Lack of efficacy of a partial adenosine A1 receptor agonist in neuropathic pain models in mice

Previous studies suggest that adenosine A(1) receptors (A(1)R) modulate the processing of pain. The aim of this study was to characterize the distribution of A(1)R in nociceptive tissues and to evaluate whether targeting A(1)R with the partial agonist capadenoson may reduce neuropathic pain in mice. The cellular distribution of A(1)R in dorsal root ganglia (DRG) and the spinal cord was analyzed using fluorescent in situ hybridization. In behavioral experiments, neuropathic pain was induced by spared nerve injury or intraperitoneal injection of paclitaxel, and tactile hypersensitivities were determined using a dynamic plantar aesthesiometer. Whole-cell patch-clamp recordings were performed to assess electrophysiological properties of dissociated DRG neurons. We found A(1)R to be expressed in populations of DRG neurons and dorsal horn neurons involved in the processing of pain. However, administration of capadenoson at established in vivo doses (0.03-1.0 mg/kg) did not alter mechanical hypersensitivity in the spared nerve injury and paclitaxel models of neuropathic pain, whereas the standard analgesic pregabalin significantly inhibited the pain behavior. Moreover, capadenoson failed to affect potassium currents in DRG neurons, in contrast to a full A(1)R agonist. Despite expression of A(1)R in nociceptive neurons, our data do not support the hypothesis that pharmacological intervention with partial A(1)R agonists might be a valuable approach for the treatment of neuropathic pain.