Researchers determine the complex structure of the receptors related to the addictive effects of opioids
Receptors, macrostructures and pharmacological activity
Peer-Reviewed PublicationIMAGE: FROM LEFT TO RIGHT, THE EXPERTS NATÀLIA LLOPART, ESTEFANÍA MORENO, VERÒNICA CASADÓ AND VICENT CASADÓ. view more
CREDIT: UNIVERSITY OF BARCELONA
A study published in the journal Pharmacological Research reveals the oligomeric molecular structure of the MOR-Gal1R complex, a component present in the brain which is involved in the analgesic and addictive effects of certain opioids. The study includes the participation of the experts Vicent Casadó, Estefanía Moreno and Verònica Casadó-Anguera, from the Molecular Neuropharmacology Research Group of the Faculty of Biology and the Institute of Biomedicine of the University of Barcelona (IBUB).
The study is coordinated by the experts Vicent Casadó (UB-IBUB), Leonardo Pardo (UAB), Leigh Daniel Plant (Boston Northeastern University, United States) and Sergi Ferré (National Institute on Drug Abuse, NIH, United States).This preclinical study, based on the use of cellular models and leading biophysical, biochemical and pharmacological techniques (total internal reflection fluorescence microscopy, TIRF), has been distinguished for its scientific interest in the website of the NIH’s National Institute on Drug Abuse.
Receptors, macrostructures and pharmacological activity
Gal1R and MOR receptors belong to the family of G protein-coupled receptors (GPCRs) that take part in the transduction of different cellular signals and the control of essential cell functions. These structures can form dimers —homodimers or heterodimers— that determine functional and pharmacological properties that are different from those of the individual components.
The study shows different in vitro evidences that reveal the preference of Gal1R and MOR receptors to form homodimeric complexes (MOR-MOR or Gal1R-Gal1R) in cell cultures when they are expressed separately. When expressed together, tetrameric complexes (heterotetramers) are formed by homodimers of both receptors (MOR-MOR-Gal1R-Gal1R-Gal1R).
"This heterotetrameric structure is even more complex because when the homodimers of both receptors join to form the MOR-MOR macrocomplex, the interaction and corresponding signalling is maintained by means of their characteristic G protein (the G protein inhibitory to adenylate cyclase or Gi)", says Vicent Casadó, member of the Department of Biochemistry and Molecular Biomedicine and the IBUB.
"However, Gal1R-Gal1R exchanges its characteristic inhibitory G-protein for the adenylyl cyclase-stimulating G-protein (Gs). This higherorder oligomeric complex contains more than 10 protein subunits considering the four receptors, the two heterotrimeric G-proteins and the adenylyl cyclase enzyme on which both G-proteins act to up- or down-regulate the intracellular levels of the cyclic AMP messenger", adds the expert. Determining the molecular characteristics of this macrostructure would explain the molecular mechanism by which the neuropeptide galanin —which has neurotrophic and neuroprotective properties— causes a decrease in the release of dopamine into the nucleus accumbens induced by opioids, as described by the same team (Journal of Neuroscience, 2016).
"This would be possible because when the Gal1R ligand binds to the heteromer, it activates the Gs protein, which interacts with the same adenylyl cyclase that was inhibited by the MOR-activated Gi protein, so it counteracts the secondary effects that opioid ligands have in activating the MOR receptors in the ventral tegmental area", says researcher Estefanía Moreno, member of the Department of Biochemistry and Molecular Biomedicine and IBUB.
Searching for new non-addictive drugs
In previous studies, the team from the Faculty of Biology and the IBUB had already showed that the greater proportion of analgesic —and not euphoric— effects of methadone administration make this compound the most indicated non-addictive option for the treatment of chronic pain (Journal of Clinical Investigation, 2019). This could be explained by the fact that methadone acts preferentially on MOR receptors when they do not form heteromers with Gal1R receptors, and therefore, its effect is mainly peripheral.
"Now, knowing this tetrameric macrostructure of the receptor complex —in addition to the differential capacities of opioid ligands to activate MOR depending on the formation of oligomeric complexes with other receptors— will facilitate the future design of opioid drugs that can bind with a greater affinity or can bind more effectively the signal pathways with mu-opioid receptor homodimers than with the MOR-Gal1R heterotetramers”, notes researcher Verònica Casadó-Anguera.
Specifically, it would be about μ-opioid receptor drugs capable of discriminating between homodimers of these compounds and their heterotetramers with galanin receptors. "It is also possible to design a strategy that combines opioid ligands with Gal1R ligands that bind to the heterotetramer and inhibit the activation of the dopamine system and, therefore, addiction. Thus, these therapies are expected to have a greater analgesic effect and less addictive activity", concluded the research team.
JOURNAL
Pharmacological Research
METHOD OF RESEARCH
Experimental study
SUBJECT OF RESEARCH
Cells
ARTICLE TITLE
Preferential Gs protein coupling of the galanin Gal1 receptor in the μ-opioid-Gal1 receptor heterotetramer
Marshall researcher receives NIH grant to study genetic mechanisms of addiction
HUNTINGTON, W.Va. – Price E. Dickson, Ph.D., an assistant professor of biomedical sciences at the Marshall University Joan C. Edwards School of Medicine, has received a $407,000 grant from the National Institutes of Health to study the genetic and genomic mechanisms driving the relationship between social reward and cocaine addiction.
During the two-year R21 grant, Dickson and his research team will study the genetic and genomic mechanisms driving social reward and the preference for a social reward over a drug reward. Social rewards refer to the reinforcing social stimuli that individuals experience during interactions with others. A strong drive to seek out social interactions rather than drugs of abuse may confer addiction resistance, whereas the absence of this drive may result in addiction vulnerability, Dickson explains.
"Despite the importance of social rewards in addiction, the genetic mechanisms underlying variation in the preference for a social reward over a drug reward have been unexplored," Dickson said. “Because the mouse genome is very similar to the human genome, genetic studies using mice can provide valuable information about the genetics underlying human addiction."
To model the vast genetic diversity in humans, the team will use mice from the Collaborative Cross mouse panel, which contains almost all of the genetic diversity present in both wild and laboratory mice. To identify the genetic mechanisms underlying the preference for social interactions rather than addictive drugs, individual Collaborative Cross mice will have the choice to intravenously self-administer cocaine or to briefly interact with another mouse. Single-cell RNA sequencing will then be used to identify genetic signatures associated with these preferences in the reward circuitry of the brain.
“The successful completion of this project will provide a foundation for future deep characterization of identified genetic mechanisms driving the preference for a social reward over a drug reward in mice and contribute to the development of novel, more effective addiction treatments, Dickson said."
Since joining Marshall’s faculty in 2020, Dickson has authored or co-authored four publications in academic journals and four presentations at scientific conferences. He is a recipient of a 2020 K99/R00 program grant from the National Institute on Drug Abuse to further his research on the genetic relationship between stress and addiction. Dickson joined the School of Medicine faculty in June 2020, following seven years of postdoctoral research at the Jackson Laboratory in Bar Harbor, Maine.
The grant (1R21DA054929-01A1) was announced July 12 by U.S. Senators Joe Manchin (D-WV) and Shelley Moore Capito (R-WV).
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