Paradoxical potentiation of the exercise pressor reflex by endomorphin 2 in the presence of naloxone

Abstract

When contracting muscles are freely perfused, the acid-sensing ion channel 3 (ASIC3) on group IV afferents plays a minor role in evoking the exercise pressor reflex. We recently showed in dorsal ganglion neurons innervating the gastrocnemius muscles that two mu opioid receptor agonists, endomorphin 2 and oxycodone, potentiated the sustained inward ASIC3 current evoked by acidic solutions. This finding prompted us to determine if endomorphin 2 and oxycodone, infused into the arterial supply of freely perfused muscles, potentiated the exercise pressor reflex. We found that infusion of endomorphin 2 and naloxone in decerebrated rats potentiated the pressor responses to contraction. The endomorphin 2-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, 27.2 ± 8.1 mmHg after naloxone and endomorphin 2 infusion, and 20 ± 8 mmHg after APETx2 and endomorphin 2 infusion (n=10). Infusion of endomorphin and naloxone did not potentiate the pressor responses in ASIC3 knockout rats (n=6). Oxycodone infusion significantly increased the exercise pressor reflex over its control level, but subsequent APETx2 infusion failed to restore the increase to its control level. The peak pressor response averaged 23.1 ± 8.6 mmHg for control, 33.2 ± 11 mmHg after naloxone and oxycodone were infused, and 27 ± 8.6 mmHg after APETx2 and oxycodone were infused (n=9). Our data suggest that after opioid receptor blockade, ASIC3 stimulation by endomorphin 2 potentiated the exercise pressor reflex.