Promising pain drugs discovered in animal studies commonly fail in clinical trials—contributing to what scientists often refer to as the “leaky” drug development pipeline. To understand why, pain researchers are increasingly using tissues and cells from human organ donors to test potential pain relievers and study how these drugs might work in the human nervous system.
The latest findings from this area of research were highlighted at Spring Pain, part of the 2019 Scientific Meeting of the American Pain Society that took place April 3-6 in Milwaukee, Wisconsin. There, a panel of pain researchers including Michael Gold, David Bulmer, Annemarie Dedek, and Rob Gereau presented their work and perspectives on this emerging topic in pain research.
These scientists share the goal of understanding whether physiological differences in the pain system exist between humans and laboratory animals—especially mice and rats—used in pain studies.
Their investigations have revealed new insights into the potential driving factors of pain in the human central nervous system (spinal cord and brain) and peripheral nervous system (nerve fibers outside of the spinal cord/brain). In many cases, they have found important differences between the pain-sensing neurons of rodents and those of humans, and their work shows that researchers overlook those differences at their own peril in the search for new pain drugs.
Most of all, paying attention to such discrepancies between lab animals and people could help fix the leaky drug development pipeline and pave the way to better medications for people with pain.
A leaky pipeline
Michael Gold, a pain researcher at the Pittsburgh Center for Pain Research at the University of Pittsburgh, opened his talk by pointing to the challenges of drug development. Moving any given drug (not just pain drugs) from initial discovery to the market can take 10-17 years and upwards of 500 million dollars. What’s more, the vast majority of drugs fail along the way, pouring out of the pipeline and leaving patients without new options.
Pain researchers think that one cause of this is potential physiological differences in the nervous system of humans and laboratory animals such as mice and rats. Gold and other researchers have reasoned that knowing more about human pain physiology and testing potential pain relievers in human tissues, before embarking on a clinical trial, would be an informative step towards plugging up the pipeline.
If a drug works the same way in human tissues as it does in animal tissues, it would provide greater confidence in moving forward with a clinical trial. However, if it doesn’t function the same way, the drug might be unlikely to provide pain relief in people, and therefore shouldn’t be moved into clinical testing.
This initial screen could save pain researchers an enormous amount of time and resources, and maybe even firm up the drug development pipeline. But how can pain scientists gain access to tissue from the human nervous system?
Nondividing tissues and where to find them
Unlike cells that make up tissues such as the skin and lining of the intestines, neurons are non-dividing cells. That is, they do not reproduce themselves. This means (with a couple of exceptions) that the neurons we are born with are the neurons we will have for the rest of our lives.
The nondividing nature of neurons presents a major challenge to pain researchers: it’s problematic to remove tissue that cannot be replaced.
To overcome this obstacle, pain investigators are working with transplant services and organ procurement organizations. Once vital organs for transplant (the heart, lungs, or liver, for instance) are removed from recently deceased donors, additional tissues can be removed for research. This includes tissue that contains pain-sensing nerve cells, including the skin, internal organs, and even the spinal cord. Alternatively, researchers can use tissue that has been removed during a patient’s previously planned surgical procedure.
Several groups of pain researchers now have access to human tissue and can keep that tissue healthy, in a laboratory dish, for days to weeks while performing experiments.
Discoveries in pain processing using human tissue
An overarching goal of pain researchers is to understand how pain is normally processed within the nervous system and the ways pain processing goes awry in chronic pain conditions.
For instance, irritable bowel syndrome (IBS) is an intestinal disorder that causes severe pain in many patients, yet why pain arises is unknown. David Bulmer, a researcher at the University of Cambridge in the United Kingdom, is tackling this question by using colon tissue, along with its accompanying nerve fibers, which has been surgically removed from patients undergoing treatment for colon cancer or other bowel diseases. To study how IBS might affect the function of colon nerve fibers that contribute to pain, Bulmer also collects colon biopsy samples from IBS patients and extracts molecules that have been linked to the disorder.
Back in the lab, Bulmer’s team records the electrical activity of the colon pain-sensing nerve fibers. They discovered that these nerve fibers become more active when exposed to molecules linked to IBS. Bulmer thinks that enhanced activity of pain-sensing nerve fibers, driven by changes in the molecular environment within the colon, might underlie the pain experienced by IBS patients.
