Propelling pain research forward with human tissues

Over the last 70 years, scientists’ understanding of the cellular neurobiology of human pain disorders has relied heavily on experiments in animal models. While this work provided foundational insights into the basic science of pain, the findings often fail to translate into efficacious pain treatments for humans. Now, Theodore Price, a neuroscientist at the University of Texas at Dallas, is catapulting the field to new heights by studying the mechanisms of human pain directly at the source: in tissue samples of the spinal cord and the clusters of neurons just outside of it.

In 2022, Price’s team was one of three in the nation awarded funding from the NIH PRECISION Human Pain Network to establish human tissue banks (1). The goal of the projects in this program is to gain a molecular understanding of human pain disorders and how their mechanisms may differ through the meticulous analysis of sample tissues using cutting-edge techniques such as single-cell sequencing techniques, proteomics, electrophysiology, and calcium imaging. “We're basically trying to create this environment of techniques where we can do everything that we used to do in animals in human tissue,” said Price.

This new approach could pave the way for developing therapeutics that are better suited to human physiology and that allow for a precision medicine approach to treating each individual’s pain disorder.

A man in a white lab coat standing in a lab.

Theodore Price leads a project to establish a human tissue bank at the University of Texas at Dallas. He hopes that studying these tissues will reveal the molecular mechanisms of human pain.

Credit: University of Texas at Dallas

Why is studying human tissue an important approach for basic pain research?

We don't have good information on the molecular make-up of the cells in the human nervous system that are important for pain. We know a lot about them from animal models, and that information has been incredible for helping us understand the basic principles of how the cells work. But sequencing and other work has shown that there are fundamental differences in drug target expression in the nervous system structures between each vertebra of the spine, called the dorsal root ganglia, in humans compared to other animals (2,3). For example, we’ve seen changes associated with injury in humans that are not equivalent to what we see in the mouse (4).

I imagine that most people would expect these differences, but it's a particularly important gap when we're trying to develop therapeutics to treat pain and neuropathies in humans. To do that, we need incredible precision in our understanding of the human nervous system, and we just haven't had that information so far. That's our main motivation for studying human tissue directly.

How will studying human tissue help treat pain with a precision medicine approach?

The idea that we could make a common pain therapeutic that could help everybody has not panned out. Pain is a very complex thing. People's pains differ, and so do the underlying mechanisms driving them. Ultimately, what everybody in the field would like is to have a therapeutic that not only alleviates an individual’s pain but also fixes the underlying problem.

One good example is rheumatoid arthritis. TNF inhibitors have been amazing in how they decrease the inflammatory problem, but some people don't respond to them (5). And for many people, TNF inhibitors decrease their inflammation without greatly improving their pain. So, figuring out what causes pain on an individual level will be important for understanding why TNF inhibitors work for some and not for others.

I recently had a lot of interesting discussions at the American College of Rheumatology meeting with physicians and researchers interested in this problem, and it was clear that the dorsal root ganglia sequencing data that we generate provides new insights very quickly. There is a huge opportunity here to use these human tissue datasets to understand what drives pain in a specific disease and generate and test new hypotheses.

What has it been like setting up one of the first human tissue banks, and what is its current status?

We’ve been getting tissue samples from several different sources; our primary source is donor organs from the Southwest Transplant Alliance. That gives us tissue from people who were otherwise young and healthy but tragically died from a traumatic accident. We also recover tissues from surgeries, like peripheral nerve samples from people who had amputations.

A group of scientists wearing blue lab coats in a lab.

Shiva Nematgorgani, a PhD student in Theodore Price's lab, studies the molecular neurobiology of human tissue samples.

Credit: Alyssa Galganov

The biggest challenge was setting up the partnership with the Southwest Transplant Alliance. They were receptive to working with us from the start, but there was a lot of administrative work to complete first. But now, we're a pretty well-oiled machine. We are in the operating room with them two to three times a week. Their staff is incredible and a total pleasure to work with, and we're excited about the additional contributions we can make in the organ donor's memory. That's been meaningful to our research team. Logistically, it can be a little tough because we have to be on call basically all of the time since organ donations are not scheduled.

At this point, we have completed recoveries from almost 300 organ donors. We have been building up samples of spinal cord tissues, and we have a huge bank of dorsal root ganglia tissues. So, we're now working on sequencing a large number of these samples. One goal is to understand how these cells change across the lifespan and determine whether there are underlying sex differences. We have a long way to go, but over time, we're going to make a huge contribution to understanding these cells.

What has your team discovered by studying human tissue samples so far?

The most important work so far from our group was published in Science Translational Medicine in 2022 (3). That work really laid out the subtypes of human sensory neurons. One type of sensory neuron called a nociceptor is widely viewed as the origin of pain signals before they are perceived through cortical processing. We focus on understanding these neurons in human tissue because we know that they become hyperactive in chronic pain conditions and likely underlie the generation of pain signals. In our paper, we reported that there is one striking fundamental difference between human nociceptors and rodent nociceptors; in rodents, there are peptidergic and nonpeptidergic subsets of nociceptors involved in processing different types of pain, but we found evidence that in humans, that distinction does not exist.

Ultimately, what everybody in the field would like is to have a therapeutic that not only alleviates an individual’s pain but also fixes the underlying problem.
– Theodore Price, University of Texas at Dallas

In a paper published in 2023 in BRAIN, we also reported that there are some fundamental sex differences in pain mechanisms between men and women (4). That has changed how many people view the need for different drugs for men and women with neuropathic pain. There is pretty broad acceptance now that it’s a strong possibility in the future.

Why are you excited about studying human tissue samples for designing new therapeutics?

I've been a pain patient myself, and I was lucky that I had a surgery that helped me recover quickly. I had a lumbar spine injury with herniation that went into the central canal. It was pretty gnarly. The lower part of my left leg was paralyzed, and it was extraordinarily painful. I had two wonderful surgeons at McGill University, where I was a postdoctoral fellow already studying pain at the time, who fixed me up. I still have pain from time to time, but it's nothing like prior to the surgery. That was a life-changing experience for me because I realized on a very personal level how consuming neuropathic pain can be. It was hard for me to imagine how I would get back to any semblance of a normal life with that level of pain.

I was already totally dedicated to the field of pain research before that. My injury was not why I chose to study this. But there are people who have pain like I had that lasts for years, and they deserve better than what we have available right now. Our work presents an opportunity to reduce human suffering.

This interview has been edited for length and clarity.