The National Institute of Neurological Disorders and Stroke has awarded Duke Anesthesiology’s Andrea Nackley, PhD, a $2,973,554 R01 grant for her project titled, “Defining the Role of Peripheral Adrb3 in Chronic Pain and Inflammation.” The five-year award builds on discoveries from Nackley’s laboratory that reveal an unexpected role for fat cells, or adipocytes, in the development and persistence of chronic primary pain.
“Chronic primary pain conditions affect more than 100 million Americans, yet we still lack treatments that address their underlying causes,” says Nackley, associate professor of anesthesiology, pharmacology and cancer biology. “Our work suggests that adipose tissue is not simply a passive energy store, but that it can actively communicate with the nervous system to influence pain. This new funding will allow us to define those mechanisms and identify new peripheral targets for safer, more effective therapies.”
The award follows a recent study from Nackley’s team published in the Journal of Clinical Investigation, “Catecholamine-Mediated Release of miR-133a-3p from Adipocytes Regulates the Onset of Chronic Primary Pain.” The study identified miR-133a-3p, a small regulatory RNA produced by adipocytes, as a potential biomarker and regulator of chronic primary pain. Levels of miR-133a-3p were reduced in people with fibromyalgia and vestibulodynia and in animal models of primary pain. In mice, restoring miR-133a-3p specifically in adipose tissue reversed mechanical hypersensitivity at multiple body sites. The findings suggest that stress-related catecholamine signaling alters miR-133a-3p in adipocyte-derived extracellular vesicles, potentially changing pain-related gene expression and sensory neuron activity in the spinal cord.
The new R01 will extend these findings by investigating how catecholamine activation of beta-3 adrenergic receptors (Adrb3) on adipocytes drives pain, inflammation and neuroinflammation. Nackley’s team will 1) examine Adrb3-dependent remodeling across adipose depot, 2) determine how adipocyte-derived extracellular vesicles carrying miR-133a-3p regulate pain-related genes in the spinal cord, and 3) characterize a newly identified population of adipocytes located alongside sensory neurons in dorsal root ganglia in mice and humans. Together, these studies have the potential to establish a new adipose–neural communication axis in chronic pain and provide a foundation for developing peripherally targeted analgesics that avoid the central side effects of many current pain medications.
Nackley also serves as co-director of the Center for Translational Pain Medicine and director of the Translational Pain Research Laboratory within Duke Anesthesiology, which aims to improve the management of chronic pain by discovering the molecular and cellular mechanisms that drive it.