ANTONIO (April 26, 2010) —
were published April 26 in the Journal of Clinical Investigation.
The senior investigator was 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 Center's Department
of Pharmacology who worked under Dr. Hargreaves' supervision,
is the lead author.
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."
been called a "complex epidemic" in the United States. Nearly
50 million Americans live with chronic pain caused by disease
or injury. Few physicians or dentists specialize in the field
of pain medicine. With pain medication options largely limited
to opioids (such as morphine) and aspirin-like drugs, some patients
become addicted or dependent upon these drugs, or suffer side
effects such as kidney or liver damage.
at the UT Health Science Center found a new family of fatty
acids, produced by the body itself, that play an important role
in the biology of pain.
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 non-addictive therapies."
chili pepper effect
used flaps of skin 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.
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.
from the heated skin 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.
that in the skin flaps heated at greater than 43 degrees Celsius,
the cells' 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).
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. However, little else is understood
about these substances. The metabolites that were consistently
seen in increased amounts in the mouse skin biopsies exposed
to heat temperatures greater than 43 degrees Celsius are called
9- and 13-HODE (hydroxyoctadecadienoic acid).
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."
has led Dr. Hargreaves' 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.
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; Nikita Ruparel, D.D.S., Ph.D.,
a graduate student in the Department of Cellular and Structural
Biology, and Charis Uhlson, a research associate at the University
of Colorado Health Sciences Center. Robert Murphy, Ph.D., professor
of pharmacology at the University of Colorado Health Sciences
Center, is also a co-author.
University of Texas Health
Science Center at San Antonio