Holland, Ruby A.
(2023)
Midbrain Kappa Opioid Receptor-Expressing Neurons Modulate Multiple Dimensions of Opioid Withdrawal.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Opioid withdrawal is a multidimensional, whole-body response to the abrupt cessation of chronic opioids. Treatment options are limited, and the distressing, debilitating symptoms of opioid withdrawal represent a significant barrier to recovery from opioid use disorder. It is believed that opioids promote withdrawal through the adaptation of aversive signals to counteract hyperactive reward systems. However, much remains unclear about the neural circuits influenced by opioids due to the varying actions of opioids on the broadly expressed delta, mu, and kappa opioid receptors. Recently, the kappa opioid receptor (KOR) and its endogenous ligand dynorphin have gained special attention for their roles in aversive states such as stress and chronic pain, particularly through acting on neurons emanating from the ventral tegmental area (VTA). However, less is known about the anatomy of VTA neurons which express KOR (VTAKOR neurons) or the projection-specific contributions of VTAKOR neurons to the aversive, negative affective, and autonomic effects of opioid withdrawal. To address these gaps in knowledge, we utilized a combination of genetic, physiological, and behavioral approaches to selectively target VTAKOR neurons in vivo. Through a combination of cre-dependent viral tracing, immunohistochemistry, and RNAscope FISH, we found that VTAKOR neurons express multiple neurotransmitters and project to distinct regions throughout the forebrain, midbrain, and hindbrain. Chronic opioids increase dynorphin expression in VTA input regions, decrease morphine-induced neuronal activation in the VTA, and alter the firing properties of VTAKOR neurons and their inputs. Consistent with this, chemogenetic activation of VTAKOR neurons attenuated withdrawal-associated behaviors such as jumping, shakes and tremors, body weight loss, diarrhea, and urination, indicating VTAKOR neural inhibition is necessary in opioid withdrawal symptoms. Chemogenetic activation of VTAKOR neurons also abolished withdrawal-induced conditioned place aversion and attenuated withdrawal-associated anxiety-like and depressive-like behaviors. When we selectively activated VTAKOR neurons projecting to the ventrolateral periaqueductal gray (VTAvlPAGKOR neurons), withdrawal-associated body weight loss, diarrhea, and urination were selectively attenuated. Taken together, these results demonstrate that chronic opioids inhibit the activity of VTAKOR neurons, and that this inhibition is necessary for the precipitation of withdrawal. Furthermore, these results highlight the critical role of central midbrain mechanisms by which opioids modulate the gastrointestinal system.
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Details
| Item Type: |
University of Pittsburgh ETD
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| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
| Title | Member | Email Address | Pitt Username | ORCID |
|---|
| Thesis Advisor | Ross, Sarah E. | saross@pitt.edu | | | | Committee Chair | Koerber, H. Richard | | | | | Committee Member | Grace, Anthony | | | | | Committee Member | Gold, Michael S. | | | | | Committee Member | Torregrossa, Mary | | | |
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| Date: |
8 December 2023 |
| Date Type: |
Publication |
| Defense Date: |
6 July 2023 |
| Approval Date: |
8 December 2023 |
| Submission Date: |
18 August 2023 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
134 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Neurobiology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
opioid withdrawal, kappa opioid receptor, ventral tegmental area, periaqueductal gray |
| Date Deposited: |
08 Dec 2023 19:41 |
| Last Modified: |
08 Dec 2023 19:41 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/45352 |
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