Pain researchers at the University of Texas Health Science Center-San Antonio found a new family of fatty acids produced by injured cells that play an important role in the biology of pain. Substances similar to capsaicin are generated at the site of pain, and the researchers have developed two new types of agents that block these molecules at the source rather than traveling to the brain – thus creating the basis for a new class of non-addictive painkillers.
“Capsaicin is an ingredient in hot chili peppers and causes pain by activating a receptor called transient potential vanilloid 1 (TRPV1),” says UT professor Kenneth Hargeaves, DDS, PhD, a co-author of a study published April 27 in The Journal of Clinical Investigation. “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,’ he 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.”
Researchers used flaps of skin from laboratory mice that were heated in a water bath at temperatures greater than 43 degrees Celsius [109.4 degrees Fahrenheit]. 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.
The TRPV1 receptor 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 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.
“We found 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).
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. 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). “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. 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.
Source: University of Texas Health Science Center – San Antonio news release, Apr 27, 2010