Funded Projects

Researchers will develop multi-organ, microphysiological systems (MPSs) based on human induced pluripotent stem cell-derived midbrain-fated dopamine (DA)/gamma-aminobutyric acid neurons on a three-dimensional platform that incorporates microglia, blood–brain barrier (BBB), and liver metabolism. RNA sequencing and metabolomics analyses will complement the primary DA release measure to identify novel mechanisms contributing to chronic opioid-induced plasticity in DA responsiveness. The chronic pain-relevant aspect of the model will be realized by examination of aversive kappa-mediated opioid effects on DA transmission in addition to commonly abused mu opioid receptor agonists, and by incorporation of inflammatory-mediating microglia. Incorporation of BBB and liver metabolism modules into the microphysiologic system platform will permit screening of drugs. Throughput will be increased by integration of online sensors for online detection of DA and other analytes. Researchers will use a curated set of 100 chemical genomics probes.

A current obstacle to developing more effective therapies for chronic low back pain is the lack of clinical trials assessing the feasibility and potential effectiveness of promising new targets for neuromodulation. This project will explore the feasibility of using deep brain stimulation of a new brain target for treating chronic low back pain. The study will also explore imaging biomarkers in patients with chronic low back pain that can be used to predict whether someone is a candidate or may respond to deep brain stimulation therapy, to guide programming and patient selection for this therapy in the future.

Oral cancer pain is debilitating and difficult to treat, in part because even the most effective available pain remedies are limited by side effects. Opioid-based pain medications have several side effects including dependence and tolerance, in which the body gets used to a medicine so that either more medicine is needed or different medicine is needed. Another side effect is hyperalgesia, in which people taking opioids become more sensitive to certain painful stimuli and may misuse the drugs and risk addiction. This project will evaluate lab-made versions of cannabinoid molecules known to block pain signals in nerve cells, but which cannot enter the brain to cause neurological side effects. The research aims to advance promising versions of the molecules to testing in human research participants.

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.

Chronic pain results in long-term changes throughout the central nervous system. These include abnormal structure and function of the frontal cortex region of the brain, which relays pain messages and also the common pain-related conditions depression, anxiety, and cognitive impairment. Peripheral nerve injury results in widespread and long-lasting changes to DNA in the frontal cortex. DNA methylation, in which chemical tags are attached to DNA, is one way the body controls the activity of genes over time. This control occurs via proteins that recognize tagged DNA, and some of these proteins do not work properly in the frontal cortex many months after nerve injury. These changes occur after nerve injury and are linked to mechanical sensitivity. This project will determine this DNA-binding protein is a good target for finding new medications for chronic pain. 

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.

Genomic medicine offers hope for improved diagnostic methods and for more effective, patient-specific therapies. Genome-wide associated studies (GWAS) elucidate genetic markers that improve clinical understanding of risks and mechanisms for many diseases and conditions and that may ultimately guide diagnosis and therapy on a patient-specific basis. Previous phenome-wide association studies (PheWAS) established a systematic and efficient approach to identifying novel disease-variant associations and discovering pleiotropy using electronic health records (EHRs). This proposal will develop novel methods to identify associations based on patterns of phenotypes using a phenotype risk score (PheRS) methodology to systematically search for the influence of Mendelian disease variants on common disease. By doing so, it also creates a way to assess pathogenicity for rare variants and will identify patients at highest risk of having undiagnosed Mendelian disease. The project is enabled by large DNA biobanks coupled to de-identified copies of EHR.

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.

Opioids are widely used pain treatments, despite their relative ineffectiveness for chronic pain and their high potential for misuse and addiction. There is thus an urgent need for alternative, non-addictive pain treatments. Genetic and functional studies of human pain disorders and animal models of pain have validated Nav1.7, a voltage-gated sodium channel as an attractive target for new pain treatments. Currently available blockers of these channels can sometimes provide symptomatic relief for patients but have worrisome side effects affecting the brain and heart. This study aims to develop and validate an innovative site-directed RNA editing strategy that will offer the ability to create new versions of molecules to block Nav1.7, toward establishing a novel, non-addictive approach to treat chronic pain.

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.

Neuropathic pain is characterized by neuronal hyperexcitability and spontaneous activity, properties associated with activity of hyperpolarization-activated, cyclic nucleotide-regulated (HCN1-4) channels, the source of the pacemaker current, Ih. Inhibition of HCN1-mediated Ih elicits marked antihyperalgesia in multiple animal models of neuropathic pain, including models for direct nerve injury and chemotherapy-induced peripheral neuropathy, and does so with little or no disruption to either normal pain processing or baseline behaviors and activities. The overall objective is to develop a peripherally restricted HCN1 inverse-agonist as a therapeutic for neuropathic pain. Researchers have generated a novel small molecule that combines an antihyperalgesic HCN1 inhibitor with a motif that controls distribution and membrane presentation and is a potential non-opioid antihyperalgesic treatment for peripheral neuropathic pain.

Routine treatment of pain with prescription opioid medications may evolve into opioid use disorder, addiction, and potentially overdose. New, non-opioid molecular targets for pain are needed as a key element of responding to the opioid and overdose crisis. Ion channels are molecular gateways that convert electrical signals into physiological responses, and many have been implicated in transmitting pain signals. The ion channel Kir6.1/KCNJ8 has been linked to the control of postoperative and cancer pain. Studies in animal models show that low levels of this ion channel are evident after an injury. This research will identify compounds that can open the Kir6.1/KCNJ8 channel as potential treatment strategy for pain.

Neuropilin 1 receptor (NRP1) is a protein receptor that is active in neurons and is hypothesized to be a key mediator of sensory neuron sensitization that can lead to pain. This project will study the cellular mechanisms by which NRP1 leads to sensitization and which cell types—sensory neurons, microglia, or both—are responsible for NRP1’s role in pain. The findings can help validate NRP1 in sensory neurons and the spinal cord as a target to treat pain following nerve injury.