PT  - JOURNAL ARTICLE
AU  - Malgorzata Zaremba
AU  - Victor Ruiz-Velasco
TI  - Opioid-mediated modulation of acid-sensing ion channel (ASIC) currents in adult rat sensory neurons
AID  - 10.1124/mol.118.114918
DP  - 2019 Jan 01
TA  - Molecular Pharmacology
PG  - mol.118.114918
4099  - http://molpharm.aspetjournals.org/content/early/2019/02/26/mol.118.114918.short
4100  - http://molpharm.aspetjournals.org/content/early/2019/02/26/mol.118.114918.full
AB  - Muscle ischemia, associated with peripheral artery disease (PAD), leads to the release of pro-inflammatory mediators that decrease extracellular pH and trigger the activation of proton-activated acid-sensing ion channels (ASIC). Claudication pain, linked with low blood flow, can be partially relieved by endogenous opioid peptide release. However, we previously reported that sustained ASIC currents in dorsal root ganglion (DRG) neurons were enhanced by naturally occurring endomorphin-1 and -2 opioid peptides, indicating a role of opioid involvement in hyperalgesia. The aim of the present study was to examine whether clinically employed synthetic (fentanyl, remifentanil) and the semi-synthetic opioid (oxycodone) would also potentiate sustained ASIC currents, which arise from ASIC3 channel isoforms. Here, we show that exposure of each opioid to DRG neurons resulted in potentiation of the sustained ASIC currents. On the other hand, the potentiation was not observed in DRG neurons from ASIC3 knockout rats. Further, the enhancement of the ASIC currents was resistant to pertussis toxin treatment, suggesting that Gαi/Gαo G-proteins are not involved. Additionally, the potentiation of sustained ASIC currents was greater in DRG neurons isolated from rats with ligated femoral arteries-a model of PAD. The effect of all three opioids on the transient ASIC peak current was mixed (increase, decrease, no effect). The inhibitory action appears to be mediated by the presence of ASIC1 isoform, while the potentiating effect is primarily due to ASIC3 isoform expression. These findings reveal that, under certain conditions, these three opioids can increase ASIC channel activity and give rise to opioid-induced hyperalgesia.