Funded Projects

Epidural/spinal administration of analgesics such as opioids, ziconotide and local anesthetics have profound efficacy in some of the most intractable pain conditions such as severe neuropathic pain after failed back surgery, cancer pain and post-operative pain after major abdominal/thoracic surgeries. Contulakin G (CGX) is a snail venom derived peptide that has homology with mammalian neurotensin and was shown to be safe in humans in preliminary studies. A small pilot study demonstrated CGX?s analgesic effect in some patients with spinal cord injury-associated pain. Preliminary findings from mechanistic studies in rodents identified neurotensin receptor 2 (NTSR2) as the mediator for analgesic effects of CGX. This project aims to validate spinal NTSR2 as an analgesic target utilizing three species (rat, mice and human), and two pain models (neuropathic pain and post-surgical pain). The project will utilize pharmacological and gene editing tools such as CRISPR-Cas9 and will include assessment of both sensory and affective measures of pain. A two-site parallel confirmation study is designed based on multisite clinical trials to further authenticate spinal NTSR2 as an analgesic target. Successful completion of this project could lead to the development of a non-opioid spinal analgesic that has high translational potential.

The development of non-addictive pain therapeutics can help counter opioid addiction and benefit patients, including those who suffer from neuropathic pain, in particular diabetic neuropathic pain (DNP). This project’s goal is to develop a safe, efficacious, and non-addictive small-molecule drug that activates Kv7 voltage-gated potassium channels to address overactive neuronal activity in DNP. Researchers will discover Kv7 activators that favor Kv7 isoforms altered in DNP and found in dorsal root ganglia, decrease off-target side effects observed with the use of earlier non-biased Kv7 activators, and optimize the absorption, distribution, metabolism, excretion, and toxicity profiles of these activators. This screening paradigm is intended to establish a clinic-ready, well-tolerated, and widely effective product to treat neuropathic pain.

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.

As prescription opioid drug abuse and overdose-related deaths continue to skyrocket in the United States, the need for new and more effective non-addictive pain drugs to treat chronic pain remains critical. This research is conducting studies in animal models of a small molecule that has high potential to treat chronic pain conditions associated with neuropathy and/or inflammation. The goal of this project is to conduct dosing and other studies leading up to an animal model study of the potential drug in a toxicology study for 28 days. Results may lead to Investigative New Drug regulatory clearance to begin clinical studies to validate the potential drug’s efficacy and safety.

Neuropathic corneal pain (NCP) causes patients to have severe discomfort and a compromised quality of life (QoL). The lack of signs observed by standard examination has resulted in misdiagnosis as dry eye disease (DED). An optical biopsy using laser in vivo confocal microscopy (IVCM) revealed that microneuromas (bulbs at the ends of severed nerves caused by buildup of molecular constituents) are present in NCP but not DED and may serve as a biomarker for NCP. The aims are to (1) use a database of more than 2,000 DED/NCP subjects and more than 500,000 IVCM images to confirm that the presence of microneuromas is an appropriate biomarker for NCP, (2) provide biological validation of microneuromas, (3) develop a validated artificial intelligence (AI) program for automated identification of microneuromas, and (4) establish the clinical utility of microneuromas observed by IVCM as a biomarker for NCP in a prospective, multicenter study.

Pain associated with surgery is experienced by millions of patients every year. Although post-surgical pain usually resolves as the surgical site heals, up to half of the patients develop chronic pain after surgery. Opioids remain the mainstay treatment for post-surgical pain which are fraught with serious side-effects and abuse liabilities. The endogenous mechanism that leads to the resolution of post-surgical pain remain unclear, specifically the effects of surgery on the metabolism of sensory neurons and how those changes influence the resolution of post-surgical pain are not known. Preliminary findings suggest that surgical trauma suppresses pyruvate oxidation while increased glutamine catabolism was associated with the resolution of post-surgical pain. This project will test the hypothesis that tissue incision and surgery disrupt the expression of the glutamine transporter ASCT2, which then prevents the resolution of post-incisional pain and aims to validate ASCT2 as a therapeutic target. This project will also employ pharmacological, genetic and animal pain model studies test a novel RNA expression-based strategy to enhance ASCT2 expression in DRG sensory neurons and alleviate postoperative pain in animal model systems. Successful completion of this project would validate ASCT2 as a novel endogenous non-opioid and non-addictive mechanism-based target for the resolution of postoperative pain.

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.

Up to 5 percent of adolescents suffer from high-impact chronic musculoskeletal (MSK) pain, and only about 50 percent with chronic MSK pain who present for treatment recover. Current treatments for chronic MSK pain are suboptimal and have been tied to the opioid crisis. Discovery of robust markers of the recovery versus persistence of pain and disability is essential to develop more resourceful and patient-specific treatment strategies, requiring measurements across multiple dimensions in the same patient cohort in combination with a suitable computational analysis pipeline. Preliminary data has implicated novel candidates for neuroimaging, immune, quantitative sensory, and psychological markers for discovery. In addition, a standardized specimen collection, processing, storage, and distribution system is in place, along with expertise in machine learning approaches to extract reliable and prognostic bio-signatures from a large and complex data set. This project will facilitate risk stratification and a resourceful selection of patients who are likely to respond to current multidisciplinary pain treatment approaches.

There is a clear public health imperative to improve the care and outcomes of people who experience severe acute and chronic pain. The Early Phase Pain Investigation Clinical Network (EPPIC-Net) is charged with conducting deep phenotyping and biomarker studies for specific pain conditions – and with conducting high-quality phase II clinical trials to test novel non-opioid pain treatments with academic and industry partners. This research will extend EPPIC-Net’s current portfolio to develop novel and efficient data-analytic methodologies for complex medical data, such as those that are expected to be generated by the clinical trials conducted by EPPIC-Net.

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.

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.