Nguyen, Eileen
(2021)
Kappa opioid signaling in the brainstem and spinal cord for itch and pain.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
This is the latest version of this item.
Abstract
In the following dissertation I examine two of my primary studies that highlight the importance of opioid balance in itch and pain. In particular, these two studies focus on neurons that participate in kappa-opioid receptor signaling. In Part I, I describe the role of dynorphin spinal cord neurons in the modulation of itch. In Part II, I focus on neurons in the brainstem containing the kappa-opioid receptor and their role in the modulation of itch and pain.
In Part I, I discuss the role of neurons in the spinal cord that participate in kappa signaling that are modulated by mu agonists such as morphine. For this study, we used animal models and found that neuraxial morphine causes itch through spinal neurons and not mast cells. In particular, we found that spinal dynorphin (Pdyn) neurons are both necessary and sufficient for morphine-induced itch in mice. Agonism of the kappa-opioid receptor alleviated morphine-induced itch in mice and nonhuman primates. Thus, our work revealed that morphine causes itch through a mechanism of disinhibition of a kappa-sensitive pathway within the spinal cord. This mechanism, in which a mu agonist reduces the impact of endogenous dynorphin, is illustrative of the delicate balance between mu and kappa tone that, when accidentally disrupted, elicits abnormal itch sensations.
In Part II, I describe a cellular circuit involving brainstem neurons containing the kappa-opioid receptor that inhibits pain and itch in mice. Using a combination of molecular, tracing, and behavioral approaches, we found that spinally-projecting neurons in the medulla containing the kappa-opioid receptor inhibit itch and pain. With chemogenetic inhibition, we determined that these neurons are required for stress-induced analgesia. Furthermore, we found a dynorphinergic pathway arising from the midbrain that modulates nociception within the medulla. These discoveries highlight the role of kappa signaling in the brainstem modulate itch and pain.
Thus, both investigations, centered in the brainstem and in the spinal cord, emphasize the importance the balance between endogenous opioids in normal somatosensory functions.
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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: |
11 April 2021 |
| Defense Date: |
9 July 2021 |
| Approval Date: |
17 September 2021 |
| Submission Date: |
10 August 2021 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
293 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Neurobiology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
opioids, kappa opioid receptor, mu opioid receptor, itch, pain, descending modulation, spinal cord, somatosensation, dynorphin, opioid-induced pruritus, rostral ventromedial medulla, RVM |
| Date Deposited: |
17 Sep 2021 13:19 |
| Last Modified: |
17 Sep 2021 13:19 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/41702 |
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