BOLD Imaging in Awake Wild-Type and Mu-Opioid Receptor Knock-Out Mice Reveals On-Target Activation Maps in Response to Oxycodone
Blood oxygen level dependent (BOLD) imaging in awake mice was used to identify differences in brain activity between wild-type, and Mu (µ) opioid receptor knock-outs (MuKO) in response to oxycodone (OXY). Using a segmented, annotated MRI mouse atlas and computational analysis, patterns of integrate...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2016-11-01
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| Series: | Frontiers in Neuroscience |
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| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fnins.2016.00471/full |
| _version_ | 1818112385251016704 |
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| author | Kelsey Moore Dan Madularu Sade Iriah Jason Richard Yee Praveen Kulkarni Emmanuel Darcq Brigitte L. Kieffer Craig F Ferris |
| author_facet | Kelsey Moore Dan Madularu Sade Iriah Jason Richard Yee Praveen Kulkarni Emmanuel Darcq Brigitte L. Kieffer Craig F Ferris |
| author_sort | Kelsey Moore |
| collection | DOAJ |
| description | Blood oxygen level dependent (BOLD) imaging in awake mice was used to identify differences in brain activity between wild-type, and Mu (µ) opioid receptor knock-outs (MuKO) in response to oxycodone (OXY). Using a segmented, annotated MRI mouse atlas and computational analysis, patterns of integrated positive and negative BOLD activity were identified across 122 brain areas. The pattern of positive BOLD showed enhanced activation across the brain in WT mice within 15 min of intraperitoneal administration of 2.5 mg of OXY. BOLD activation was detected in 72 regions out of 122, and was most prominent in areas of high µ opioid receptor density (thalamus, ventral tegmental area, substantia nigra, caudate putamen, basal amygdala and hypothalamus), and focus on pain circuits indicated strong activation in major pain processing centers (central amygdala, solitary tract, parabrachial area, insular cortex, gigantocellularis area, ventral thalamus primary sensory cortex and prelimbic cortex). Importantly, the OXY-induced positive BOLD was eliminated in MuKO mice in most regions, with few exceptions (some cerebellar nuclei, CA3 of the hippocampus, medial amygdala and preoptic areas). This result indicates that most effects of OXY on positive BOLD are mediated by the µ opioid receptor (on-target effects). OXY also caused an increase in negative BOLD in WT mice in few regions (16 out of 122) and, unlike the positive BOLD response the negative BOLD was only partially eliminated in the MuKO mice (cerebellum), and in some case intensified (hippocampus). Negative BOLD analysis therefore shows activation and deactivation events in the absence of the µ receptor for some areas where receptor expression is normally extremely low or absent (off-target effects). Together, our approach permits establishing opioid-induced BOLD activation maps in awake mice. In addition, comparison of WT and MuKO mutant mice reveals both on-target and off-target activation events, and set an OXY brain signature that should, in the future, be compared to other µ opioid agonists. |
| first_indexed | 2024-12-11T03:18:06Z |
| format | Article |
| id | doaj.art-48b6897ff42849e7afe66bbf280beaf4 |
| institution | Directory Open Access Journal |
| issn | 1662-453X |
| language | English |
| last_indexed | 2024-12-11T03:18:06Z |
| publishDate | 2016-11-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Neuroscience |
