Details of receptors linked to opioid addiction revealed

Scientists have succeeded in determining the complex structure of receptors involved in the addictive effects of opioids.

A new study reveals the oligomeric molecular structure of the MOR-Gal1R complex, a component present in the brain and involved in the analgesic and addictive effects of certain opioids.

Vicent Casadó, Estefanía Moreno and Verònica Casadó Anguera, from the Molecular Neuropharmacology Research Group of the Faculty of Biology and the Institute of Biomedicine (IB) of the University of Barcelona (UB), have participated in the research.

The study was coordinated by Vicent Casadó, Leonardo Pardo (Autonomous University of Barcelona), Leigh Daniel Plant (Northeast University in Boston, United States) and Sergi Ferré (National Institute on Drug Abuse, one of the National Institutes of Health of the United States). Joined).

This preclinical study, based on the use of cell models and various cutting-edge biophysical, biochemical and pharmacological techniques (such as total internal reflection fluorescence microscopy, TIRFM), has been highlighted for its scientific interest on the website of the aforementioned National Institute on Drug Abuse.

From left to right: Natàlia Llopart, Estefanía Moreno, Verònica Casadó and Vicent Casadó. (Photo: UB)

Receptors, macrostructures and pharmacological activity

Gal1R and MOR receptors belong to the family of G protein-coupled receptors (GPCR) that participate in the transduction of different cellular signals and the control of essential cell functions. These structures can form dimers —homodimers or heterodimers— that have functional and pharmacological properties different from those of their separate components.

The work presents different in vitro evidence that, in cell cultures, Gal1R and MOR receptors tend to form homodimeric complexes (MOR-MOR or Gal1R-Gal1R) when they are expressed separately. When they are expressed together, tetrameric complexes (heterotetramers) formed by homodimers of both receptors (MOR-MOR-Gal1R-Gal1R) are formed.

“This heterotetrameric structure is even more complex, since, when the homodimers of both receptors join and form the MOR-MOR macrocomplex, the interaction and corresponding signaling is maintained through its characteristic G protein (the inhibitory G protein of adenylate cyclase, or Gi)”, explains Professor Vicent Casadó, member of the Department of Biochemistry and Molecular Biomedicine and the Institute of Biomedicine.

“Instead —he points out—, Gal1R-Gal1R changes its characteristic inhibitory G protein for the adenylate cyclase (Gs) stimulatory G protein. This higher-order oligomeric complex contains more than ten protein subunits if we take into account the four receptors, the two heterotrimeric G proteins, and the enzyme adenylate cyclase on which both G proteins act to upregulate or downregulate intracellular levels of the messenger. cyclic AMP”.

Determining the molecular characteristics of this macrostructure would make it possible to explain the molecular mechanism by which the neuropeptide galanin —with neurotrophic and neuroprotective properties— causes a decrease in the release of dopamine in the nucleus accumbens induced by opioids, as described by the team itself ( Journal of Neuroscience, 2016).

“This would be possible because within the heteromer, when it binds to the Gal1R ligand, the Gs protein is activated, which interacts with the same adenylate cyclase that was inhibited by the Gi protein activated by MOR, thus counteracting the secondary effects that the opioid ligands are produced by activating the MOR receptors of the ventral tegmental area”, details the researcher Estefanía Moreno, from the Department of Biochemistry and Molecular Biomedicine and the Institute of Biomedicine.

In search of new non-addictive drugs

It should be remembered that, in previous works, the team from the Faculty of Biology and the Institute of Biomedicine had already shown that the greater proportion of analgesic effects —and not euphoric— of the administration of methadone make this compound the most non-addictive opiate indicated to treat chronic pain (Journal of Clinical Investigation, 2019). This would be explained because methadone acts preferentially on MOR receptors when they do not form heteromers with Gal1R and, therefore, its effect is mainly peripheral.

“Now, we know this tetrameric macrostructure of the receptor complex, as well as the differential abilities of opioid ligands to activate MOR based on the formation of oligomeric complexes with other receptors. This knowledge will facilitate the future design of opioid drugs that can bind with greater affinity or signal pathways more effectively with mu opioid receptor homodimers than with MOR-Gal1R heterotetramers”, explains researcher Verònica Casadó-Anguera.

Specifically, it would be μ-opioid receptor drugs capable of discriminating between homodimers of these compounds and their heterotetramers with galanin receptors. “A strategy could also be designed that combines opioid ligands with Gal1R ligands that bind to the heterotetramer and inhibit the activation of the dopaminergic system and, therefore, addiction. Thus, predictably, these therapies will have a greater analgesic effect and less addictive activity”, concludes the research team.

The study is titled “Preferential Gs protein coupling of the galanin Gal1 receptor in the μ-opioid-Gal1 receptor heterotetramer”. And it has been published in the academic journal Pharmacological Research. (Source: UB)