Funded Projects

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.

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.

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.

The research team has developed ultrasonic drug uncaging for neuroscience, in which neuromodulatory agents are uncaged from ultrasound-sensitive biocompatible and biodegradable drug-loaded nanocarriers. This project will clinically translate ultrasonic ketamine uncaging for chronic pain therapy. In the UG3 phase, the research team will scale our nanoparticle production processes to human scales and adapt them to pharmaceutical standards. In the UH3 phase, they will complete a first-in-human evaluation of the safety and efficacy of ultrasonic ketamine uncaging by quantifying how much ketamine is released relative to the ultrasound dose and assessing whether the uncaged ketamine can modulate the sensitivity and affective response to pain, in patients suffering from chronic osteoarthritic pain. This project aims to yield a novel, noninvasive, non-opioid therapy for chronic pain that maximizes the therapeutic efficacy of ketamine over its side effects, by targeting its action to a critical hub of pain processing.

TWIK-related spinal cord K+ (TRESK) channel is abundantly expressed in all primary afferent neurons (PANs) in trigeminal ganglion (TG) and dorsal root ganglion (DRG), mediating background K+ currents and controlling the excitability of PANs. TRESK mutations cause migraine headache but not body pain in humans, suggesting that TG neurons are more vulnerable to TRESK dysfunctions. TRESK knock out (KO) mice exhibit more robust behavioral responses than wild-type controls in mouse models of trigeminal pain, especially headache. We will investigate the mechanisms through which TRESK dysfunction differentially affects TG and DRG neurons. Based on our preliminary finding that changes of endogenous TRESK activity correlate with changes of the excitability of TG neurons during estrous cycles in female mice, we will examine whether estrogen increases migraine susceptibility in women through inhibition of TRESK activity in TG neurons. We will test the hypothesis that frequent migraine attacks reduce TG TRESK currents.

The ability to de-risk lead compounds during pre-clinical development with advanced “organoid-on-a-chip” technologies shows promise. Development of microphysiological models of the peripheral nervous system is lagging. The technology described herein allows for 3D growth of high-density axonal fiber tracts, resembling peripheral nerve anatomy. The use of structural and functional analyses should mean drug-induced neural toxicity will manifest in these measurements in ways that mimic clinical neuropathology. The goals of this proposal are to establish our human model using relevant physiological measurements in tissues fabricated from human iPS cells and to validate the model system with a library of compounds, comparing against conventional cell culture models. Validating the peripheral nerve model system with drugs known to induce toxicity via a range of mechanisms will demonstrate the ability of the system to predict various classifications of neuropathy, yielding a high-content assay far more informative than traditional in vitro systems.

Wound care procedures (WCPs), such as dressing changes, cause moderate to severe pain in 74% of patients, nearly half of whom experience severe pain. Mainstay recommendations to prevent pain during WCPs have focused on either administration of preventive and procedural analgesia or use of expensive, non-adherent dressings. However, it is unclear which patients to target for analgesia or expensive dressings, leading to their inappropriate over- or underuse. To achieve the aims of the study, a comprehensive set of wound, patient, and biological factors will be measured concurrently with pain during a dressing change among a sample of 450 inpatients with open wounds. A predictive model will be developed and biological mechanisms will be examined using logistic regression. The proposed study has the potential to make significant contributions because clinicians will be able to target those patients requiring preventive pain control, thereby eliminating the spiraling impact of painful procedures on nociceptor sensitization.

Previous studies found that African American (AA) and low socioeconomic status (SES) patients are less likely to receive guideline-concordant pain care relative to White and high SES patients. According to research and theory, enhancing clinician perspective-taking is a promising strategy for improving the care of AA and low SES patients. We have developed an innovative methodology that utilizes computer-simulated patients and environments to assess, understand, and remediate pain treatment disparities. Our approach allows for the intervention to be individually tailored to each trainee, thereby enhancing its impact. It also allows for individual trainees to gain exposure to a greater range of racially and socioeconomically diverse patients than can normally be obtained in traditional training settings. We hypothesize that our perspective-taking intervention will increase trainees’ knowledge of their own biases, enhance trainees’ empathy toward patients, and reduce trainees’ anxiety/threat toward patients, and that these changes will reduce pain treatment disparities.

While traditional epidural spinal cord stimulation (SCS) for intractable pain has been very efficacious for the patients responsive to it, the success rate has held at approximately 55%. Dorsal root ganglion (DRG) stimulation has shown promise in early trials to provide greater pain relief. Although the decrease in back pain at 3 months was significantly greater in the DRG arm vs. SCS, the adverse event rate related to the device or implant procedure was significantly higher in the DRG arm. Researchers will develop the “Injectrode” system to make the procedure simpler and safer by using an alternative to implantation: using an injectable pre-polymer liquid composite that cures quickly after injection adjacent to the DRG. They will compare an Injectrode-based system with traditional electrode stimulation at the DRG as an alternative to opioid administration. Researchers will perform benchtop characterization and refinement as a precursor to a clinical study, use modeling and animal testing to refine the efficiency of energy transfer from a transcutaneous electrical nerve stimulation unit to an Injectrode/Injectrode collector concept, and optimize the procedure for the complex anatomy of the human DRG.

This project will develop a human cell-based model of the afferent pain pathway in the dorsal horn of the spinal cord. The research team’s approach utilizes novel human pluripotent stem cell (hPSC)-derived phenotypes in a model that combines 3D organoid culture with microfabricated systems on an integrated, three-dimensional (3D) microelectrode array. Researchers will establish the feasibility of a physiologically relevant, human 3D model of the afferent pain pathway that will be useful for evaluation of candidate analgesic drugs. They will then improve the physiological relevance of the system by promoting neural network maturation before demonstrating the system’s utility in modeling adverse effects of opioids and screening compounds to validate the model. Completion of the study objective will establish novel protocols for deriving dorsal horn neurons from hPSCs and create the first human microphysiological model of the spinal cord dorsal horn afferent sensory pathway.

An extensive literature provides compelling evidence that selective antagonists or negative allosteric modulators (NAMs) of the metabotropic glutamate (mGlu) receptor, mGlu5, have exciting potential as a novel approach for treatment of multiple pain conditions that could provide sustained antinociceptive activity without the serious adverse effects and abuse liability associated with opioids. Researchers have developed a novel series of highly selective mGlu5 NAMs that are structurally unrelated to previous compounds, have properties for further development, and avoid the formation of toxic metabolites that were associated with previous mGlu5 NAMs. Based on existing preclinical models, as well as clinical trial data showing efficacy of an mGlu5 NAM in migraine patients, researchers anticipate that their compounds will have broad-spectrum analgesic activity in patients with a variety of chronic pain conditions.

Therapeutic virtual reality (VR) has emerged as a promising and evidence-based treatment modality for musculoskeletal pain, including chronic low back pain (cLBP). Users of VR wear a pair of goggles with a close-proximity stereoscopic screen that creates a sensation of being transported into lifelike, three-dimensional worlds. By stimulating the visual cortex while engaging other senses, VR modulates the user’s processing of nociceptive stimuli. Functional magnetic resonance imaging (fMRI) of the brain reveals that VR has similar effects on the sensory and insular cortex as opioids, and head-to-head trials show that VR achieves similar or greater analgesia as hydromorphone. Since there are few data regarding long-term efficacy and safety of VR in cLBP, this study will measure patient-reported outcomes, biometric outcomes, and opioid use in nonspecific cLBP patients under various experimental conditions using VR therapy.