| spelling | doaj.art-48b6897ff42849e7afe66bbf280beaf42022-12-22T01:22:42ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2016-11-011010.3389/fnins.2016.00471218719BOLD Imaging in Awake Wild-Type and Mu-Opioid Receptor Knock-Out Mice Reveals On-Target Activation Maps in Response to OxycodoneKelsey Moore0Dan Madularu1Sade Iriah2Jason Richard Yee3Praveen Kulkarni4Emmanuel Darcq5Brigitte L. Kieffer6Craig F Ferris7Northeastern UniversityMcGill UniversityNortheastern UniversityNortheastern UniversityNortheastern UniversityMcGill UniversityMcGill UniversityNortheastern UniversityBlood oxygen level dependent (BOLD) imaging in awake mice was used to identify differences in brain activity between wild-type, and Mu (µ) opioid receptor knock-outs (MuKO) in response to oxycodone (OXY). Using a segmented, annotated MRI mouse atlas and computational analysis, patterns of integrated positive and negative BOLD activity were identified across 122 brain areas. The pattern of positive BOLD showed enhanced activation across the brain in WT mice within 15 min of intraperitoneal administration of 2.5 mg of OXY. BOLD activation was detected in 72 regions out of 122, and was most prominent in areas of high µ opioid receptor density (thalamus, ventral tegmental area, substantia nigra, caudate putamen, basal amygdala and hypothalamus), and focus on pain circuits indicated strong activation in major pain processing centers (central amygdala, solitary tract, parabrachial area, insular cortex, gigantocellularis area, ventral thalamus primary sensory cortex and prelimbic cortex). Importantly, the OXY-induced positive BOLD was eliminated in MuKO mice in most regions, with few exceptions (some cerebellar nuclei, CA3 of the hippocampus, medial amygdala and preoptic areas). This result indicates that most effects of OXY on positive BOLD are mediated by the µ opioid receptor (on-target effects). OXY also caused an increase in negative BOLD in WT mice in few regions (16 out of 122) and, unlike the positive BOLD response the negative BOLD was only partially eliminated in the MuKO mice (cerebellum), and in some case intensified (hippocampus). Negative BOLD analysis therefore shows activation and deactivation events in the absence of the µ receptor for some areas where receptor expression is normally extremely low or absent (off-target effects). Together, our approach permits establishing opioid-induced BOLD activation maps in awake mice. In addition, comparison of WT and MuKO mutant mice reveals both on-target and off-target activation events, and set an OXY brain signature that should, in the future, be compared to other µ opioid agonists.http://journal.frontiersin.org/Journal/10.3389/fnins.2016.00471/fullOxycodoneAddictionknockout mousemu-opioid receptorBOLD fMRIopioid receptors |
| spellingShingle | Kelsey Moore Dan Madularu Sade Iriah Jason Richard Yee Praveen Kulkarni Emmanuel Darcq Brigitte L. Kieffer Craig F Ferris BOLD Imaging in Awake Wild-Type and Mu-Opioid Receptor Knock-Out Mice Reveals On-Target Activation Maps in Response to Oxycodone Frontiers in Neuroscience Oxycodone Addiction knockout mouse mu-opioid receptor BOLD fMRI opioid receptors |
| title | BOLD Imaging in Awake Wild-Type and Mu-Opioid Receptor Knock-Out Mice Reveals On-Target Activation Maps in Response to Oxycodone |
| title_full | BOLD Imaging in Awake Wild-Type and Mu-Opioid Receptor Knock-Out Mice Reveals On-Target Activation Maps in Response to Oxycodone |
| title_fullStr | BOLD Imaging in Awake Wild-Type and Mu-Opioid Receptor Knock-Out Mice Reveals On-Target Activation Maps in Response to Oxycodone |
| title_full_unstemmed | BOLD Imaging in Awake Wild-Type and Mu-Opioid Receptor Knock-Out Mice Reveals On-Target Activation Maps in Response to Oxycodone |
| title_short | BOLD Imaging in Awake Wild-Type and Mu-Opioid Receptor Knock-Out Mice Reveals On-Target Activation Maps in Response to Oxycodone |
| title_sort | bold imaging in awake wild type and mu opioid receptor knock out mice reveals on target activation maps in response to oxycodone |
| topic | Oxycodone Addiction knockout mouse mu-opioid receptor BOLD fMRI opioid receptors |
| url | http://journal.frontiersin.org/Journal/10.3389/fnins.2016.00471/full |
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