PGE2 and HCN2 ion channels are critical mediators of pain initiated by angiotensin II.

Angiotensin II is well known to have an important influence on blood pressure, mediated via the angiotensin II type 1 receptor (AT1R), but more recent studies have shown that angiotensin II may play an important additional role in eliciting pain via a distinct action at the angiotensin II type 2 receptor (AT2R). Signalling pathways that link activation of AT2R to a sensation of pain are, however, incompletely understood. Here we use rodent inflammatory pain models to confirm that selective activation of AT2R triggers aversive responses, and that these are abolished by either antagonism or genetic deletion of AT2R. Pain induced by AT2R activation is abolished by pharmacological block or genetic deletion of the HCN2 ion channel, which other studies have implicated in several distinct pain modalities. We found, however, no evidence for direct activation of isolated nociceptive neurons by AT2R agonists. In agreement, the effect of AT2R agonists was completely abolished by the cyclooxygenase (COX) inhibitor indomethacin or by selective antagonism of the EP4 receptor for PGE₂, showing that PGE₂ is a critical extracellular mediator that transmits the signal from AT2R to nociceptive neurons and causes activation of HCN2 ion channels. When inflammatory pain was induced by injection of carrageenan, pharmacological inhibition or genetic deletion of AT2R gave near-complete pain relief, together with a reduction in chemokine and PGE₂ release. This study shows that angiotensin II is an important pro-inflammatory mediator that causes pain indirectly by activating AT2 receptors on non-neuronal cells, stimulating the release of PGE₂ that mediates activation of HCN2 ion channels in nociceptive neurons.