Adenosine A2A receptor signaling in neuroinflammation, glial modulation, and mechanisms associated with chronic pain.

Chronic pain is increasingly recognized as a complex and multidimensional condition that extends beyond peripheral nociceptive input, encompassing maladaptive central mechanisms such as persistent neuroinflammation, glial dysfunction, aberrant synaptic plasticity, and disturbances in affective-motivational circuits. Adenosine, an endogenous purine nucleoside, plays a pivotal role in central nervous system homeostasis through activation of four G protein-coupled receptors (A1, A2A, A2B, and A3). Among these, the adenosine A2A receptor (A2AR) has emerged as an important modulator of neuroimmune signaling, astrocyte-neuron communication, synaptic excitability, and behavior. Although adenosinergic signaling has been extensively investigated in the context of pain and neurological disorders, the specific contribution of A2AR to pain-related mechanisms is often addressed indirectly, as many studies focus on upstream neurobiological processes rather than nociception itself. In this narrative review, we integrate recent experimental, translational and observational evidence from in silico, in vitro, ex vivo, in vivo, and human studies to examine how A2AR-dependent signaling may influence mechanisms associated with pain modulation. The literature is organized according to conceptual and mechanistic criteria into four thematic axes: (i) neuroinflammation and central sensitization, (ii) astrocytic regulation and synaptic modulation, (iii) neurological disorders with pain-related components, and (iv) affective and emotional processes associated with the pain experience. Across these domains, convergent evidence suggests that A2AR signaling is involved in interactions between glial activation, inflammatory signaling, synaptic plasticity, and affective regulation. Together, these findings provide a framework for understanding how A2AR-related mechanisms contribute to process associated with chronic pain development and persistence, even in experimental contexts not explicitly designed to assess nociception. This integrative perspective supports further investigation of A2AR as a potential therapeutic target in chronic pain and related neuroinflammatory conditions.