The role of adenosine receptor ligands on inflammatory pain: possible modulation of TRPV1 receptor function

Chronic pain has a debilitating consequences on health and lifestyle. The currently available analgesics are often ineffective and accompanied by undesirable adverse effects. Although adenosine receptors (AR) activation can affect nociceptive, inflammatory, and neuropathic pain states, the specific regulatory functions of its subtypes (A(1), A(2A), A(2B) and A(3) ARs) are not fully understood. The aim of this study was to investigate the role of different AR ligands on inflammatory pain. The von Frey filament test was used to assess the anti-nociceptive effects of adenosine ligands on Complete Freund's Adjuvant (CFA)-induced mechanical allodynia in (180-220 g) adult male Sprague Dawley rats (expressed as paw withdrawal threshold, PWT). Neither the A(2A)AR selective agonist CGS 21680 hydrochloride (0.1, 0.32 and 1 mg/kg) nor the A(2B)AR selective agonist BAY 60-6583 (0.1, 0.32 and 1 mg/kg) produced any significant reversal of the PWT. However, the A(1)AR selective agonist ( +/-)-5'-Chloro-5'-deoxy-ENBA, the A(3)AR selective agonist 2-Cl-IB-MECA, the A(2A)AR selective antagonist ZM 241385 and the A(2B)AR selective antagonist PSB 603 produced a significant reversal of the PWT at the highest dose of 1 mg/kg. Co-administration of the selective antagonists of A(1)AR and A(3)AR PSB36 (1 mg/ml) and MRS-3777 (1 mg/ml); respectively, significantly reversed the anti-nociceptive effects of their corresponding agonists. Furthermore, calcium imaging studies reveled that the effective AR ligands in the behavioral assay also significantly inhibit capsaicin-evoked calcium responses in cultured rat dorsal root ganglia (DRG) neurons. In conclusion, modulating the activity of the transient receptor potential vanilloid 1 (TRPV1) receptor by ARs ligands could explain their anti-nociceptive effects observed in vivo. Therefore, the cross talk between ARs and TRPV1 receptor may represent a promising targets for the treatment of inflammatory pain conditions.