Breakthrough discovery paves the way for profound new treatment possibilities in fibromyalgia and other "pain of unknown sources."
A new study may explain why only half of patients experiencing chronic nerve pain achieve even partial relief from existing therapeutics, according to neurologists at Albany (NY) Medical College and their translational science entity, Integrated Tissue Dynamics, LLC.
The study, published online June 6 in the journal PAIN,* reveals that certain types of chronic pain may be caused by signals from the skin itself, rather than damage to nerves within the skin, as previously thought.
Unraveling a Medical Mystery
An earlier international study headed by the AMC team, published in 2009, pointed to a hitherto unsuspected separate ‘hidden’ sensory system in the skin – apparently in the blood vessels and sweat glands - that the researchers thought could lead to an explanation of fibromyalgia and other “pain of unknown sources.”
Their discovery resulted from a study of tissues from two people who lacked all the nerve endings we normally associate with skin sensations – all of the normal nerves that signal temperature, pain or mechanical stimuli - yet “had adequate sensation for daily living.”
Subsequently two members of the team founded Integrated Tissue Dynamics (www.Intidyn.com) - a biotechnology company that could facilitate further collaborative studies of pain sensing networks and work with pharmaceutical companies as needed to translate findings to “development of effective and safe therapeutics.”
Researchers in the field had recognized for years that increased amounts of a molecule called Calcitonin Gene-Related Peptide (CGRP), known to play a role in pain transmission, are found in the skin of chronic pain patients.
But they thought the source of the increased CGRP was certain types of sensory nerve fibers in the skin that normally make and release a type of "isoform" called CGRP-alpha.
Curiously, however, the authors of the current study found that nerve fibers in the skin containing CGRP-alpha are actually reduced under painful conditions – leading them to investigate where the increased CGRP in the skin came from.
Their latest finding is that, surprisingly, the skin cells themselves generate increased amounts of a lesser-known "beta" isoform of CGRP.
This skin cell-derived CGRP-beta is increased in painful conditions and may be sending pain signals to remaining sensory nerve fibers in the skin.
The discovery of CGRP-beta as a therapeutic target presents a potentially important new treatment approach. "Since CGRP-alpha normally plays an important role in both the regulation of blood flow and normal inflammatory responses, targeting this molecule as a treatment for chronic pain could cause undesired side-effects on circulation," explains corresponding author Phillip J. Albrecht, PhD, assistant professor of neuroscience at Albany Medical College and a VP of Integrated Tissue Dynamics.
A Two-for-One Discovery
"However, since we know that these two forms of CGRP are derived from separate genes,” Dr. Albrecht adds, “we may be able to selectively manipulate the beta isoform without affecting the alpha, and dramatically reduce unwanted toxicities - a common problem limiting the successful development of novel pain therapeutics.
“This is really a two-for-one discovery: a novel mechanism we can specifically target in a novel skin location."
Potentially Profound for Many Pain Conditions
The discovery that CGRP-beta from keratinocyte cells of skin (cells in the outermost layer of skin) may be causing pain has profound implications for the treatment and study of a host of chronic neuropathic pain conditions such as shingles, diabetic neuropathy, and physical injury, which altogether affect approximately 30 million people in the U.S. who collectively spend more than $4.5 billion each year to treat chronic nerve pain.
"Furthermore, the identification of beta CGRP in skin keratinocytes may become a useful independent biomarker for the therapeutic effectiveness of chronic neuropathic pain treatments," says co-author Frank L. Rice, PhD.
"As a co-discovery in the labs of Albany Medical College and Integrated Tissue Dynamics, we are filing a patent to develop our research and commercialization options," he adds.
* Article: “Keratinocyte Expression of CGRP beta: Implications for Neuropathic and Inflammatory Pain Mechanisms,” Pain, June 6, 2011, by Quanzhi Hou, MD, Philip J Albrecht, PhD, et al.
Sources: Including Integrated Tissue Dynamics, LLC news release, Jun 8, 2011