Dr. Nackley Awarded NIH Grant for Innovative Pain Therapy Research

The National Institutes of Health (NIH) has awarded Duke Anesthesiology’s Andrea Nackley, PhD, a two-year $1,846,202 R61 grant for her project titled, “Development of Adrb3 Antagonists for the Treatment of Pain” - part of the NIH’s HEAL Initiative: Planning Studies for Initial Analgesic Development. 

Chronic primary ‘overlapping’ pain conditions (CPPCs), including fibromyalgia, headache, temporomandibular disorder, low back pain, and irritable bowel syndrome, affect more than 100 million Americans, predominantly females, and cost the economy billions of dollars every year. Chronic pain is the leading cause of adult disability and accounts for nearly 20% of medical visits and 10% of prescription drug sales. CPPCs are typically treated with orally-delivered analgesics, such as antidepressants and opioids. However, these conventional medications have poor efficacy for managing chronic pain and possess serious central side-effects, including an altered mental state, addiction, and life-threatening respiratory depression. Thus, the investigation of novel targets for the development of safer, more effective treatments is critical.

In this study, Nackley and her team will develop novel Adrb3 antagonists for the treatment of CPPCs. This work is innovative in three ways: 1) Inhibition as a therapeutic indication of Adrb3 remains largely unexplored. Few Adrb3 specific antagonists have been disclosed in the literature, and none are currently approved for clinical use, 2) Adrb3 is a novel therapeutic target for pain, and peripherally-restricted Adrb3 antagonists will likely be devoid of central side-effects. In contrast to current analgesics that act on receptors and ion channels in the central nervous system, including opioids, cannabinoids, and Trp channels, a peripherally selective Adrb3 antagonist may have increased therapeutic utility and decreased central side-effects (eg, addiction), and 3) The Adrb3-targeted therapeutics developed in this study may also translate to other pain and health conditions associated with deficiencies in catecholamine metabolism (eg, burn, trauma, and surgical pain, cancer risk and cancer pain) or hyper-responses to sympathetic release of norepinephrine, as occurs in neuropathic pain and complex regional pain syndrome.

The objective of this study is to develop a drug discovery platform for Adrb3 antagonists that includes further assessment of Adrb3 as a critical target and a robust medicinal chemistry effort, while establishing the multidisciplinary team of experts needed for U19 follow-on funding. The three research aims include 1) testing the analgesic and potential side-effect profiles of Adrb3 antagonists in a mouse model of CPPCs, 2) developing novel peripherally-restricted Adrb3 antagonists, and 3) developing a multidisciplinary team of experts to progress their lead-like compounds to a successful U19 therapeutics discovery platform.

“Successful completion of our research will support follow-on funding to develop new peripherally-restricted analgesics that are suitable for advancement into human trials with the potential to have a positive impact on the quality of life for millions of patients who suffer from chronic primary pain,” says Nackley, associate professor in anesthesiology, pharmacology and cancer biology and associate director of the Center for Translational Pain Medicine.