A1R agonists(University of Camerino)

While pain is frequent manisfestation of several disease processes, chronic pain has been described as an established disorder with debilitating ramifications on health and lifestyle. The currently available analgesics for the treatment of chronic pain are often ineffective and accompanied by undesirable adverse effects, which invites for safer and more efficacious alternatives. Adenosine is a naturally‐occurring purinergic nucleoside that is involved in cell signaling in multiple tissue types. Although the activation of adenosine receptors can affect nociceptive, inflammatory, and neuropathic pain states, the specific regulatory functions of its subtypes (A1, A2A, A2B and A3 receptors) are not fully understood. The aim of this work was to investigate the role played by different adenosine receptor ligands on inflammatory pain conditions. Inflammatory pain was induced by intra‐plantar injection of Complete Freund’s Adjuvant (CFA) into the left hindpaw of adult male Sprague Dawley rats. Von Frey filaments were applied to the mid‐plantar aspect of the left hind paw using the “up‐down” method to determine the CFA‐induced mechanical allodynia (expressed as paw withdrawal threshold, PWT). Neither the A2A selective agonist CGS 21680 hydrochloride (0.1, 0.32 and 1 mg/kg) nor the A2B selective agonist BAY 60‐6583 (0.1, 0.32 and 1 mg/kg) produced any significant reversal of the PWT. However, both the A1 selective agonist (±)‐5′‐Chloro‐5′‐deoxy‐ENBA, and the A3 selective agonist 2‐Cl‐IB‐MECA produced a significant reversal of the PWT at the highest dose of 1 mg/kg, suggesting antinociceptive effects of the A1 and A3 adenosine receptors. Co‐administration of the selective antagonists of A1 and A3 receptors PSB36 (1 mg/ml) and MRS‐3777 (1 mg/ml); respectively, significantly reduced the anti‐nociceptive effects of both (±)‐5′‐Chloro‐5′‐deoxy‐ENBA, and 2‐Cl‐IB‐MECA (1 mg/kg) on PWT one hour post‐drug administration. Both the A2A selective antagonist ZM 241385 and the A2B selective antagonist PSB 603 produced a significant reversal of the PWT at the highest dose of 1 mg/kg. In conclusion, A1, A2A, A2B and A3 adenosine receptors are involved in mediating inflammatory pain states, and represent promising targets for the treatment of chronic pain conditions.

Recent studies on interactions between striatal adenosine and dopamine and one of its main targets, the adenosine A_2A receptor-dopamine D₂ receptor (A2AR-D2R) heteromer, have provided a better understanding of the mechanisms involved in the psychostimulant effects of caffeine and have brought forward new data on the mechanisms of operation of classical orthosteric ligands within G protein-coupled receptor heteromers. The striatal A2AR-D2R heteromer has a tetrameric structure and forms part of a signaling complex that includes a Gs and a Gi protein and the effector adenyl cyclase (subtype AC5). Another target of caffeine, the adenosine A₁ receptor-dopamine D₁ receptor (A1R-D1R) heteromer, seems to have a very similar structure. Initially suggested to be localized in the striatum, the A1R-D1R heteromer has now been identified in the spinal motoneuron and shown to mediate the spinally generated caffeine-induced locomotion. In this study, we review the recently discovered properties of A2AR-D2R and A1R-D1R heteromers. Our studies demonstrate that these complexes are a necessary condition to sustain the canonical antagonistic interaction between a Gs-coupled receptor (A2AR or D1R) and a Gi-coupled receptor (D2R or A1R) at the adenylyl cyclase level, which constitutes a new concept in the field of G protein-coupled receptor physiology and pharmacology. A2AR antagonists targeting the striatal A2AR-D2R heteromer are already being considered as therapeutic agents in Parkinson's disease. In this study, we review the preclinical evidence that indicates that caffeine and A2AR antagonists could be used to treat the motivational symptoms of depression and attention-deficit/hyperactivity disorder, while A1R antagonists selectively targeting the spinal A1R-D1R heteromer could be used in the recovery of spinal cord injury.