Opioid tolerance and pain hypersensitivity associated with mTOR activation
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
AUTHOR CONTACT:
Yuan-Xiang Tao
Rutgers, the State University of New Jersey, Newark, NJ, USA
Phone: 9739729812; Fax: 9739721664; E-mail: yt211@njms.rutgers.edu
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
AUTHOR CONTACT:
Hossein Ardehali
Northwestern University, Chicago, IL, USA
Phone: 312-503-2342; Fax: 312-503-0137; E-mail: h-ardehali@northwestern.edu
View this article at: http://www.jci.org/articles/view/72931?key=9b3d0d3c914bc63e96f7
ALSO IN THIS ISSUE
TITLE: Irradiation and anti–PD-L1 treatment synergistically promote antitumor immunity in mice
AUTHOR CONTACT:
Yang-Xin Fu
The University of Chicago, Chicago, IL, USA
Phone: 773-702-0929; Fax: 773-834-8940; E-mail: yfu@midway.uchicago.edu
View this article at: http://www.jci.org/articles/view/67313?key=01e06eba76dd83aad5fb
TITLE: Positive feedback between NF-κB and TNF-α promotes leukemia-initiating cell capacity
AUTHOR CONTACT:
Mineo Kurokawa
Department of Hematology & Oncology, Graduate School of Medicine, Universit, Tokyo, , JPN
Phone: +81-3-58009092; Fax: +81-3-58408667; E-mail: kurokawa-tky@umin.ac.jp
View this article at: http://www.jci.org/articles/view/68101?key=9641bb0687c996b39b04
TITLE: Erythropoietin promotes breast tumorigenesis through tumor-initiating cell self-renewal
AUTHOR CONTACT:
William Kim
University of North Carolina, Chapel Hill, NC, USA
Phone: 919-966-4765; Fax: ; E-mail: wykim@med.unc.edu
View this article at: http://www.jci.org/articles/view/69804?key=6bc0c0f0192bf2f9b6e6
TITLE: Orexin neurons suppress narcolepsy via 2 distinct efferent pathways
AUTHOR CONTACT:
Michihiro Mieda
Faculty of Medicine, Kanazawa University, Kanazawa, , JPN
Phone: 81762652171; Fax: 81762344224; E-mail: mieda@med.kanazawa-u.ac.jp
View this article at: http://www.jci.org/articles/view/71017?key=cc00eff4250e5b8f2900
TITLE: Sustained activation of SMAD3/SMAD4 by FOXM1 promotes TGF-β–dependent cancer metastasis
AUTHOR CONTACT:
Suyun Huang
UT MD Anderson Cancer Center, Houston, TX, USA
Phone: (713) 834-6232; E-mail: suhuang@mdanderson.org
View this article at: http://www.jci.org/articles/view/71104?key=319839e42c24c4354ad3
TITLE: OTX2 loss causes rod differentiation defect in CRX-associated congenital blindness
AUTHOR CONTACT:
Anand Swaroop
National Eye Institute, Bethesda, MD, USA
Phone: (301) 435-5754; E-mail: swaroopa@nei.nih.gov
View this article at: http://www.jci.org/articles/view/72722?key=546e0c6bec3baf2197c4
Journal
Journal of Clinical Investigation