Currently, opioids are the standard treatment for chronic pain. Patients on opioids for long periods of time become desensitized to these drugs or become paradoxically hypersensitive to pain (hyperalgesia); however, the adaptive mechanisms are not well understood.
In this issue of the Journal of Clinical Investigation, Yuan-Xiang Tao and colleagues from the New Jersey Medical School at Rutgers University report that the protein mTOR, which is a global regulator of translation, plays a major role in morphine tolerance. Using animal models of opioid exposure, the authors found that mTOR is highly expressed in neurons of the dorsal horn, which is where opioid desensitization and hyperalgesia are thought to originate. Inhibition of mTOR activity with the drug rapamycin prevented and treated opioid tolerance and hyperalgesia in rats that had been exposed to chronic morphine injections. Chronic morphine injection increased activity of mTOR and two of its target proteins in the neurons of the dorsal horn.
Furthermore, the authors determined that mTOR links a key opioid receptor to downstream proteins that are known to be involved in morphine tolerance and hyperalgesia, and that blocking mTOR reduced the production of these proteins. This study details a potential mechanism that drives opioid desensitization and hyperalgesia and suggests that targeting the mTOR pathway may improve pain management.
TITLE:Opioid receptor–triggered spinal mTORC1 activation contributes to morphine tolerance and hyperalgesia
View this article at: http://www.jci.org/articles/view/70236?key=8e6dfbd947463946789e
Doxorubicin-associated mitochondrial iron accumulation promotes cardiotoxicity
Doxorubicin is a widely used as a component of chemotherapy regimes; however, the use of doxorubicin is associated with severe cardiotoxicity. It is unclear exactly how doxorubicin promotes cardiotoxicity, but it has been proposed that doxorubicin-associated cardiomyopathy develops as the result of reactive oxygen species (ROS) production and iron accumulation.
In this issue of the Journal of Clinical Investigation, Hossein Ardehali and colleagues at Northwestern University determined that doxorubicin accumulates within the mitochondria of cardiomyocytes and this accumulation promotes mitochondrial ROS production and iron accumulation. In a mouse model of doxorubicin-associated cardiotoxicity, overexpression of a protein that enhances mitochondrial iron transport reduced mitochondrial iron, ROS, and protected animals from doxorubicin-induced cardiomyopathy. Treatment of animals with dexrazoxane, which attenuates doxorubicin-induced cardiotoxicity, decreased mitochondrial iron levels and reversed doxorubicin-induced cardiac damage.
Furthermore, heart samples from patients undergoing doxorubicin therapy revealed higher levels of mitochondrial iron in patients with cardiomyopathies compared to patients without cardiac complications. These data suggest that therapies that limit mitochondrial iron accumulation have potential to limit doxorubicin-associated cardiotoxicity.
TITLE:Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation
View this article at:http://www.jci.org/articles/view/72931?key=9b3d0d3c914bc63e96f7