Snyder, Lindsey
(2017)
Modulation of Multiple Modalities of Somatosensory Information by Peripheral Kappa Opioid Receptors.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
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
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| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| 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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