Previous studies have shown heteromers of µ-opioid receptors (MORs) and galanin Gal receptors (GalRs) localized in the mesencephalon impact the dopaminergic effects of opioids. The current research uses a peptide-interfering approach combined with biophysical and biochemical techniques, including total internal reflection fluorescence microscopy to study the structure of these receptors (Pharmacological Research, August 2022). The team found that when MOR and GalR are expressed individually, they show a predominant homodimeric structure. However, the two form functional heterotetramers when co-expressed.

A heteromerization-dependent change in the GalR homodimeric interface leads to a switch in G-protein coupling from inhibitory Gi to stimulatory Gs proteins. The MOR-GalR heterotetramer, bound to Gs via the GalR homodimer and Gi via the MOR homodimer, provides the framework for a Gs-Gi antagonist interaction at the adenylyl cyclase level.

By identifying the nature of these receptors, it will facilitate the future design of opioid drugs that can bind with a greater affinity or can bind more effectively the signal pathways with µ-opioid receptor homodimers than with the MOR-Gal1R heterotetramers.

In essence, the µ-opioid receptor drugs would be capable of discriminating between homodimers of these compounds and their heterotetramers with galanin receptors. Combining opioid ligands with Gal1R ligands that bind to the heterotetramer would inhibit activating the dopamine system and, therefore, addiction.