Funded Projects

NOFO Title: HEAL Initiative: Non-addictive Analgesic Therapeutics Development [Small Molecules and Biologics] to Treat Pain (UG3/UH3 Clinical Trial Optional)
NOFO Number: RFA-NS-21-010
Summary:

Overreliance on opioids to treat chronic pain has been a contributor to the increase in individuals experiencing opioid addiction. This project aims to develop an innovative treatment approach for chronic pain that targets the cannabinoid receptor 1 (CB1R) to block the sensation of pain. The approach seeks to identify molecules that interact with a different part of the CBR1 receptor than do endocannabinoids and the primary active component of cannabis, tetrahydrocannabinol. Molecules that bind to and activate CBR1 in this different way (at an “allosteric” site) may produce nerve signaling that might differ from the effects of cannabis and endocannabinoids. This redirection of signaling pathways could help eliminate the risk of adverse effects observed with natural cannabinoids and other CBR1-binding molecules. The goal of this project is to identify a CB1R allosteric molecule, conduct studies toward obtaining federal permission to develop it as a medication, and to test it in a Phase I clinical study.

NOFO Title: Discovery and Validation of Novel Targets for Safe and Effective Pain Treatment (R01 Clinical Trial Not Allowed)
NOFO Number: RFA-NS-18-043
Summary:

A major recent advancement for the field of pain research is the recognition of immune system dysregulation as a contributor to the most serious adverse consequences of pain from injury. Accumulating data from clinical and laboratory studies place the activation of B lymphocytes at the center of much of this work, particularly with respect to chronic pain and disability-related outcomes. Validation of this B cell hypothesis could lead directly to trials testing the efficacy of novel or existing immunomodulating agents on posttraumatic pain. To achieve these goals a well-validated core mouse model of limb fracture will be employed with additional studies to be conducted in incisional and nerve injury models to broaden the assessment of B cell mediated effects on pain. Age and sex will be included as variables to enhance rigor.

NOFO Title: Discovery and Validation of Novel Targets for Safe and Effective Pain Treatment (R01 Clinical Trial Not Allowed)
NOFO Number: RFA-NS-18-043
Summary:

It is unclear what changes in the brain mediate the development of chronic pain from acute pain and how chronic pain may change responses to opioid reward for the altered liability of opioid abuse under chronic pain. Preliminary studies have found that Dnmt3a, a DNA methyltransferase that catalyzes DNA methylation for gene repression, is significantly downregulated in the brain in a time-dependent manner during the development of chronic pain and after repeated opioid treatment. This project will investigate whether Dnmt3a acts as a key protein in the brain for the development of chronic pain, and whether Dnmt3a could be a novel epigenetic target for the development of new drugs and therapeutic options for the treatment of chronic pain while decreasing abuse liability of opioids.

NOFO Title: Discovery of Biomarkers, Biomarker Signatures, and Endpoints for Pain (R61/R33 Clinical Trial Optional)
NOFO Number: RFA-NS-18-041
Summary:

Chronic pain is a major health burden associated with immense economic and social costs. Predictive biomarkers that can identify individuals at risk of developing severe and persistent pain, which is associated with worse disability and greater reliance on opioids, would promote aggressive, early intervention that could halt the transition to chronic pain. The applicant’s team uncovered evidence of a unique cortical biomarker signature that predicts pain susceptibility (severity and duration). This biomarker signature could be capable of predicting the severity of pain experienced by an individual minutes to months in the future, as well as the duration of pain (time to recovery). Analytical validation of this biomarker will be conducted in healthy participants using a standardized model of the transition to sustained myofascial temporomandibular pain. Specifically the biomarker signature will be tested for its ability to predict an individual’s pain sensitivity, pain severity, and pain duration and will perform initial clinical validation.

NOFO Title: Optimization of Non-addictive Therapies [Small Molecules and Biologics] to Treat Pain (UG3/UH3 Clinical Trial Not Allowed)
NOFO Number: RFA-NS-19-010
Summary:

Although opioid-based analgesics have been proven effective in reducing the intensity of pain for many neuropathic pain conditions, their clinical utility is grossly limited due to the substantial risks involved in such therapy, including nausea, constipation, physical dependence, tolerance, and respiratory depression. Cumulative evidence suggests that human Mas-related G protein-coupled receptor X1 (MRGPRX1) is a promising target for pain with limited side effects due to its restricted expression in nociceptors within the peripheral nervous system; however, direct activation of MRGPRX1 at peripheral terminals is expected to induce itch side effects, limiting the therapeutic utility of orthosteric MRGPRX1 agonists. This finding led to the exploration of positive allosteric modulators (PAMs) of MRGPRX1 to potentiate the effects of the endogenous agonists at the central terminals of sensory neurons without activating peripheral MRGPRX1. An intrathecal injection of a prototype MRGPRX1 PAM, ML382, effectively attenuated evoked, persistent, and spontaneous pain without causing itch side effects. The goal of this study is to develop a CNS-penetrant small-molecule MRGPRX1 PAM that can be given orally to treat neuropathic pain conditions.

NOFO Title: HEAL Initiative: Non-addictive Analgesic Therapeutics Development [Small Molecules and Biologics] to Treat Pain (UG3/UH3 Clinical Trial Optional)
NOFO Number: RFA-NS-21-010
Summary:

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.

NOFO Title: Discovery and Validation of Novel Targets for Safe and Effective Pain Treatment (R01 Clinical Trial Not Allowed)
NOFO Number: RFA-NS-18-043
Summary:

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.

