Chronic muscle ischaemia leads to accumulation of lactic acid and other inflammatory mediators with a subsequent drop in interstitial pH. Acid-sensing ion channels (ASICs), expressed in thin muscle afferents, sense the decrease in pH and evoke a pressor reflex known to increase mean arterial pressure. The naturally occurring endomorphins are also released by primary afferents under ischaemic conditions. We examined whether high affinity mu opioid receptor (MOR) agonists, endomorphin-1 (E-1) and -2 (E-2), modulate ASIC currents and the lactic acid-mediated pressor reflex. In rat dorsal root ganglion (DRG) neurons, exposure to E-2 in acidic solutions significantly potentiated ASIC currents when compared to acidic solutions alone. The potentiation was significantly greater in DRG neurons isolated from rats whose femoral arteries were ligated for 72 h. Sustained ASIC current potentiation was also observed in neurons pretreated with pertussis toxin, an uncoupler of G proteins and MOR. The endomorphin-mediated potentiation was a result of a leftward shift of the activation curve to higher pH values and a slight shift of the inactivation curve to lower pH values. Intra-arterial co-administration of lactic acid and E-2 led to a significantly greater pressor reflex than lactic acid alone in the presence of naloxone. Finally, E-2 effects were inhibited by pretreatment with the ASIC3 blocker APETx2 and enhanced by pretreatment with the ASIC1a blocker psalmotoxin-1. These findings have uncovered a novel role of endomorphins by which the opioids can enhance the lactic acid-mediated reflex increase in arterial pressure that is MOR stimulation-independent and APETx2-sensitive.
Background We hypothesized that preconditioning with a short exposure to isoflurane (ISO) would reduce neurodegeneration induced by prolonged exposure to ISO in neonatal rats, as previously shown in neuronal cell culture. Methods We randomly divided 7-day-old Sprague-Dawley rats into 3 groups: control, 1.5% ISO, and preconditioning (PC) + 1.5% ISO. The control group was exposed to carrier gas (30% oxygen balanced in nitrogen) for 30 min and then carrier gas again for 6 h the following day. The 1.5% ISO group was exposed to carrier gas for 30 min and then 1.5% ISO for 6 h the following day. The PC + 1.5% ISO group was preconditioned with a 30 min 1.5% ISO exposure and then exposed to 1.5% ISO for 6 h the following day. Blood and brain samples were collected 2 h after the exposures for determination of neurodegenerative biomarkers, including caspase-3, S100β, caspase-12, and an autophagy biomarker Beclin-1. Results Prolonged exposure to ISO significantly increased cleaved caspase-3 expression in the cerebral cortex of 7-day old rats compared to the group preconditioned with ISO and the controls using Western blot assays. However, significant differences were not detected for other markers of neuronal injury. Conclusion The ISO-mediated increase in cleaved caspase-3 in the postnatal day 7 rat brain is ameliorated by preconditioning with a brief anesthetic exposure, and differences were not detected in other markers of neuronal injury.
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