Funded Projects

There is increasing evidence that satellite glial cells (SGCs) surrounding neurons in the dorsal root ganglia modulate sensory processing and are important for chronic pain. Tissue inhibitor of metalloproteinase 3 (TIMP3) signaling occurs in SGCs and has unique plethoric functions in inhibiting matrix metalloproteinases, the tumor necrosis factor-?-converting enzyme, and the vascular endothelial growth factor receptor 2, all of which have been implicated in inflammation and pain. This study will test the hypothesis that expression of TIMP3 in SGCs is critical for the neuroimmune homeostasis in sensory ganglia, as well as for the development of pain, and therefore could be a novel therapeutic target for acute and chronic pain. Given the expression of TIMP3 in human SGCs and the strong validation of multiple small molecules targeting TIMP3 signaling, including FDA-approved drugs, in various animal models of pain and in cultured human SGCs, the successful completion of this research project has a high likelihood of rapid translation into therapeutic testing in inflammatory pain conditions that are a risk for opioid abuse.

The research team will develop HD64—a high-resolution, 64-channel spinal cord stimulation therapy to provide more pain relief for those suffering from chronic neuropathic pain and opioid dependence. HD64 provides an ultra-thin conformal blanket of stimulation contacts across the width of the spinal cord and enables more precise targeting of the lateral structures of the spinal cord to enhance pain relief. A cadaveric pilot run followed by a non-significant risk intraoperative study will be performed to inform the design parameters of HD64 arrays. The study will evaluate activation of medial and lateral spinal targets. At the end of Phase 1, the clinical feasibility of HD64 surgical leads will be established. In Phase 2, researchers will develop an external active lead pulse generator and charger. They will perform an early feasibility study human trial using active HD64 and mechanical and electrical design verification testing and chronic safety studies in large animals.

A key marker of inflammation in Osteoarthritis (OA) is accompanied by significantly increased sensory innervation within the diseased joint. This study aims to validate the hypothesis that defective bone resorbing cells are responsible for the enlarged bone cavity, giving rise to the inflammatory marker causing further increases in levels sensory innervation and resulting in increased OA pain perception.

Pain caused by the degeneration of discs between vertebrae in the spine makes up a significant proportion of all chronic low back pain conditions. Although opioids are prescribed as treatments for this chronic condition, they often do not provide effective pain management, and currently there are no treatments that target the underlying disc disease. Notochordal cells mature into the cells that make up discs between vertebrae. Preliminary studies have shown that notochordal cells can be made from induced pluripotent stem cells, offering a potential replacement for diseased cells between discs. This study aims to develop a novel treatment for painful disc degeneration using a microgel/microtissue embedded with human notochordal cells made in the lab from induced pluripotent stem cells.

Chronic pain diminishes the quality of life for millions of patients, and new drugs that have better efficacy and/or fewer side effects are needed. A promising target is the sphingosine-1-phosphate (S1P) receptor system, which mediates central nervous system (CNS) neuromodulatory functions. FTY720-phosphate, the active metabolite of FTY720 (FTY), acts as an agonist at four of the five S1P receptors (S1P1, 3, 4, 5). We propose that the S1P1 receptor is a target for treatment of neuropathic pain. We will test whether S1P1 receptors mediate anti-hyperalgesic effects in a mouse neuropathic pain model. The specific aims are to: 1) determine the role of S1P1Rs in alleviation of neuropathic pain by S1PR ligands; 2) determine the role of FTY-induced S1PR adaptation in FTY-mediated reversal of neuropathic pain; and 3) determine the role of S1P and S1P1 receptors in spinal glia in CCI-induced neuropathic pain and its reversal by FTY.

Inhaled nitrous oxide, N₂O, is used in emergency departments in Europe to treat pain associated with sickle cell disease as well as for labor, painful fractures, and to manage serious gynecological pain. It is not a viable therapeutic option for home use for reasons such as poor dosing control, potential inhalation equipment issues, and variability in patient ventilation and lung absorption. This project seeks to optimize, characterize, and develop an oral formulation of N₂O that could be used by patients at home for unpredictable and severe episodes of pain associated sickle cell disease. Once developed, the new oral formulation of N₂O will be evaluated to determine whether it or an optimized version is ready for more clinical testing.

