The Department of Defense has awarded Brian Schmidt, DDS, MD, PhD, and Nigel Bunnett, PhD, a joint, $2.4 million, three-year grant to study how receptors inside nerve cells generate chronic pain. They will investigate headache, nerve injury, and infectious colitis, which are prevalent in military personnel and veterans.
This work also has broad implications beyond the military, the researchers said, noting that one in five people suffer from chronic pain during their lifetime. Opioid effectiveness wanes with extended use, with larger doses required as tolerance develops. Current treatments also generate debilitating side effects including profound sedation and addiction.
Schmidt and Bunnett will investigate receptors on and within nerve cells. Pain-sensing nerve cells are covered with receptors that react to painful stimuli. These receptors can detect many substances that are produced by injured tissues and some types of cancer. One pain-relieving strategy involves blocking the activity of receptors on the surface of pain-sensing nerves.
Bunnett discovered that chronic pain can develop when activated receptors on the cell surface are endocytosed (internalized within the cell) or when endocytosed receptors are activated internally by endocytosed pain mediators.
“Conventional drugs do not penetrate nerves and thus cannot effectively inhibit endocytosed receptors,” said Bunnett, a professor in the departments of surgery and pharmacology at Columbia University. “Drugs that inhibit receptors inside nerve cells, rather than on the cell surface, might provide superior and long-lasting pain relief.”
“Our nerve receptor research has potentially groundbreaking clinical applications,” said Schmidt, director of the Bluestone Center for Clinical Research at the New York University College of Dentistry. “This work could define a new class of drugs for chronic pain treatment—non-addictive drugs that produce fewer deleterious side effects.”
Bunnett notes that the research also has important implications beyond pain treatment.
“Hundreds of members of this receptor family are found on all cells,” Bunnett said. “A third of all clinically used drugs act on these receptors. The knowledge derived from our work might be useful for modification of existing drugs used to treat a wide variety of diseases including heart disease and cancer.”