TY - JOUR
T1 - PGE2 and HCN2 ion channels are critical mediators of pain initiated by angiotensin II
AU - Pinto, Larissa Garcia
AU - Vilar, Bruno
AU - McNaughton, Peter A.
N1 - Publisher Copyright:
© 2025 The Authors
PY - 2025/3
Y1 - 2025/3
N2 - 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.
AB - 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.
KW - Angiotensin II
KW - Angiotensin II receptor
KW - AT2R
KW - Chemokine
KW - HCN2
KW - Inflammation
KW - Ion channel
KW - Pain
KW - PGE2
KW - Prostaglandin E2
UR - http://www.scopus.com/inward/record.url?scp=85215118415&partnerID=8YFLogxK
U2 - 10.1016/j.bbi.2024.12.156
DO - 10.1016/j.bbi.2024.12.156
M3 - Article
C2 - 39736364
AN - SCOPUS:85215118415
SN - 0889-1591
VL - 125
SP - 268
EP - 279
JO - Brain, Behavior, and Immunity
JF - Brain, Behavior, and Immunity
ER -