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Uncovering the Mechanisms of Adenosine Receptor-Mediated Pain Control: Focus on the A₃ Receptor Subtype.

ABSTRACT: Agonists of the G_i protein-coupled A₃ adenosine receptor (A₃AR) have shown important pain-relieving properties in preclinical settings of several pain models. Active as a monotherapy against chronic pain, A₃AR agonists can also be used in combination with classic opioid analgesics. Their safe pharmacological profile, as shown by clinical trials for other pathologies, i.e., rheumatoid arthritis, psoriasis and fatty liver diseases, confers a realistic translational potential, thus encouraging research studies on the molecular mechanisms underpinning their antinociceptive actions. A number of pathways, involving central and peripheral mechanisms, have been proposed. Recent evidence showed that the prototypical A₃AR agonist Cl-IB-MECA and the new, highly selective, A₃AR agonist MRS5980 inhibit neuronal (N-type) voltage-dependent Ca²⁺ currents in dorsal root ganglia, a known pain-related mechanism. Other proposed pathways involve reduced cytokine production, immune cell-mediated responses, as well as reduced microglia and astrocyte activation in the spinal cord. The aim of this review is to summarize up-to-date information on A₃AR in the context of pain, including cellular and molecular mechanisms underlying this effect. Based on their safety profile shown in clinical trials for other pathologies, A₃AR agonists are proposed as novel, promising non-narcotic agents for pain control.

SUBMITTER: Coppi E

PROVIDER: S-EPMC8347395 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Increasing evidence suggests that G protein-coupled receptors form functional dimers or larger oligomeric complexes through homo- or heterodimerization, and that various transmembrane (TM) domains contribute dimerization interfaces. In this study, monomeric receptor structures - either the monomeric crystallographic structure of bovine rhodopsin or an A(3) adenosine receptor (AR) homology model - were dimerized by computational methods assuming various TM contact regions, optimized, and compared. The semi-empirical oligomeric structure of mouse rhodopsin studied in a native disc membrane with atomic force microscopy was used to establish the distance between monomers in the initial dimeric models. Among eight variations of symmetrical homodimers of bovine rhodopsin, the favored dimeric assembly closely resembled the semi-empirical model, in which TM domains 4 and 5 were the contact site, thus validating this approach. We used similar methods to generate eight homodimers of the A(3)AR and found the favored dimeric interface similarly to be TM4-5. By this method, dimeric variations - TM1-2, TM2-3, TM2-4, TM3-4, TM4-5, TM5-6, TM6-7, and TM7-1 - were constructed with the SYBYL 7.0 program by using a novel "fit-centroids-normal" method. Fitting atoms considered one of eight TM-TM centroids or seven-TM centroids, two centroids of each monomer, and a normal atom passing through the plane containing all centroids. Following molecular dynamics, the most energetically favorable contact modes were identified. In addition to TM4-5, which was favored in both rhodopsin and A(3)AR dimeric models, TM1-2 dimers in which helices 8 also contacted each other were judged favorable. The largest contact surface area between the monomers among the various homodimers, determined by van der Waals calculation with the MOLCAD surface program, was for the TM4-5 dimer. This contact surface also showed a high degree of shape complementarity. In addition, the TM4-5 dimers made by this theoretical method were more stable than the semi-empirically determined dimer.

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Uncovering the Mechanisms of Adenosine Receptor-Mediated Pain Control: Focus on the A₃ Receptor Subtype.

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Uncovering the Mechanisms of Adenosine Receptor-Mediated Pain Control: Focus on the A₃ Receptor Subtype.