Potential adaptations to acute hypoxia: Hct, stress proteins, and set point for temperature regulation

Abstract

Severe, intermittent hypoxia (hypoxic conditioning, HC) increases survival time during subsequent lethal hypoxia in mice. This protective effect was blocked by naloxone, suggesting an opioid-dependent mechanism. We proposed and evaluated three potential mechanisms of this acute adaptation: 1) increased hematocrit (Hct), 2) protein synthesis, and 3) decreased set point for temperature regulation (set point). Increased hematocrit is a well-studied adaptation to chronic hypoxia and could be acutely initiated by sympathetically mediated splenic contraction. Survival during stress can be prolonged by synthesis of stress proteins. We tested this hypothesis using two protein synthesis inhibitors, anisomycin and cycloheximide. Our third hypothesis is that set point is decreased after HC. A regulated decrease in body temperature would lower oxygen demand during hypoxia. Our studies indicate that hematocrit and protein synthesis are not dominant mechanisms of acute adaptation to hypoxia. However, we have observed a naloxone blockable decrease in set point after HC, supporting a mechanism in which acute adaptation involves an endogenous opioid-dependent decrease in set point. These studies also demonstrate that set point could be a more dominant contributor than body temperature to hypoxic tolerance.

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

“…reported that morphine had a protective action against acute hypoxia; i.e., increasing the survival rate of the mice subjected to acute hypoxia, while a high dose of naloxone decreased the survival rate. On the other hand, Mayfield et al [13-15]. showed that hypoxic conditioning increases survival time during subsequent lethal hypoxic conditions in mice; this protective effect was blocked by naloxone, suggesting an opioid-dependent mechanism.…”

“…Although scattered studies on other functions of DOR can be found in the literature, the outcomes and conclusions of these studies are inconsistent, and sometimes very contradictory. For instance, some studies suggested that opioid agonists were neuroprotective against hypoxic or ischemic injury [11-15], while others showed that opioid antagonists (e.g., naloxone, a non-selective opioid antagonist) had the same effect [16-19]. These controversies may be attributed to many factors including inappropriate methodologies and ligands.…”

Attenuation of heat shock-induced cardioprotection by treatment with the opiate receptor antagonist naloxone

“…5). Interestingly, a study by Mayfield et al (18) suggests that hypoxic preconditioning is mediated by an opioid-dependent mechanism. They hypothesized that hypoxic preconditioning results in the release of endogenous opioids, which function to lower the set point of the animal by reducing body temperature and potentially reducing oxygen demand during hypoxia.…”

“…They observed that the decrease in set point was abolished by naloxone treatment. Although the stress of hypoxia is different from that of hyperthermia, it appears that endogenous opioids may be released in response to both stimuli, and, in terms of heat stress, the response of endogenous opioid release may be a decrease in set point, as suggested by Mayfield et al (18), producing a decrease in metabolism and potentially resulting in protection of the animal during severe stress. If this were the case, the administration of naloxone would be expected to eliminate the afforded protection as is suggested by our results.…”

The physiology of artificial hibernation

“…Growing evidence suggests the latter, as delta-opioids appear to be directly involved in hypoxic signaling. In mice, exposure to hypoxia has been suggested to decrease Ztn via delta-1-opioid receptor agonism [103][104][105][106]. Other studies have suggested that the delta-2 opioid receptor rather than a delta-1 opioid receptor is responsible for the effects on the Ztn [107][108][109], supported by the limited presence of delta-1-opioid receptors in the hypothalamic region [110,111].…”