δ-Opioid Receptor Activation and MicroRNA Expression of the Rat Cortex in Hypoxia

Abstract

Prolonged hypoxic/ischemic stress may cause cortical injury and clinically manifest as a neurological disability. Activation of the δ-opioid receptor (DOR) may induce cortical protection against hypoxic/ischemic insults. However, the mechanisms underlying DOR protection are not clearly understood. We have recently found that DOR activation modulates the expression of microRNAs (miRNAs) in the kidney exposed to hypoxia, suggesting that DOR protection may involve a miRNA mechanism. To determine if the miRNAs expressed in the cortex mediated DOR neuroprotection, we examined 19 miRNAs that were previously identified as hypoxia- and DOR-regulated miRNAs in the kidney, in the rat cortex treated with UFP-512, a potent and specific DOR agonist under hypoxic condition. Of the 19 miRNAs tested, 17 were significantly altered by hypoxia and/or DOR activation with the direction and amplitude varying depending on hypoxic duration and times of DOR treatment. Expression of several miRNAs such as miR-29b, -101b, -298, 324-3p, -347 and 466b was significantly depressed after 24 hours of hypoxia. Similar changes were seen in normoxic condition 24 hours after DOR activation with one-time treatment of UFP-512. In contrast, some miRNAs were more tolerant to hypoxic stress and showed significant reduction only with 5-day (e.g., miR-31 and -186) or 10-day (e.g., miR-29a, let-7f and -511) exposures. In addition, these miRNAs had differential responses to DOR activation. Other miRNAs like miRs-363* and -370 responded only to the combined exposure to hypoxia and DOR treatment, with a notable reduction of >70% in the 5-day group. These data suggest that cortical miRNAs are highly yet differentially sensitive to hypoxia. DOR activation can modify, enhance or resolve the changes in miRNAs that target HIF, ion transport, axonal guidance, free radical signaling, apoptosis and many other functions.

δ-Opioid Receptor Activation and MicroRNA Expression in the Rat Heart Under Prolonged Hypoxia

“…There are also other studies showing that DOR agonists can prolong survival of peripheral organs, such as the lungs, heart, liver, and kidney, and that DOR activation is protective against hypoxic/ischemic injury in the heart [22,23]. Since there is a growing body of evidence indicating that miRNAs play several regulatory roles in opioid pharmacology [24,25], and our previous studies demonstrate the involvement of DOR in the regulation of miRNA expression in the brain and kidney [26,27], we wanted to know whether DOR affects miRNA expression in the heart when exposed to prolonged hypoxia.…”

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

“…We monitored hypoxia-induced changes in the liver and body weights and investigated 20 miRNAs (miR-7a-5p, miR-10a-5p, miR-25-3p, miR-26b-5p, miR-30e-5p, miR-34a-5p, miR-34c-5p, miR-107-3p, miR-122-5p, miR-125a-5p, miR-128a-3p, miR-135b-5p, miR-142-5p, miR-145-5p, miR-146a-5p, miR-181a-5p, miR-182, miR-184, miR-192-5p, and miR-204-5p) that differentially respond to hypoxic stress based on our microarray and PCR analyses of miRNAs in the hypoxic kidney [26], cortex [25], and heart [27]. …”

“…Chronic hypoxia was induced as described in our previous work [25-27]; the O 2 level was maintained at 9.5%–10% in the plexiglass box to induce hypoxia. The rats of Groups C and D were kept in the hypoxic box for 1, 5, or 10 days.…”

“…Moreover, we found the involvement of DOR in the regulation of miRNA expression in the brain, kidney and heart [25-27]. All the brain, heart and kidney are hypoxia/ischemia sensitive organs.…”

Effect of δ-Opioid Receptor Activation on BDNF-TrkB vs. TNF-α in the Mouse Cortex Exposed to Prolonged Hypoxia

“…Immediately before use, the stock solution was diluted in saline to the expected concentrations. The doses of UFP-512 was 1 mg/kg based on the previous works [47,48]. …”