June 14, 2013
By David Martin
|Peter Smith, Ph.D., and Anuradha Chakrabarty, Ph.D.|
A hormone that has been used to control blood pressure may hold the key to a new approach for treating pain, according to research at the University of Kansas Medical Center.
The hormone, angiotensin II, constricts blood vessels and releases a substance that causes the body to retain salt and water. KU neuroscientist Peter Smith, Ph.D., and his colleagues have found that blocking angiotensin II receptors prevents the increase in sensitivity that normally accompanies inflammation. The mechanics of the angiotensin II system's ability to regulate pain pathways was not appreciated before, Smith says.
The study has been published online in The Journal of Pain.
The finding is based on a previous study of estrogen that Smith, professor of molecular and integrative physiology and director of the Institute for Neurological Discoveries at KU, published in 2008. "We know that the hormone estrogen makes women more prone to many painful conditions, and we found that estrogen actually caused some pain-sensing nerve cells to grow," he says, adding that many chronically painful conditions are accompanied by an increase in pain-sensing nerves.
In looking at what genes were affected by estrogen, Smith and his colleagues were surprised to learn that nerve cells started making more of a protein that allows cells to respond to angiotensin II. This led the researchers to speculate that the protein, angiotensin II receptor type 2, or AT2, might be important to pain.
Tests on rodents confirmed the relationship. In the experiment, rats' hind paws were injected with an irritant. Exposure to touch and heat revealed the paws' sensitivity.
Some of the rats received a chemical known to inhibit AT2. In these rats, angiotensin II did not cause pain-sensing nerves to sprout, and paw sensitivity was the same as in rats that did not receive the irritant. In short, the AT2 blocker uncoupled the link between inflammation and the nerve response.
"It appears that AT2 is critical for the sensations of pain, and that AT2 receptor inhibitors are about as effective as morphine — but without all of the dangerous side effects," says senior scientist Anuradha Chakrabarty, Ph.D., the paper's first author. Zhaohui Liao, M.D., also contributed to the study.
The study, Smith says, confirms that the proliferation of pain-sensing nerves associated with chronic pain syndromes is meaningful. "More sprouting means more pain," he says.
The study is the first to shed light on the mechanism of overgrowth of pain-sensing nerves, Smith says. Inhibiting AT2, he adds, "represents one of the few drug therapies that actually is known to be directed at the underlying biological mechanisms that may be responsible for some aspects of chronic pain."
Chronic pain has been estimated to cost the U.S. between $560 and $635 billion in health care costs and lost productivity. Nonsteroidal anti-inflammatory drugs may not work for all patients and have the potential to damage the tissue of the gastrointestinal tract, kidney and liver. Opiates pose the risk of addiction and overdose and are unsuitable for long-term treatment of chronic pain.
An Australian pharmaceutical company is currently testing an AT2 receptor blocker in a clinical trial with patients with postherpetic neuralgia, nerve pain caused by shingles.
The KU study was supported by the National Institutes of Health grant RO1HD049615.