PGE2 and HCN2 ion channels are critical mediators of pain initiated by angiotensin II, 2024, Pinto et al.

PGE2 and HCN2 ion channels are critical mediators of pain initiated by angiotensin II
Pinto; Vilar; McNaughton

Angiotensin II is well known to have an important influence on blood pressure, mediated via the angiotensin II type 1 receptor (AT1R), and 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 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 which in turn activates HCN2 ion channels in nociceptive neurons.


HIGHLIGHTS
• Angiotensin II, acting on AT2R receptors, is a critical mediator of both short-term and long-term inflammatory pain.

• AT2R receptors are not present on nociceptive neurons, so an extracellular mediator is needed to carry the signal to nociceptive neurons

• We show that activation of AT2R triggers the release of prostaglandin E2, an extracellular mediator that acts on EP4 receptors expressed on nociceptive neurons to elevate intracellular cAMP.

• Elevation of cAMP triggers activation of HCN2 ion channels. The consequent neuronal membrane depolarization elicits firing of nociceptive neurons, triggering a sensation of pain.

• The discovery of the pathway linking angiotensin II to the initiation of pain opens up the possibility of developing drugs to treat long-term inflammatory conditions such as rheumatoid and osteoarthritis.

Link (Brain, Behavior, and Immunity) [Paywall]