Funded Projects

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.

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.

Interstitial cystitis/bladder pain syndrome is a debilitating disease affecting many women. Opioid-based pain management is a common feature of current treatment approaches but is associated with the risk of addiction. The causes of this disorder remain unknown, and no effective treatments are available. This project will provide new insights using genetic, medication-based and other approaches in a mouse model, along with single-cell gene expression studies conducted with cells from mice and human patients who have this condition. The analyses will help provide targeted, safe, and effective treatment approaches for individuals with interstitial cystitis/bladder pain syndrome.

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.

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.

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.

African American adults are less likely to receive analgesics, particularly opioids. Research in the pediatric surgical population is limited, but the pattern of disparate use of opioids appears consistent with adults. Furthermore, adolescent access to prescribed opioids has increased, both through physician prescribing and misuse of medications prescribed to family members or friends. This study will explore the interrelated impacts of policy, clinical need, and sociodemographic factors by combining Medicaid claims and electronic health record data with findings from a statewide opioid policy inventory. We will focus on discharge prescribing of opioids in three high-volume pediatric surgical procedures: tonsillectomy/adenoidectomy, supracondylar fracture, and appendectomy. We aim to 1) determine the extent of racial disparities in postoperative discharge opioid prescribing since the 2011 onset of enhanced opioid prescription reduction activities and 2) develop an expanded model to assess the linkage between differential opioid use for pediatric postoperative pain and opioid use-related outcomes.

Current medications for chronic pain are largely ineffective and rely heavily on opioids, one contributor to the nation’s opioid crisis. The endocannabinoid system that consists of cannabinoid receptors (CB1R and CB2R) and their endogenous ligands is a natural pathway in the human body and has emerged as an alternative target for developing new pain medications with few side effects. Current molecules that bind to CB1R in the brain and spinal cord have psychoactive side effects, limiting their therapeutic use for treating chronic pain. This study aims to develop new molecules to bind to CB1R tightly and selectively, are metabolically stable, and are also unable to enter the brain.

Migraine is a painful and debilitating neurological condition, the development and maintenance of which involves the neuropeptide calcitonin gene-related peptide (CGRP). An exciting development in the treatment of migraine is the recent FDA approval of a new class of CGRP-targeted therapies designed to prevent migraine. However, these drugs meet a clinically relevant endpoint for only about half of the patients. This project will test the hypothesis that the high-affinity CGRP receptor AMY1 is a novel and unexplored target that mediates specific migraine-related behaviors in the brain and/or periphery to cause migraine. Validation of CGRP and AMY1 receptor involvement in migraines will create a new direction for the development of novel drugs and provide alternatives to opioids for management of migraine and potentially for other chronic pain conditions.

Many non-opioid drugs target G Protein-Coupled Receptors (GPCRs), a family of proteins involved in many pathophysiological processes including pain, fail during clinical trials for unknown reasons. A recent study found GPCRs not only function at the surface of nerve cells but also within a cell compartment called the endosome, where their sustained activity drives pain. This study will build upon this finding and test whether the clinical failure of drugs targeting plasma membrane GPCRs is related to their inability to target and engage endomsomal GPCRs (eGPCRs). This study will use stimulus-responsive nanoparticles (NP) to encapsulate non-opioid drugs and selectively target eGPCR dyads to investigate how eGCPRs generate and regulate sustained pain signals in neuronal subcellular compartments. This study will also validate eGCPRs as therapeutic targets for treatment of chronic inflammatory, neuropathic and cancer pain. Using NPs to deliver non-opioid drugs, individually or in combinations, directly into specific compartments in nerve cells could be a potential strategy for new pain therapies.

Oral cancers are painful and often require use of opioid medications to manage pain. However, the effectiveness of opioids often wanes quickly, and many patients require higher doses because they develop tolerance to these medications. This project will study the potential value of blocking epidermal growth-factor receptors interacting with peripheral nerves to treat oral cancer pain. The findings will advance understanding of the molecular mechanisms underlying oral cancer pain and provide a rationale for repurposing epidermal growth-factor receptor blockers, which is already approved for head and neck cancer treatment for treating oral cancer and associated pain.

Multi-protein complexes have emerged as a mechanism for spatiotemporal specificity and efficiency in the function and regulation of myriad cellular signals. In particular, many ion channels are clustered either with the receptors that modulate them, or with other ion channels whose activities are linked. Often the clustering is mediated by scaffolding proteins, such as the AKAP79/150 protein that is a focus of this research. This research will focus on three different channels critical to nervous function. One is the"M-type" (KCNQ, Kv7) K+ channel that plays fundamental roles in the regulation of excitability in nerve and muscle. It is thought to associate with Gq/11- coupled receptors, protein kinases, calcineurin (CaN), calmodulin (CaM) and phosphoinositides via AKAP79/150. Another channel of focus is TRPV1, a nociceptive channel in sensory neurons that is also thought to be regulated by signaling proteins recruited by AKAP79/150. The third are L-type Ca2+ (CaV1.2) channels that are critical to synaptic plasticity, gene regulation and neuronal firing. This research will probe complexes containing AKAP79/150 and these three channels using"super-resolution" STORM imaging of primary sensory neurons and heterologously-expressed tissue-culture cells, in which individual complexes can be visualized at 10-20 nm resolution with visible light, breaking the diffraction barrier of physics. The researchers hypothesize that AKAP79/150 brings several of these channels together to enable functional coupling, which the researchers will examine by patch-clamp electrophysiology of the neurons. Förster resonance energy transfer (FRET) will also be performed under total internal reflection fluorescence (TIRF) or confocal microscopy, further testing for complexes containing KCNQ, TRPV1 and CaV1.2 channels. Since all three of these channels bind to AKAP79/150, the researchers hypothesize that they co-assemble into complexes in neurons, together with certain G protein-coupled receptors. Furthermore, the researchers hypothesize these complexes to not be static, but rather to be dynamically regulated by other cellular signals, which the researchers will examine using rapid activation of kinases or phosphatases. Several types of mouse colonies of genetically altered AKAP150 knock-out or knock-in mice will be utilized.

Chronic pain is maintained, in part, by persistent changes in sensory neurons, including a pathological increase in peptides derived from the neurosecretory protein VGF (non-acronymic). Preliminary findings show that the C-terminal VGF peptide, TLQP-62, contributes to spinal cord neuroplasticity and that TLQP-62 immunoneutralization attenuates established mechanical hypersensitivity in a traumatic nerve injury model of neuropathic pain. This project will test the hypothesis that spinal cord TLQP-62 signaling can be targeted for the development of new chronic pain treatments through immunoneutralization and/or receptor inhibition. It will pursue discovery and validation of TLQP-62-based therapeutic interventions along two parallel lines: identification of TLQP-62 receptor(s) and validation of anti-TLQP-62 antibodies as a potential biological therapeutic option for chronic neuropathic pain conditions.