A single peri-sciatic nerve administration of the adenosine 2A receptor agonist ATL313 produces long-lasting anti-allodynia and anti-inflammatory effects in male rats

•Prior work showed that intrathecal A2a agonists produced long term pain suppression.•This study explores efficacy of the A2a agonist ATL313 at the site of nerve injury.•A single peri-sciatic ATL313 dose created long-term suppression of neuropathic pain.•Pain suppression correlated with decreased sciatic nerve inflammatory markers. Neuropathic pain is a widespread problem which remains poorly managed by currently available therapeutics. Peripheral nerve injury and inflammation leads to changes at the nerve injury site, including activation of resident and recruited peripheral immune cells, that lead to neuronal central sensitization and pain amplification. The present series of studies tested the effects of peri-sciatic nerve delivery of single doses of adenosine 2A receptor (A2aR) agonists on pain and neuroinflammation. The data provide converging lines of evidence supportive that A2aR agonism at the site of peripheral nerve injury and inflammation is effective in suppressing ongoing neuropathic pain. After A2aR agonism resolved neuropathic pain, a return of pain enhancement (allodynia) was observed in response to peri-sciatic injection of H-89, which can inhibit protein kinase A, and by peri-sciatic injection of neutralizing antibody against the potent anti-inflammatory cytokine interleukin-10. A2aR agonist actions at the nerve injury site suppress neuroinflammation, as reflected by decreased release of interleukin-1β and nitric oxide, as well as decreased sciatic expression of markers of monocytes/macrophages and inducible nitric oxide synthase. Taken together, the data are supportive that A2aR agonists, acting at the level of peripheral nerve injury, may be of therapeutic value in treating chronic pain of neuroinflammatory origin.