Discovery of pain-causing compounds leads to new nonaddictive painkillers
The senior investigator is Kenneth Hargreaves, D.D.S., Ph.D., professor and chair of the Department of Endodontics in the Dental School at the UT Health Science Center. Amol M. Patwardhan, M.B.B.S., Ph.D., a graduate of the Health Science Centerís Department of Pharmacology who worked under Dr. Hargreavesí supervision, is the lead author. The findings were published April 26 in The Journal of Clinical Investigation.
"Nearly everyone will experience persistent pain at some point in their lifetime," Dr. Hargreaves said. "Our findings are truly exciting because they will offer physicians, dentists and patients more options in prescription pain medications. In addition, they may help circumvent the problem of addiction and dependency to pain medications and will have the potential to benefit millions of people who suffer from chronic pain every day."
"Capsaicin is an ingredient in hot chili peppers and causes pain by activating a receptor called transient potential vanilloid 1 (TRPV1). We started out seeking the answer to the question "Why is TRPV1 consistently activated in the body upon injury or painful heat? We wanted to know how skin cells talk to pain neurons," Dr. Hargreaves said. "What we found was much more surprising and exciting. We have discovered a family of endogenous capsaicin-like molecules that are naturally released during injury, and now we understand how to block these mechanisms with a new class of nonaddictive therapies."
Researchers used cells from laboratory mice that were heated in a water bath at temperatures greater than 43 degrees Celsius. The degree of heat used was significant because the human body normally begins to feel discomfort and pain at 43 degrees Celsius and higher, Dr. Hargreaves noted.
TRPV1 resides on the membranes of pain- and heat-sensing neurons. When a person eats a hot chili pepper, for example, he immediately feels a burning sensation because the capsaicin, the primary ingredient in the chili pepper, has activated the TRPV1 protein in the pain neurons. In high concentrations, capsaicin can also cause a burning effect on other sensitive areas of the skin.
The fluid from the heated cells was then applied to sensory neurons cultured from two sets of laboratory mice, including one set of animals in which a gene was deleted or "knocked out." Neurons from the wild type (non-altered) mice were sensitive to capsaicin, the main ingredient in chili peppers. The neurons of the knockout mice, in which the TRPV1 gene was deleted, were not sensitive to capsaicin and were used as the control.†
"We found that in the cells heated at greater than 43 degrees Celsius, the pain neurons showed tremendous activity in the wild type, but not in neurons from mice that lacked TRPV1," Dr. Hargreaves said. He indicated that this novel phenomenon was taking place because the cells, in response to the heat, began to create their own natural endogenous capsaicins, which they later identified as a series of compounds or fatty acids called oxidized linoleic acid metabolites (OLAMs).
Linoleic acid is one of the most abundant fatty acids in the human body. Under conditions such as inflammation, low blood pressure and some other illnesses, linoleic acid is rapidly oxidized to form biologically active metabolites.
"This is a major breakthrough in understanding the mechanisms of pain and how to more effectively treat it," Dr. Hargreaves said. "These data demonstrate, for the first time, that OLAMs constitute a new family of naturally occurring capsaicin-like agents, and may explain the role of these substances in many pain conditions. This hypothesis suggests that agents blocking either the production or action of these substances could lead to new therapies and pharmacological interventions for various inflammatory diseases and pain disorders such as arthritis, fibromyalgia and others, including pain associated with cancer."
The research has led Dr. Hargreavesí team to develop two new classes of analgesics using drugs that either block the synthesis of OLAMs or antibodies that inactivate them. These drugs could eventually come in the form of a topical agent, or a pill or liquid that could be ingested, or in the form of an injection. Both approaches have the potential to block pain at its source, unlike opioid narcotics that travel to the brain and affect the central nervous system.†
Co-authors of the study with Drs. Hargreaves and Patwardhan from the UT Health Science Center San Antonio are: Armen N. Akopian, Ph.D., assistant professor of endodontics; Anibal Diogenes, D.D.S., Ph.D., assistant professor of endodontics; Susan Weintraub, Ph.D., professor of biochemistry; and Nikita Ruparel, D.D.S., Ph.D., a graduate student in the Department of Cellular and Structural Biology. Co-authors from the University of Colorado Health SciencesCenter are Charis Uhlson, a research associate, and Robert Murphy, Ph.D., professor of pharmacology.
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