NOFO Title: Administrative Supplements for Validation of Novel Non-Addictive Pain Targets (Clinical Trials Not Allowed)
NOFO Number: NOT-NS-18-073
Summary:

Spinal cord injury (SCI) impairs sensory transmission leading to chronic, debilitating neuropathic pain. While our understanding of the molecular basis underlying the development of chronic pain has improved, the available therapeutics provide limited relief. In the lab, we have shown the timing of exercise is critical to meaningful sensory recovery. Early administration of a sustained locomotor exercise program in spinal cord–injured rats prevents the development of neuropathic pain, while delaying similar locomotor training until pain was established was ineffective at ameliorating it. The time elapsed since the injury occurred also indicates the degree of inflammation in the dorsal horn. We have previously shown that chronic SCI and the development of neuropathic pain correspond with robust increases in microglial activation and the levels of pro-inflammatory cytokines. This proposal seeks to lengthen the therapeutic window where rehabilitative exercise can successfully suppress neuropathic pain by pharmacologically reducing inflammation in dorsal root ganglia.

NOFO Title: Discovery of Biomarkers, Biomarker Signatures, and Endpoints for Pain (R61/R33 Clinical Trial Optional)
NOFO Number: RFA-NS-18-041
Summary:

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.

NOFO Title: Administrative Supplements for Validation of Novel Non-Addictive Pain Targets (Clinical Trials Not Allowed)
NOFO Number: NOT-NS-18-073
Summary:

Many chronic pain conditions are dependent upon activity of the sympathetic nervous system. Sympathetic blockade is used clinically in chronic pain conditions, but the clinical and preclinical evidence for this practice is incomplete. We propose that certain pathological pain conditions require intact sympathetic innervation of the sensory nervous system at the level of the dorsal root ganglion (DRG) and that release of sympathetic transmitters enhances local inflammation and leads to pain. Our preliminary data show large, rapid, and long-lasting reduction of pain behaviors and inflammatory responses following a"microsympathectomy" (mSYMPX) in both neuropathic and inflammatory pain models. Our aims are to: 1) characterize the effects of mSYMPX on pain and on local inflammation in the DRG; 2) explore the molecular mechanisms for sympathetic regulation of inflammatory responses in the DRG; and 3) assess the functional role of sympathetic transmitters in the sympathetically mediated inflammatory responses in the DRG.

NOFO Title: Administrative Supplements to Existing NIH Grants and Cooperative Agreements. Parent Grant: HEAL Initiative: Non-addictive Analgesic Therapeutics Development [Small Molecules and Biologics] to Treat Pain (UG3/UH3 Clinical Trial Optional)
NOFO Number: Supplement: PA-20-272; Parent NOFO: NS-21-010
Summary:

Negative allosteric modulators (NAMs) of the metabotropic glutamate (mGlu) receptor, mGlu5, have shown promise for treatment of multiple pain conditions without the serious adverse effects and safety concerns associated with opioids. This project will develop and test a novel series of highly selective mGlu5 NAMs that are structurally unrelated to earlier failed compounds and do not form toxic byproducts as with previous mGlu5 NAMs. A lead candidate is now being characterized in several studies to assess readiness for testing in Phase I clinical studies.

NOFO Title: Discovery and Validation of Novel Targets for Safe and Effective Pain Treatment (R01 Clinical Trial Not Allowed)
NOFO Number: RFA-NS-18-043
Summary:

This project aims to validate Peptidase Inhibitor 16 (PI16) as a novel target for the treatment of chronic pain using mouse models and tissues of human patients with neuropathy. PI16 was identified as a novel regulator of chronic pain in preclinical bench studies. PI16 is a small molecule that has not been studied in the context of pain. Mice that are deficient for PI16 function are protected against mechanical allodynia (tactile pain from light touch) in spared nerve injury (SNI) and paclitaxel models of neuropathic pain. PI16 is only detectable in fibroblasts around peripheral nerves (perineurium), and in the meninges of dorsal root ganglia (DRG), spinal cord, and brain, but not in neurons, glia or leukocytes. PI16 levels in perineurial and DRG meningeal fibroblasts increase during neuropathic pain. Increased PI16 secretion by DRG meningeal and perineurial fibroblasts may promote chronic pain by increasing blood nerve barrier (BNB) permeability and leukocyte trafficking into nerve and DRG.

NOFO Title: Administrative Supplements to Existing NIH Grants and Cooperative Agreements (Parent Admin Supp Clinical Trial Optional)
NOFO Number: PA-18-591
Summary:

Spinal cord injury (SCI) impairs sensory transmission and leads to chronic, debilitating neuropathic pain. While our understanding of the development of chronic pain has improved, the available therapeutics provide limited relief. We will examine the peripheral immune and inflammatory response. Secondary inflammation in response to SCI is a series of temporally ordered events: an acute, transient upregulation of chemokines, followed by the recruitment of monocytes/macrophages and generation of an inflammatory environment at the lesion site in the spinal cord, but also surrounding primary nociceptors in the dorsal root ganglia (DRG). These events precede neuropathic pain development. Previous work indicates that after SCI, macrophage presence in the DRG correlates with neuropathic pain. We propose to study: 1) whether the phenotype of macrophages that infiltrate the DRG is different than those that persist chronically after SCI and 2) how manipulation of macrophage phenotype affects nociceptor activity and pain development.