uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Molecular Adaptations in the Endogenous Opioid System in Human and Rodent Brain
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Molecular Neuropsychopharmacology)
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The aims of the thesis were to examine i) whether the endogenous opioid system (EOS) is lateralized in human brain areas involved in processing of emotions and pain; ii) whether EOS responses to unilateral brain injury depend on side of lesion, and iii) whether in human alcoholics, this system is involved in molecular adaptations in brain areas relevant for cognitive control of addictive behavior and habit formation.

The main findings were that (1) opioid peptides but not opioid receptors and classic neurotransmitters are markedly lateralized in the anterior cingulate cortex involved in processing of  positive and negative emotions and affective component of pain. The region-specific lateralization of neuronal networks expressing opioid peptides may underlie in part lateralization of higher functions in the human brain including emotions and pain. (2) Analysis of the effects of traumatic brain injury (TBI) demonstrated predominant alteration of dynorphin levels in the hippocampus ipsilateral to the injury, while injury to the right hemisphere affected dynorphin levels in the striatum and frontal cortex to a greater extent than that to the left hemisphere. Thus, trauma reveals a lateralization in the mechanisms mediating the response of dynorphin expressing neuronal networks in the brain. These networks may differentially mediate effects of left or right brain injury on lateralized brain functions. (3) In human alcoholics, the enkephalin and dynorphin systems were found to be downregulated in the caudate nucleus and / or putamen that may underlie in part changes in goal directed behavior and formation of a compulsive habit in alcoholics. In contrast to downregulation in these areas, PDYN mRNA and dynorphins in dorsolateral prefrontal cortex, k-opioid receptor mRNA in orbitofrontal cortex, and dynorphins in hippocampus were upregulated in alcoholics. Activation of the k-opioid receptor by upregulated dynorphins may underlie in part neurocognitive dysfunctions relevant for addiction and disrupted inhibitory control.

We conclude that the EOS exhibits region-specific lateralization in human brain and brain-area specific lateralized response after unilateral TBI in mice; and that the EOS is involved in adaptive processes associated with specific aspects of alcohol dependence.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. , 58 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 174
Keyword [en]
Endogenous Opioid System, Dynorphins, Lateralization, Alcohol Dependence, Emotions, Traumatic Brain Injury, Anterior Cingulate Cortex, Dorsal Striatum
National Category
Pharmaceutical Sciences
Research subject
Neuroscience
Identifiers
URN: urn:nbn:se:uu:diva-205133ISBN: 978-91-554-8729-4 OAI: oai:DiVA.org:uu-205133DiVA: diva2:640845
Public defence
2013-09-30, C8:305, Husargatan 3, BMC, Uppsala University, Uppsala, 13:30 (English)
Opponent
Supervisors
Available from: 2013-09-09 Created: 2013-08-14 Last updated: 2013-09-09
List of papers
1. Asymmetry of the Endogenous Opioid System in the Human Anterior Cingulate: a Putative Molecular Basis for Lateralization of Emotions and Pain
Open this publication in new window or tab >>Asymmetry of the Endogenous Opioid System in the Human Anterior Cingulate: a Putative Molecular Basis for Lateralization of Emotions and Pain
Show others...
2015 (English)In: Cerebral Cortex, ISSN 1047-3211, E-ISSN 1460-2199, Vol. 25, no 1, 97-108 p.Article in journal (Refereed) Published
Abstract [en]

Lateralization of processing of positive and negative emotions and pain suggests an asymmetric distribution of the neurotransmitter systems regulating these functions between the left and right brain hemispheres. By virtue of their ability to selectively mediate euphoria, dysphoria and pain, the m-, d- and k-opioid receptors and their endogenous ligands may subserve these lateralized functions. We addressed this hypothesis by comparing the levels of the opioid receptors and peptides in the left and right anterior cingulate cortex (ACC), a key area for emotion and pain processing. Opioid mRNAs and peptides and five “classical” neurotransmitters were analyzed in postmortem tissues from 20 human subjects. Leu-enkephalin-Arg and Met-enkephalin-Arg-Phe, preferential d-/m- and k-/m-opioid agonists demonstrated marked lateralization to the left and right ACC, respectively. Dynorphin B strongly correlated with Leu-enkephalin-Arg in the left but not right ACC suggesting different mechanisms of conversion of this k-opioid agonist to d-/m-opioid ligand in the two hemispheres; in the right ACC dynorphin B may be cleaved by PACE4, a proprotein convertase regulating left-right asymmetry formation. These findings suggest that region-specific lateralization of neuronal networks expressing opioid peptides underlyes in part lateralization of higher functions including positive and negative emotions and pain in the human brain.

