The Role of Selective Adenosine Receptor Ligands on Inflammatory Pain

Abstract

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.