2023 IARS Mentored Research Award

Nicholas GregoryNicholas Gregory, MD, PhD
Stanford University
Palo Alto, CA

Dr. Gregory’s Research

CNS Regions Selectively Activated by Muscle Pain-Induced Hyperalgesia

Fibromyalgia (FM) is a chronic disease characterized by widespread muscle pain and mood deficits, including depression. Central sensitization, a pathologic state of painful sensitivity to previously non-painful stimuli, is strongly associated with FM. Muscle insult is a potent trigger of central sensitization, causing more intense, longer lasting, and wider spread effects than other triggers. This study will investigate the pathophysiology of central sensitization in FM using the acid-induced muscle pain model (AIMP). As with FM, it is demonstrated that AIMP causes central sensitization in the form of widespread pain and mood deficits. Using an unbiased, whole-brain approach, several regions of altered neural activity generated by AIMP were found, including the periaqueductal gray (PAG), rostroventromedial medulla (RVM), central amygdala (CeA), and secondary somatosensory cortex (SII). However, the PAG, a key component of descending inhibition, showed relatively suppressed activity in AIMP compared to controls, while the other brain regions showed increased activity. This study will test the hypothesis that AIMP produces widespread pain and mood deficits by inhibiting PAG activity. Further, the research will define the connectivity between the PAG and two structures shown to be functionally connected to the PAG—the RVM and CeA, both of which have been implicated in pain. Finally, tests will be undertaken to determine whether the RVM, CeA, and SII are necessary and sufficient to develop widespread pain and mood deficits. This innovative project will use functionally selective approaches of optogenetics, chemogenetics, advanced animal behavior models, machine learning, and statistical modeling to dissect the mechanisms by which muscle pain causes robust, widespread central sensitization. This will enhance understanding of and treatments for important chronic pain conditions like FM, which lead to substantial suffering and disability.