Adenosine modulation: a novel approach to analgesia and inflammation

Adenosine (ADO) is an endogenous purine nucleoside that functions as an extracellular signalling molecule. It is released locally at sites of cellular trauma, and acts on specific cell-surface purinergic receptors (termed P1 receptors) near its site of release to exert its effects. Four subtypes of the P1 family of G-protein-coupled receptors have been identified and cloned: A1, A2A, A2B and A3. A considerable body of evidence, including experimental animal data and preliminary clinical reports, indicates that ADO is involved in modulating endogenous antinociceptive processes in the brain and spinal cord. ADO analogues provide analgesic activity after systemic or spinal administration in a broad spectrum of animal pain models. In addition, iv. ADO infusion has shown benefit in human pain states. The spinal cord is a key site for ADO-mediated modulation of nociception. ADO is well known to act as an inhibitory neuromodulator in the central and peripheral nervous system, and it may act to control N-methyl-D-aspartate (NMDA)- and substance P-mediated events in nociception and central sensitisation at the spinal level. ADO is also released at sites of inflammation and it exerts anti-inflammatory effects via multiple mechanisms involving several cell types. These include effects on neutrophil function, endothelial cell permeability, in vivo and in vitro release of tumour necrosis factor (TNF-alpha and collagenase expression in synoviocytes. Accordingly, ADO analogues are effective in several animal models of inflammation, including the rat adjuvant arthritis model. Several therapeutic approaches to pain and inflammation, based on mimicking or modulating the effects of endogenous ADO, are currently under preclinical and clinical investigation. These include the use of ADO itself, the use of direct-acting ADO receptor agonists and the use of agents designed to modulate the levels and, therefore, the actions of ADO in the extracellular space (ADO kinase (AK) inhibitors). Data emerging in the next several years should indicate whether these strategies represent a therapeutically useful new approach to analgesia and inflammation.