Synapse-specific Opioid Modulation of Thalamo-cortico-striatal Circuits

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Abstract

The medial thalamus (MThal), anterior cingulate cortex (ACC) and striatum play important roles in affective-motivational pain processing and reward learning. Opioids affect both pain and reward through uncharacterized modulation of this circuitry. This study examined opioid actions on glutamate transmission between these brain regions in mouse. Mu-opioid receptor (MOR) agonists potently inhibited MThal inputs without affecting ACC inputs to individual striatal medium spiny neurons (MSNs). MOR activation also inhibited MThal inputs to the pyramidal neurons in the ACC. In contrast, delta-opioid receptor (DOR) agonists disinhibited ACC pyramidal neuron responses to MThal inputs by suppressing local feed-forward GABA signaling from parvalbumin-positive interneurons. As a result, DOR activation in the ACC facilitated poly-synaptic (thalamo-cortico-striatal) excitation of MSNs by MThal inputs. These results suggest that opioid effects on pain and reward may be shaped by the relative selectivity of opioid drugs to the specific circuit components.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files. All code and data are deposited in https://gitlab.com/maolab/opi_syn_circuit. ecfa1f13.

Article and author information

Author details

William T Birdsong

Vollum Institute, Oregon Health and Science University, Portland, United States

For correspondence
wtbird@med.umich.edu

Competing interests
The authors declare that no competing interests exist.
Bart C Jongbloets

Vollum Institute, Oregon Health and Science University, Portland, United States

Competing interests
The authors declare that no competing interests exist.
Kim A Engeln

Vollum Institute, Oregon Health and Science University, Portland, United States

Competing interests
The authors declare that no competing interests exist.
Dong Wang

Department of Anesthesiology, Perioperative and Pain Medicine, Department of Molecular and Cellular Physiology, Department of Neurosurgery, Stanford University, Palo Alto, United States

Competing interests
The authors declare that no competing interests exist.
Gregory Scherrer

Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Palo Alto, United States

Competing interests
The authors declare that no competing interests exist.
Tianyi Mao

Vollum Institute, Oregon Health and Science University, Portland, United States

For correspondence
mao@ohsu.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-3532-8319

Funding

National Institute of Neurological Disorders and Stroke (R01NS081071)

Tianyi Mao

New York Stem Cell Foundation

Gregory Scherrer

National Institute on Drug Abuse (R01DA042779)

William T Birdsong

National Institute on Drug Abuse (R01DA044481)

Gregory Scherrer

National Institute on Drug Abuse (R01NS106301)

Gregory Scherrer

National Institute of Neurological Disorders and Stroke (R01NS104944)

Tianyi Mao

National Institute of Neurological Disorders and Stroke (U01NS094247)

Tianyi Mao

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All procedures were approved by Oregon Health & Science University Institutional Animal Care and Use Committee (IACUC) and all experiments were performed strictly according the approved protocols. IACUC protocol IP00000955, and Institutional Biosafety Committee protocol IBC-10-40.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.