Place, publisher, year, edition, pages
United kingdom: , 2015
Keyword
Anterior Cingulate Cortex, Lateralization, Endogenous Opioid System, Emotions, Pain
National Category
Neurosciences
Research subject
Neuroscience
Identifiers
urn:nbn:se:uu:diva-204053 (URN)10.1093/cercor/bht204 (DOI)000347417600010 ()23960211 (PubMedID)
Note

De tre första författarna delar första författarskapet.

Hiroyuki Watanabe, Sylvia Fitting, and Muhammad Z. Hussain contributed equally to this work.

Available from: 2013-07-21 Created: 2013-07-21 Last updated: 2017-12-06Bibliographically approved
2. Lateralized Response of Dynorphin A Peptide Levels after Traumatic Brain Injury
Open this publication in new window or tab >>Lateralized Response of Dynorphin A Peptide Levels after Traumatic Brain Injury
Show others...
2012 (English)In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 29, no 9, 1785-1793 p.Article in journal (Refereed) Published
Abstract [en]

Traumatic brain injury (TBI) induces a cascade of primary and secondary events resulting in impairment of neuronal networks that eventually determines clinical outcome. The dynorphins, endogenous opioid peptides, have been implicated in secondary injury and neurodegeneration in rodent and human brain. To gain insight into the role of dynorphins in the brain's response to trauma, we analyzed short-term (1-day) and long-term (7-day) changes in dynorphin A (Dyn A) levels in the frontal cortex, hippocampus, and striatum, induced by unilateral left-side or right-side cortical TBI in mice. The effects of TBI were significantly different from those of sham surgery (Sham), while the sham surgery also produced noticeable effects. Both sham and TBI induced short-term changes and long-term changes in all three regions. Two types of responses were generally observed. In the hippocampus, Dyn A levels were predominantly altered ipsilateral to the injury. In the striatum and frontal cortex, injury to the right (R) hemisphere affected Dyn A levels to a greater extent than that seen in the left (L) hemisphere. The R-TBI but not L-TBI produced Dyn A changes in the striatum and frontal cortex at 7 days after injury. Effects of the R-side injury were similar in the two hemispheres. In naive animals, Dyn A was symmetrically distributed between the two hemispheres. Thus, trauma may reveal a lateralization in the mechanism mediating the response of Dyn A-expressing neuronal networks in the brain. These networks may differentially mediate effects of left and right brain injury on lateralized brain functions.

Keyword
dynorphins, lateralization, neurodegeneration, neuronal networks, traumatic brain injury
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-177241 (URN)10.1089/neu.2011.2286 (DOI)000304924000008 ()
Available from: 2012-07-05 Created: 2012-07-04 Last updated: 2017-12-07Bibliographically approved
3. Downregulation of the endogenous opioid peptides in the dorsal striatum of human alcoholics
Open this publication in new window or tab >>Downregulation of the endogenous opioid peptides in the dorsal striatum of human alcoholics
Show others...
2015 (English)In: Frontiers in Cellular Neuroscience, ISSN 1662-5102, E-ISSN 1662-5102, Vol. 9, 187Article in journal (Refereed) Published
Abstract [en]

