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Promising Discovery of Protein Involved in Face, Head, and Neck Pain Has Researchers Cautiously Optimistic

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Promising Protein Discovery

Promising Discovery of Protein Involved in Face, Head, and Neck Pain Has Researchers Cautiously Optimistic

January 18, 2007
By: Jean Johnson for Dental1

If the new discovery of a protein associated with face, head, and neck pain pans out in human studies, it could mean relief for people suffering with conditions like gum disease, dental surgery, migraines, TMJ (temporomandibular joint disorder), and trigeminal neuralgia.
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The following thoughts on dental and facial pain are adapted from the National Institutes of Health:
  • Face pain may be dull, throbbing or intense, or stabbing discomfort in one or both sides of the face or forehead.
  • Pain that originates in the face may be caused by a nerve disorder, an injury, or an infection in a structure of the face. Face pain may also begin elsewhere in the body.
  • Sometimes face pain occurs for no known reason.

    Common Causes of Dental and Facial Pain
  • Injury to the face
  • Abscessed tooth (continuous throbbing pain on one side of the lower face aggravated by eating or touching
  • Sinusitis or sinus infection (dull pain and tenderness around the eyes and cheekbones that worsens when bending forward
  • Tic douloureux (trigeminal neuralgia
  • Herpes zoster (shingles) or herpes simplex (cold sores) infection
  • Cluster headache
  • Migraine


  • That would be exceptionally good news for the 10 percent of Americans that the National Institute of Health estimates are plagued by chronic craniofacial pain.

    “We are cautiously optimistic that one day our discovery will be introduced in the clinic,” Agnieszka Balkowiec, MD, PhD – principal investigator at Oregon Health and Science University (OHSU) in Portland, assistant professor of integrative biosciences in the OHSU School of Dentistry, and adjunct assistant professor of physiology and pharmacology in the OHSU School of Medicine – told us.

    The results of Balkowiec and her students’ study were published in the December 2006 issue of the Journal of Neurochemistry.

    “So far our research was conducted on the animal model so now we need to see if the same mechanism working there also operates in humans,” Balkowiec said. “It looks extremely promising. Recent studies show that blocking a protein previously not considered in craniofacial problems relieves pain in other parts of the body.”

    In addition to identifying the protein – called brain-derived neurotrophic factor or BDNF – Balkowiec and her students also found that the mechanism by which craniofacial pain is stimulated is more complicated than researchers previously thought. It’s not surprising, she noted, since faced with understanding the marvels of creation, the science proceeds at glacial speeds.

    “I recently bought the new Honey Crisp apple and was surprised to learn that it actually took 30 years to develop,” she said. “When we deal with human beings, it can slow down even more than that since we have to be so very cautious in order to avoid advancing a therapy that could fail.” But that’s the nature of the game, Balkowiec says. Advancing knowledge takes generations, with each crop of fresh recruits standing on the shoulders of their predecessors.

    “I love the Honey Crisp apple, but some of those gardeners who developed it are probably not alive today. Many of us will not live long enough to get the full satisfaction of knowing that people are benefiting from our work.”

    The Long and Winding Road

    Balkowiec certainly has a grasp on the long time frame: she’s invested years of her life in becoming a medical researcher and in her discovery of the relationship between BDNF and craniofacial pain. “Originally my dream was to become a neurosurgeon,” she said, “but I just fell in love with research. The idea of making a significant discovery related to the nervous system that many, many people could benefit from, I embraced it.”

    Once the compelling die was cast, Balkowiec spent several more years completing her degree and residency. Then in 1997 she came to the United States and began working with Dr. David M. Katz, Ph.D., at Case Western Reserve University in Cleveland, Ohio, a scientist with an established name in research focused on BDNF’s role in respiration.

    After five years under Katz’s tutelage, Balkowiec received a grant from the American Heart Association to study the role of BDNF in regulation of blood pressure, and joined the faculty at OHSU. “While studying the system that controls blood pressure, I learned that BDNF is made by spinal pain-sensing neurons,” Balkowiec said, with clear excitement in her voice, “and consequently that there was a possibility the protein might have a role in the trigeminal nerve as well.”

    Her hypothesis was that BDNF is made by trigeminal neurons, and as such, plays a role in craniofacial pain mechanisms. At that time, in 2003, Balkowiec and her students searched the literature and found no prior studies.

    How BDNF Influences Head, Neck, and Face Pain

    Formerly, studies found that trigeminal nerve cells released another protein, called calcitonin gene-related peptide (CGRP), at the peripheral end of the trigeminal nerve that runs throughout the face. While recent studies have shown that blocking CGRP helps alleviate some types of craniofacial pain like migraines, the full mechanism is not understood. In addition to CGRP, BDNF is likely to be another key protein involved in head, neck and face pain. Where the trigeminal nerve connects with the brain itself is where Balkowiec’s team thinks CGRP triggers the release of BDNF.

    “BDNF has previously been shown to play an important role in pain signaling from other parts of the body, but this is the first time it has been considered to be a factor in head pain,” said Balkowiec. “What we now need to better understand is how the interaction between CGRP and BDNF affects pain signaling to the brain in various disorders.”

    What’s Next?

    According to Balkowiec, “It will be a long process – just like the development of the Honey Crisp apple – and take upwards of 30 years. We are just at the very beginning of the journey. We need to examine whether BDNF modulates pain transmission because we do not know that yet. The first step, then, is looking at activity of pain sensing nerve cells in the intact animal. This will probably take one to two years.” The next step is moving into pre-clinical studies and then clinical trials to make sure it is safe for patients. Although a long road, it is undeniably worth it in the end.

    Nowadays, in addition to advancing her research, Balkowiec works at local schools to share her enthusiasm for science with children. “In very simple language we talk about the brain and its pain pathways. They genuinely want to learn and it really charges my batteries.”

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