Skin cell-derived CGRP-beta may cause chronic pain

Skin cell target for pain discovered using novel translational research platform

A new study may explain why only 50% of patients experiencing chronic nerve pain achieve even partial relief from existing therapeutics. The study, published in the June 6 online version of the international research 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.

A Medical Mystery

The answer, surprisingly, was that 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," said the paper's corresponding author, Phillip J. Albrecht, Ph.D., Assistant Professor of Neuroscience at Albany Medical College and Vice President at Integrated Tissue Dynamics, LLC, whose team conducted the research. "However, since we know that these two forms of CGRP are derived from separate genes, 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."

The discovery that CGRP-beta from keratinocyte cells 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.

A New Translational Research Platform

The present study was a comprehensive translational research project that integrated results from cell culture, animal models of chronic pain and human pain condition tissues to confirm that CRGP is generated in keratinocytes in each of those systems. The study also demonstrates how a translational research platform can be utilized to discover novel targets and provide drug companies with better predictive data that can be used to make time- and cost-reducing decisions early in the drug discovery process.

To observe differences between CGRP in healthy and inflamed or painful skin, the researchers used an imaging methodology called chemomorphometric analysis (CMA), a technique they use to observe, quantify, and characterize molecules like CGRP in the microscopic structure of skin samples half the size of a pencil eraser. A commercially expanded version of the technique, pioneered by Integrated Tissue Dynamics, LLC, interpreted those results and integrated them with assessments of the genetic activity for each CGRP isoform, which led to the discovery that the beta molecule, not the alpha, predominated in keratinocytes.

"We are especially excited by our translational research results because the identification of beta CGRP in keratinocytes will have immediate value in the clinical setting, and also demonstrates how our CMA technology can deliver on the promise of translational medicine," said Frank L. Rice, Ph.D., Professor of Neuroscience at Albany Medical College and CEO at Integrated Tissue Dynamics, LLC. "Furthermore, the identification of beta CGRP in skin keratinocytes may become a useful independent biomarker for the therapeutic effectiveness of chronic neuropathic pain treatments."

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