The endogenous opioid peptides dynorphins and enkephalins may be involved in brain-area specific synaptic adaptations relevant for different stages of an addiction cycle. We compared the levels of prodynorphin (PDYN) and proenkephalin (PENK) mRNAs (by qRT-PCR), and dynorphins and enkephalins (by radioimmunoassay) in the caudate nucleus and putamen between alcoholics and control subjects. We also evaluated whether PDYN promoter variant rs1997794 associated with alcoholism affects PDYN expression. Postmortem specimens obtained from 24 alcoholics and 26 controls were included in final statistical analysis. PDYN mRNA and Met-enkephalin-Arg-Phe, a marker of PENK were downregulated in the caudate of alcoholics, while PDYN mRNA and Leu-enkephalin-Arg, a marker of PDYN were decreased in the putamen of alcoholics carrying high risk rs1997794 C allele. Downregulation of opioid peptides in the dorsal striatum may contribute to development of alcoholism including changes in goal directed behavior and formation of a compulsive habit in alcoholics.

Keyword
Caudate nucleus, putamen, prodynorphin, proenkephalin, alcoholism
National Category
Neurosciences
Research subject
Neuroscience
Identifiers
urn:nbn:se:uu:diva-204055 (URN)10.3389/fncel.2015.00187 (DOI)000354804000001 ()26029055 (PubMedID)
Funder
Swedish Research Council
Available from: 2013-07-21 Created: 2013-07-21 Last updated: 2017-12-06Bibliographically approved
4. The endogenous opioid system in human alcoholics: molecular adaptations in brain areas involved in cognitive control of addiction
Open this publication in new window or tab >>The endogenous opioid system in human alcoholics: molecular adaptations in brain areas involved in cognitive control of addiction
Show others...
2013 (English)In: Addiction Biology, ISSN 1355-6215, E-ISSN 1369-1600, Vol. 18, no 1, 161-169 p.Article in journal (Refereed) Published
Abstract [en]

The endogenous opioid system (EOS) plays a critical role in addictive processes. Molecular dysregulations in this system may be specific for different stages of addiction cycle and neurocircuitries involved and therefore may differentially contribute to the initiation and maintenance of addiction. Here we evaluated whether the EOS is altered in brain areas involved in cognitive control of addiction including the dorsolateral prefrontal cortex (dl-PFC), orbitofrontal cortex (OFC) and hippocampus in human alcohol-dependent subjects. Levels of EOS mRNAs were measured by quantitative reverse transcription-polymerase chain reaction (qRT-PCR), and levels of dynorphins by radioimmunoassay (RIA) in post-mortem specimens obtained from 14 alcoholics and 14 controls. Prodynorphin mRNA and dynorphins in dl-PFC, κ-opioid receptor mRNA in OFC and dynorphins in hippocampus were up-regulated in alcoholics. No significant changes in expression of proenkephalin, and µ- and δ-opioid receptors were evident; pro-opiomelanocortin mRNA levels were below the detection limit. Activation of the κ-opioid receptor by up-regulated dynorphins in alcoholics may underlie in part neurocognitive dysfunctions relevant for addiction and disrupted inhibitory control.

Keyword
Alcohol dependence, dynorphin, endogenous opioid system, human brain, κ-opioid receptor, prodynorphin
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-166255 (URN)10.1111/j.1369-1600.2011.00366.x (DOI)000312740500016 ()
Available from: 2012-01-11 Created: 2012-01-11 Last updated: 2017-12-08Bibliographically approved

Open Access in DiVA

fulltext(3438 kB)442 downloads
File information
File name FULLTEXT01.pdfFile size 3438 kBChecksum SHA-512
6267ed24a75ec8772c66fe651c25294c4b41f006bbd640175c41721cac93c4b1aaa288f4b80375cb4a8a0caedf722284e124b87c91a4ffe014a7e555c68f74c7
Type fulltextMimetype application/pdf

Authority records BETA

Hussain, Muhammad Zubair

Search in DiVA

By author/editor
Hussain, Muhammad Zubair
By organisation
Department of Pharmaceutical Biosciences
Pharmaceutical Sciences

Search outside of DiVA

GoogleGoogle Scholar
Total: 442 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

isbn
urn-nbn

Altmetric score

isbn
urn-nbn
Total: 615 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf