JCI online early table of contents: Jan. 5, 2009

NEUROBIOLOGY: Nerve cells in the brain and spinal cord sense pain caused by physical insult The most common way of managing the pain that accompanies inflammation is to use drugs such as aspirin and ibuprofen. These work by selectively blocking the protein COX2, which functions to produce soluble molecules known as prostaglandins. Although it is known that blocking COX2 in the tissue and in the brain and spinal cord (the CNS) reduces the pain that accompanies inflammation, the relative contribution of COX2 at these two sites to the pain that accompanies inflammation has not been determined. However, a team of researchers, at Massachusetts General Hospital, Boston, and University of Pennsylvania, Philadelphia, have now shown that COX2 in mouse nerve cells in the CNS is crucial for some forms of pain associated with inflammation but not others. Specifically, hypersensitivity to pain caused by the heat associated with inflammation was normal in mice lacking COX2 in nerve cells in the CNS. By contrast, hypersensitivity to pain caused by the physical insult associated with inflammation was abolished in these mice. As pain caused by physical insult is a major symptom of postoperative and arthritic inflammation, it seems that COX2 in nerve cells in the CNS is central to the pain that accompanies these conditions.

TITLE: COX2 in CNS neural cells mediates mechanical inflammatory pain hypersensitivity in mice

AUTHOR CONTACT:

Clifford Woolf
Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
Phone: (617) 724-3622; Fax: (617) 724-3632; E-mail: cwoolf@partners.org.

Garret A. FitzGerald
University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Phone: (215) 898-1185; Fax: (215) 573-9135; E-mail: garret@spirit.gcrc.upenn.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=37098

CARDIOLOGY: Molecular insight into how a heart failure drug in clinical trials works

Individuals who have persistent high blood pressure are at increased risks of a number of serious medical conditions, including heart failure. One of the factors that contributes to such heart failure is thickening of the muscle wall of the heart. Such thickening (known as hypertrophy) is a compensatory response of the heart to the high blood pressure. A team of researchers at Johns Hopkins University, Baltimore, has provided new insight into both the signaling mechanisms by which high blood pressure leads to compensatory hypertrophy of the mouse heart and the molecular mechanisms by which a heart failure drug in clinical trials works.

In the study, which was led by Eiki Takimoto and David Kass, when mice lacking the protein RGS2 were manipulated such that they had persistent high blood pressure they developed hypertrophy of the muscle wall of the heart more rapidly than normal mice manipulated in the same way. Further, these mice went on to exhibit heart failure and died at a young age. Additional analysis indicated that a drug that prevents hypertrophy by targeting the protein PDE5 was less effective at preventing hypertrophy caused by high blood pressure in RGS2-deficient mice than in normal mice. These data have clinical implications, as they provide insight into the mechanism by which PDE5 inhibitors, which have recently entered clinical trials to treat a form of heart failure, work.

TITLE: Regulator of G protein signaling 2 mediates cardiac compensation to pressure overload and antihypertrophic effects of PDE5 inhibition in mice

AUTHOR CONTACT:

Eiki Takimoto
Johns Hopkins University, Baltimore, Maryland, USA.
Phone: (410) 955-7153; Fax: (410) 502-2558; E-mail: etakimo1@jhmi.edu.

David A. Kass
Johns Hopkins University, Baltimore, Maryland, USA.
Phone: (410) 955-7153; Fax: (410) 502-2558; E-mail: dkass@jhmi.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=35620

Source: Journal of Clinical Investigation