Delta-opioid receptors (DORs) in the brain normally bind painkilling neurochemicals called enkephalins as well as opiates like morphine. Recent research has shown that these receptors are also protective when oxygen or blood flow to neurons is reduced. The protection occurs in part by reducing inflammation, but other effects are likely. One possibility is reducing ion flow across the cell membrane. Ion leak is a critical step in hypoxic damage to neurons, leading to depolarization, the toxic release of neurotransmitters, and cell death. Potassium leaks out of the cell while sodium and calcium flow in, thus all three ions are potential therapeutic targets for neurological disorders. Ying Xia's group at the Yale University School of Medicine recently demonstrated that protection by DORs occurs by inhibiting the outflow of potassium ions, and this inhibition was linked to the suppression of calcium movement. But potassium efflux is associated with sodium as well as calcium influx, so the investigators set out to test whether DORs also protect against potassium imbalance in mammalian neurons by inhibiting sodium influx.

They utilized brain slices from the mouse cortex and exposed them to decreasing sodium levels, replacing it either with a compound that cannot cross into the cells or with lithium ions that cross into the cell like sodium. They then exposed the slices to anoxia (no oxygen), which normally triggers a massive potassium efflux within minutes.

The investigators first showed that potassium efflux from neurons is linked to sodium influx. When sodium levels were decreased around the brain slices by replacement with a membrane impermeable substitute, it took longer for potassium ions to leak out of the cell during anoxia, and fewer ions in total crossed the membrane. By contrast, lowering external sodium levels using sodium-like lithium ions caused the oxygen-deprived neurons to lose greater levels of potassium even more rapidly than usual. They concluded that the loss of potassium ions from anoxic neurons is indeed linked to the inward flow of sodium ions.

The group then investigated whether the protection of anoxic neurons by DORs could occur by a similar mechanism, by decreasing the intracellular effects of sodium ions. If DOR activation decreases potassium efflux by inhibiting sodium influx, then low sodium levels should abrogate the protective effect of DORs. And indeed, receptor activation under low sodium conditions had no effect on potassium and DOR protection was lost. DOR activation, then, may protect mammalian neurons by decreasing sodium as well as calcium influx, thereby slowing the catastrophic loss of potassium.

Interestingly, one of the most anoxia-tolerant of vertebrates, the freshwater turtle, has very high levels of these receptors compared with mammals. In anoxia, turtles are also known to reduce ion flux through calcium, potassium and sodium channels. A recent article in JEB by Matthew Pamenter and Leslie Buck (J. Exp. Biol. 211, 3512-3517) showed that the inhibition of calcium channels during anoxia was linked to DOR activation; it would be of interest to see if changes in sodium and potassium ion flux are also linked to these receptors as part of the turtles' ability to withstand long periods without oxygen.