurons that express the kappa opioid receptor remain undefined. Using a newly developed KOR-cre knockin allele, viral tracing, and single-cell RT-PCR we discovered that that KOR is expressed in a specific subset of peptidergic afferents. This subset targeted multiple tissue types and expressed higher levels of transcripts known to be involved in neurogenic inflammation. Consistent with this, peripherally-restricted KOR agonists inhibited behavioral responses to chemical pain and itch stimuli, but not acute heat stimuli, and also decreased mechanical hypersensitivity following an incision injury. Unexpectedly, we also found that KOR is expressed in subsets of primary afferents that form lanceolate or circumferential endings around hair follicles, suggesting an unappreciated role for KOR signaling in the modulation of low-threshold mechanosensation. At a functional level, genetically-labeled afferents showed inhibition of voltage-gated calcium current in response to kappa agonists, and optogenetic experiments revealed that dynorphin inhibited evoked-EPSCs from the central terminals of KOR-expressing afferents. These experiments provide key insight for the rationale use of peripherally-restricted KOR agonists for the modulation of inflammatory pain, itch, and potentially mechanical allodynia.


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Details

Item Type: University of Pittsburgh ETD
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Snyder, Lindseymccleml@pitt.edumccleml
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairKoerber, H. Richardrkoerber@pitt.edu
Thesis AdvisorRoss, Sarahsaross@pitt.edu
Committee MemberUrban, Nathannurban@pitt.edu
Committee MemberDavis, Brianbmd1@pitt.edu
Committee MemberGold, Michaelmsg22@pitt.edu
Committee MemberKolber, Benedictkolberb@duq.edu
Date: 31 August 2017
Date Type: Publication
Defense Date: 25 July 2017
Approval Date: 31 August 2017
Submission Date: 17 August 2017
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 130
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 Itch Kappa Opioid Receptors
Date Deposited: 31 Aug 2017 19:45
Last Modified: 31 Aug 2017 19:45
URI: http://d-scholarship.pitt.edu/id/eprint/33114

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