The primary goal of the PRECISION Human Pain network and its participating centers is to generate comprehensive datasets of molecular signatures and cellular function phenotypes or signatures of various cell types that underlie transmission and processing of pain signals in humans. To maximize the impact of the data generated through this effort, it is vital to standardize and integrate all data generated by the various centers and make these data available in a meaningful way to the larger scientific community. As the Data Coordination and Integration Center, this project will support the network to curate, harmonize, and effectively integrate center-generated datasets as well as provide operational support for the network and conduct educational and outreach efforts.

The MGH EPPIC-Net hub will utilize two well-established collaborative entities in both patient care and clinical research at the Massachusetts General Hospital (MGH): 1) MGH Division of Pain Medicine and 2) MGH Center for Translational Pain Research. This hub-spoke network at MGH will include four core spokes consisting of both academic centers and community health care organizations, as well as over a dozen spokes that can be recruited as needed based on special requirements of phase II trials and research studies. The responsibilities of this hub-spoke network at MGH include a) coordinating phase II trials/clinical biomarker validation studies; b) recruiting well-phenotyped subjects in a timely manner; c) collecting clinical data and targeted outcome data tailored to meet the needs of each clinical trial/study; and d) maintaining communications within and outside the hub, including the NIH EPPIC-Net.

Cataract surgery is commonly performed in older adults; however, some patients subsequently experience chronic eye pain that is difficult to treat. One promising approach that is effective in some, but not all, patients uses the patient's own serum (a component of blood) as eye drops. This project seeks to identify markers that can help predict which patients will respond to serum treatment and monitor their progress. Using advanced technology and data analysis to evaluate patient histories, questionnaires, and different genetic and other molecular characteristics in the eyes and serum it aims to identify potential markers that can then be tested in a clinical study.

Spinal cord stimulators (SCS) and related devices are commonly used for hard-to-treat pain conditions, but how they work remains unclear. This knowledge is important for improving device design and stimulation patterns, as well as for determining which patients will benefit. Through a series of clinical studies in patients with SCS devices, this project will explore the hypothesis that SCS devices reduce pain by changing the excitability of peripheral sensory nerve fibers in the spinal cord. The results should guide development of biomarkers to advance research further.

Neuropathic pain conditions are difficult to treat, and novel non-narcotic analgesics are desperately needed. The G protein-coupled receptor 160 (GPR160) has emerged as a novel target for analgesic development, as GPR160 in the spinal cord may play a role in the transition from acute to chronic pain. Cocaine- and Amphetamine-Regulated transcript peptide (CARTp) was identified as a ligand for GPR160. Blocking endogenous CARTp signaling in the spinal cord attenuates neuropathic pain, whereas intrathecal injection of CARTp evokes painful hypersensitivity in rodents through GPR160-dependent extracellular signal-regulated kinase (ERK) and cyclic AMP response element-binding pathways (CREB). This project will isolate and biochemically characterize GPR160 and establish methods for biochemical characterization of GPR160 interaction with CARTp activator. Researchers will miniaturize and optimize biochemical assay and scale up protein production for future high throughput biochemical screening to identify potent inhibitors of GPR160 activation. These studies are critical for defining the molecular mechanism of CARTp/GPR160 interactions and initiating large-scale screens for new inhibitors to develop novel therapeutics.

The Data Coordinating Center (DCC) of the Early Phase Pain Investigation Clinical Network (EPPIC-Net) will be the data and biospecimen manager for pain research within the HEAL Partnership. As such, it will host, manage, standardize, curate, and provide a sharing platform for data and biospecimens for HEAL initiatives, such as the Acute to Chronic Pain Signatures initiative and the BACPAC, in addition to EPPIC-Net studies. The DCC will develop and maintain a databank for depositing data, will link these data with a repository for biological samples, and will create a platform for teams to work together to analyze and interpret data. Further, the DCC will provide leadership in the statistical design and analysis of EPPIC-Net studies and will deploy advanced systems and processes for data collection, management, quality assurance, and reporting. The DCC will create, sustain, and continually advance a robust organization for the rapid design, implementation, and performance of high-quality rigorous Phase II clinical trials to test promising therapeutics for pain.