Endomorphin-2 and oxycodone paradoxically potentiate the exercise pressor reflex via acid-sensing ion channel 3 (ASIC3) in decerebrated rat

Abstract

The exercise pressor reflex is evoked by the stimulation of group III and IV muscle afferents in response to muscle contractions. When the contracting muscles are freely perfused, acid-sensing ion channel 3 (ASIC3) on the endings of group IV afferents appear to play a minor role in evoking the exercise pressor reflex. We recently showed in isolated dorsal root ganglion (DRG) neurons innervating the gastrocnemius muscles that two μ opioid receptor agonists, namely endomorphin-2, and oxycodone, potentiated the sustained inward ASIC3 current evoked by acidic saline (pH 6.0). This in vitro finding prompted us to investigate whether endomorphin-2 and oxycodone, when infused into the arterial supply of freely perfused contracting hindlimb muscles, could potentiate the exercise pressor reflex. We found that infusing endomorphin-2 and naloxone (a μ opioid receptor antagonist) into the superficial epigastric artery of decerebrated unanesthetized rats potentiated the peak and integrated pressor responses to static contraction of the triceps surae muscles. The opioid-induced potentiation of the pressor responses to contraction were prevented by infusion of APETx2, an ASIC3 antagonist. Specifically, the peak pressor response to contraction averaged 19.3 ± 5.6 mmHg for control (n=10), 27.2 ± 8.1 mmHg after naloxone and endomorphin-2 infusion (n=10), and 20 ± 8 mmHg after APETx2 and endomorphin-2 infusion (n=10). Infusion of endomorphin-2 and naloxone did not potentiate the pressor responses to contraction in ASIC3 knockout rats (n=6), averaging 21.5 ± 7.7 mmHg for control (n=6), 20 ± 6.2 mmHg after naloxone and endomorphin-2 infusion (n=6), and 19.8 ± 6.9 mmHg after APETx2 and endomorphin-2 infusion (n=4). Similar findings were observed when oxycodone was substituted for endomorphin-2. Specifically, the peak pressor response to contraction averaged 24.3 ± 8.9 mmHg for control (n=10), 33.9 ± 10.6 mmHg after naloxone and oxycodone were infused (n=10), and 26.8 ± 8.1 mmHg after APETx2 and oxycodone were infused (n=10). Altogether, our data strongly suggest that ASIC3 stimulation by mu opioid agonists can potentiate the exercise pressor reflex, provided that mu opioid receptors on group III and IV afferents are not operative. (Supported by HL156594 and HL 156513). HL156594 and HL 156513. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.