Deletion of the adenosine A2A receptor in mice enhances spinal cord neurochemical responses to an inflammatory nociceptive stimulus

Abstract

Knockout mice lacking the adenosine A2A receptor are less sensitive to nociceptive stimuli, and this may be due to the presence of pronociceptive A2A receptors on sensory nerves. In support of this hypothesis, we have recently shown that in A2A receptor knockout mice there are marked reductions in the changes of two markers of spinal cord neuronal activity, [3H]MK801 binding to NMDA receptors and uptake of [14C]-2-deoxyglucose, in response to formalin injection. We now report that following a more prolonged inflammatory stimulus, consisting of intraplantar injections of PGE2 and paw pressure, there was in contrast an increase in [3H]MK801 binding and [14C]-2-deoxyglucose uptake in the spinal cords of the A2A receptor knockout mice which was much greater than in the wild-type mice. This increase suggests that when there is a pronounced inflammatory component to the stimulus, loss of inhibitory A2A receptors on inflammatory cells outweighs the loss of pronociceptive A2A receptors on peripheral nerves so that overall there is an increase in nociceptive signalling. This implies that although A2A antagonists have antinociceptive effects they may have only limited use as analgesics in chronic inflammatory pain.