Funded Projects

The primary goal of the PRECISION Human Pain network and its participating centers is to generate comprehensive datasets of molecular signatures and cellular function phenotypes or signatures of various cell types that underlie transmission and processing of pain signals in humans. To maximize the impact of the data generated through this effort, it is vital to standardize and integrate all data generated by the various centers and make these data available in a meaningful way to the larger scientific community. As the Data Coordination and Integration Center, this project will support the network to curate, harmonize, and effectively integrate center-generated datasets as well as provide operational support for the network and conduct educational and outreach efforts.

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.

Human oral cancer is associated with significant chronic pain, and a comprehensive understanding of the biology and mechanisms underlying this chronic pain is critical for developing better pain management strategies. This project will determine molecular characteristics, including a specific signaling system (endosomal GPCR kinase), associated with chronic oral cancer pain, using tissue samples obtained from patients with this condition. The findings will then be used to inform studies in animal models of human oral cancer pain to enhance understanding how endosomal GPCR kinase contributes to human oral cancer pain.

Activation of immune cells (microglia) in the central nervous system and neuroinflammation have emerged as key drivers of neuropathic pain. These processes can be triggered by release of ATP, the compound that provides energy to many biochemical reactions. The source and mechanism of ATP release are poorly understood but could be targets of novel treatment approaches for neuropathic pain. This project will use genetic, pharmacological, and electrophysiological approaches to determine whether a large pore channel called Swell 1 that spans the cell membrane is the source of ATP release and resulting neuropathic pain and thus could be a treatment target.

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. 

Osteoarthritis is a degenerative joint disease marked by progressively worsening chronic joint pain that affects function and quality of life. Non-opioid, alternative medications are needed for people with this condition. Joint inflammation, damage, and pain involve signaling through the interleukin-6/glycoprotein 130 pathway. This project will test blocking this pathway in rodents with a new molecule with improved drug-like properties, toward developing an oral medication for osteoarthritis. 

Acute corneal pain from eye injury or surgery can be severe and debilitating, and oral opioids can be addictive. Anesthetic eye drops, such as tetracaine, can relieve corneal pain, but are only available by prescription due to potential overuse of the drops that may affect wound healing. To date, no ocular anesthetics are approved by the U.S. Food and Drug Administration for use at home. This project aims to develop a bandage that delivers anesthetic to the eye through a specially designed contact lens filled with medication. A prototype version of the bandage lens in an animal model delivered up to 30 hours of eye pain relief without wound damage. This research will optimize the prototype version and evaluate safety and compatibility with the human body, toward future clinical testing in humans. 

Chronic post-traumatic headache (PTH) is highly debilitating, poorly understood, and difficult to treat. This project aims to identify proteins located in the membrane of certain neurons that are critical for the development, maintenance, and/or resolution of PTH. These proteins may be targets for novel treatment approaches that are nonaddictive and have minimal side effects.

Neuropathic pain is a debilitating and complex medical condition for which safe and non-addictive treatment options are urgently needed. Preliminary studies have found that lysophosphatidic acid receptor 5 (LPA5) is present in areas of the body that signal pain, including at high levels in rodent models of neuropathic pain. This project will use genetic and pharmacological approaches to determine whether blocking LPA5 signaling reduces neuropathic pain toward future testing in humans.  

There is an urgent need to find new ways to treat chronic pain through better targeting of underlying biological processes. Research shows that flexible synapses within the amygdala brain region play a role in the progression of pain from acute to chronic, but the details are not fully understood. The receptor glutamate delta 1 helps to form and maintain synapses in the amygdala in inflammatory and neuropathic pain. This project will study how the shape and characteristics of glutamate delta 1 affect pain conditions that involve the amygdala, toward informing future development of pain medications. 

Effective development of non-addictive therapies for pain requires animal models that reflect the human condition. Unfortunately, currently used models have limitations and have not always done a good job of predicting what will work in human patients. This project will refine a new way of measuring pain-related behaviors in mice that takes advantage of more natural mouse behavior and is less influenced by experimenter biases and artifacts. The research will verify that the promising results hold up in several different types of pain and that different classes of clinically used pain medications are effective. They will also make sure the data can be reproduced by an outside laboratory. If successful, this will support the use of this new read-out for future pain therapy development.