δ‐, but not µ‐, opioid receptor stabilizes K⁺ homeostasis by reducing Ca²⁺ influx in the cortex during acute hypoxia

Abstract

Past work has shown that delta-opioid receptor (DOR) activation by [D-Ala(2),D-Leu(5)]-enkephalin (DADLE) attenuated the disruption of K(+) homeostasis induced by hypoxia or oxygen-glucose deprivation (OGD) in the cortex, while naltrindole, a DOR antagonist blocked this effect, suggesting that DOR activity stabilizes K(+) homeostasis in the cortex during hypoxic/ischemic stress. However, several important issues remain unclear regarding this new observation, especially the difference between DOR and other opioid receptors in the stabilization of K(+) homeostasis and the underlying mechanism. In this study, we asked whether DOR is different from micro-opioid receptors (MOR) in stabilizing K(+) homeostasis and which membrane channel(s) is critically involved in the DOR effect. The main findings are that (1) similar to DADLE (10 microM), H-Dmt-Tic-NH-CH (CH(2)--COOH)-Bid (1-10 microM), a more specific and potent DOR agonist significantly attenuated anoxic K(+) derangement in cortical slice; (2) [D-Ala(2), N-Me-Phe(4), glycinol(5)]-enkephalin (DAGO; 10 microM), a MOR agonist, did not produce any appreciable change in anoxic disruption of K(+) homeostasis; (3) absence of Ca(2+) greatly attenuated anoxic K(+) derangement; (4) inhibition of Ca(2+)-activated K(+) (BK) channels with paxilline (10 microM) reduced anoxic K(+) derangement; (5) DADLE (10 microM) could not further reduce anoxic K(+) derangement in the Ca(2+)-free perfused slices or in the presence of paxilline; and (6) glybenclamide (20 microM), a K(ATP) channel blocker, decreased anoxia-induced K(+) derangement, but DADLE (10 microM) could further attenuate anoxic K(+) derangement in the glybenclamide-perfused slices. These data suggest that DOR, but not MOR, activation is protective against anoxic K(+) derangement in the cortex, at least partially via an inhibition of hypoxia-induced increase in Ca(2+) entry-BK channel activity.

Neuroprotection Against Hypoxic/Ischemic Injury: δ-Opioid Receptors and BDNF-TrkB Pathway

“…Soon after, we observed similar protection in the cortical neurons exposed to hypoxia [80]. Consistently, our electrophysiological studies with UFP-512 (H-Dmt-Tic-NH-CH[CH2-COOH]-Bid) [54], a more potent and specific DOR agonist, also showed that DOR is relatively specific in the protection against anoxic disruption of ionic homeostasis because MOR activation was not shown to induce any protective effect [55]. Furthermore, our transgenic studies showed that cortical DOR overexpression attenuated anoxia-induced disruption of ionic homeostasis, suggesting that an increase in DOR expression renders the cortex more tolerant to hypoxic stress [83].…”

Characteristic MicroRNA Expression Induced by δ-Opioid Receptor Activation in the Rat Liver Under Prolonged Hypoxia

“…The box was rapidly cleaned daily when the animals were removed to have their body weights recorded. The rats of Groups B and D were subjected to an intraperitoneal injection of UFP-512 (H-Dmt-Tic-NH-CH[CH2-COOH]-Bid), a specific and potent DOR agonist synthesized by our team [28]. The injections (1 mg/kg in <1 ml) were performed on day 0 (immediately before the onset of hypoxia), day 4, and day 8.…”

δ-Opioid Receptor Expression in the Ventral Tegmental Area Protects Against Elevated Alcohol Consumption

“…The ␦-opioid receptor (DOR) plays a protective role in cerebral ischemia, hypoxia, cardiac dysfunction, skeletal muscle damage, peripheral organ survival, and vulnerability to stress (Borlongan et al, 2004;Hebb et al, 2005;Hong et al, 2005;Saitoh et al, 2005;Chao et al, 2007;Förster et al, 2007). Interestingly, CNS expression of DORs is often dynamically induced following physiological challenge (Commons, 2003;Hack et al, 2005;Cahill et al, 2007) and trafficking to the plasma membrane is regulated through a variety of mechanisms, which are dependent on stimulus type and duration (Cahill et al, 2007).…”