Adenosine is a ubiquitous endogenous modulator with the main function of maintaining cellular and tissue homeostasis in pathological and stress conditions. It exerts its effect through the interaction with four G protein-coupled receptor (GPCR) subtypes referred as A₁, A_2A, A_2B, and A₃ adenosine receptors (ARs), each of which has a unique pharmacological profile and tissue distribution. Adenosine is a potent modulator of inflammation, and for this reason the adenosinergic system represents an excellent pharmacological target for the myriad of diseases in which inflammation represents a cause, a pathogenetic mechanism, a consequence, a manifestation, or a protective factor. The omnipresence of ARs in every cell of the immune system as well as in almost all cells in the body represents both an opportunity and an obstacle to the clinical use of AR ligands. This review offers an overview of the cardinal role of adenosine in the modulation of inflammation, showing how the stimulation or blocking of its receptors or agents capable of regulating its extracellular concentration can represent promising therapeutic strategies for the treatment of chronic inflammatory pathologies, neurodegenerative diseases, and cancer.

Introduction: The reduction of the inflammatory status represents one of the most important targets in rheumatoid arthritis (RA). A central role of A_2A and A₃ adenosine receptors (ARs) in mechanisms of inflammation has been reported in different pathologies. The primary aim of this study was to investigate the A_2A and A₃ARs and their involvement in RA progression measured by Disease Activity Score in 28 or 44 joints (DAS28 or DAS). Methods: ARs were analyzed by saturation binding assays, mRNA and Western blotting analysis in lymphocytes from early and established RA patients. The effect of A_2A and A₃AR agonists in nuclear factor kB (NF-kB) pathway was evaluated. Tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) release was carried out by A_2A and A₃AR activation. AR pharmacological regulation in matrix metalloproteinase-1 (MMP-1) and metalloproteinase-3 (MMP-3) release was also studied. Results: In lymphocytes obtained from RA patients, A_2A and A₃ARs were up-regulated if compared with healthy controls. A_2A and A₃AR activation inhibited the NF-kB pathway and diminished inflammatory cytokines such as TNF-α, IL-1β and IL-6. A_2A and A₃AR agonists mediated a reduction of MMP-1 and MMP-3 release. A_2A and A₃AR density inversely correlated with DAS28 and DAS suggesting a direct role of the endogenous activation of these receptors in the control of RA joint inflammation. Conclusions: Taken together these data demonstrate that the inflammatory and clinical responses in RA are regulated by A_2A and A₃ARs and support the use of A_2A and/or A₃AR agonists as novel and effective pharmacological treatment in RA patients.

The antagonistic interaction between adenosine and dopamine receptors could have important pathophysiological and therapeutic implications in Parkinson's disease (PD). The primary aim of this study was to investigate the expression, affinity, and density of A ₁ , A _2A , A _2B , and A ₃ adenosine receptors (ARs) and D ₂ dopamine receptors (D ₂ Rs) in PD. An increase in A _2A AR density in putamen was found. The presence and functionality of ARs in human lymphocyte and neutrophil membranes from patients with PD revealed a specific A _2A AR alteration compared with healthy subjects. A statistically significant linear correlation among the A _2A AR density, functionality, or tumor necrosis factor‐α (TNF‐α) levels and Unified Parkinson's Disease Rating Scale (UPDRS) motor score was reported. Adenosine concentration and TNF‐α levels were increased in plasma of patients with PD. In rat adrenal pheochromocytoma (PC12) cells, a widely useful model, adenosine antagonists decreased dopamine uptake, and an opposite effect was mediated by A _2A agonists. This is the first report showing the presence of an A _2A AR alteration in putamen in PD that mirrors a similar up‐regulation in human peripheral blood cells. Moreover, the correlation found between A _2A AR density or A _2A agonist potency and UPDRS motor score highlights the central role of A _2A ARs in the pharmacological treatment of PD.—Varani, K., Vincenzi, F., Tosi, A., Gessi, S., Casetta, I., Granieri, G., Fazio, P., Leung, E., MacLennan, S., Granieri, E., Borea, P. A. A _2A adenosine receptor overexpression and functionality, as well as TNF‐α levels, correlate with motor symptoms in Parkinson's disease. FASEB J . 24, 587–598 (2010). www.fasebj.org

Increased production of proinflammatory cytokines has a prominent role in tolerance to opioids. The objectives of this study were to examine whether μ‐opioid receptor affects proinflammatory signalling through the activation of NF‐kB in microglia. The novelty of the described research is that a low dose of morphine, exerting its effects via the μ‐opioid receptor, increases the DNA‐binding activity of NF‐kB via PKCε, while a high dose of morphine triggers a nonopiate receptor response mediated by TLR4 and, interestingly, PKCε signalling. The identification of morphine as a crucial upstream regulator of PKCε‐NF‐κB signalling in microglia argues for a central role of these pathways in neuroinflammation development and progression. Therefore, the morphine‐PKCε‐NF‐κB pathway may provide novel targets to induce neuroprotective mechanisms, thereby reducing tolerance to opioids.