Intriguingly, based on findings from complementary studies using neurons from the colons of mice, Bulmer suggested that the responses of neurons in the colon might be dictated by which genes they uniquely express—that is, which genes are turned on or off. His group is currently working towards identifying the genes that are expressed in human pain-sensing neurons involved in IBS. Bulmer is excited by this line of research because it could reveal a molecular “off switch” for pain-sensing nerve fibers and in turn lead to more tailored treatments.
Studies on human tissues have also led to exciting discoveries about pain processing within the central nervous system.
Annemarie Dedek, a PhD candidate working with Michael Hildebrand at Carleton University in Ottawa, Canada, is one researcher pushing this new knowledge forward by studying the contribution of the spinal cord to chronic pain. The spinal cord is an important pain processing hub. It receives incoming electrical signals from pain-sensing neurons in the skin and body, integrates those signals, and then relays them up to the brain, giving rise to a perception of pain. One way chronic pain is thought to develop is from errors in signal integration within the spinal cord, resulting in amplified outputs to the brain.
Dedek’s recently published work (see related Pain Research Forum news article here) looks at the molecular events within neurons that contribute to spinal cord pain processing. She and her colleagues discovered that a molecule, called STEP61, in the rat spinal cord serves as a “brake” on pain, keeping pain in check during normal circumstances.
But, following injury, spinal cord levels of STEP61 go down, which releases the brake. What this means is that the spinal cord neurons are now more electrically excitable, becoming increasingly likely to generate an amplified electrical signal that will make its way up to the brain.
Dedek also tested the effects of STEP61 in human spinal cord tissue obtained from organ donors. She saw that STEP61 played the same role here as it did in animal tissue, keeping pain under control. It appears, then, that at least some aspects of pain processing within the spinal cord are similar in rodents and people. Moreover, in the future, it may be possible to take advantage of this knowledge to develop new treatments for pain.
Pain drug targets
Because pain-sensing neurons of the peripheral nervous system relay signals from the skin and body into the spinal cord, one strategy for pain relief is to stop those signals before they make their way into the central nervous system. To do so, researchers are constantly searching for “drug targets”—molecules whose activity they can increase or decrease using drugs.
For instance, Rob Gereau, a pain researcher at Washington University in St. Louis and director of the Washington University Pain Center, previously discovered two promising drug targets for pain relief using rodent pain-sensing neurons. In this case, the targets were proteins, called mGluR5 and mGluR2/3, that influence the electrical excitability of neurons. By manipulating the activity of these proteins, Gereau’s team was able to reduce pain in laboratory mice.
But Gereau wondered whether these proteins were also present in humans. Surprisingly, mGluR5 wasn’t found in human pain-sensing neurons. As a result, he deprioritized this drug target in future research. Meanwhile, though mGluR2/3 were in fact present in the human neurons, activating them in those cells was less effective at quieting their electrical excitability, compared to what happened in mouse neurons.
Gold’s group has investigated a different class of drug targets in human pain-sensing neurons and found similar results. Here, the researchers measured the properties of proteins known as ion channels that control the electrical current that flows across neurons, which in turn affects their excitability. Many of these properties were similar between rat and human neurons.
However, Gold’s team discovered that in some cases, the human ion channel proteins were less sensitive to drugs known to block channel activity, compared to the corresponding rat ion channel proteins. Because of this, the drugs were less effective at decreasing the electrical activity of pain-sensing neurons.
In short, both Gereau’s and Gold’s initial screens revealed important species differences between rodent and human pain-sensing neurons. But just how important is this for the development of new pain drugs?
“I would argue it’s an essential screen for researchers interested in targeting primary afferents [pain-sensing neurons that first detect a potentially harmful stimulus] for novel therapeutics,” Gold said.
It’s possible that seemingly minor species differences in how a drug target functions could have a large impact on the effectiveness of a potential pain reliever.
Drip, drip, drip no more?
The findings presented at Spring Pain illustrate that human tissue is a vital resource for pain researchers. Experiments on tissue from organ donors are allowing for unprecedented discoveries of how the human nervous system processes pain. And, species differences in pain-sensing neurons of rodents and humans, like those observed by Gereau and Gold, might even explain why pain-relieving drugs that looked promising in animal studies failed in people.
When considering the drug development pipeline, Gereau emphasized that “animal models [of pain] are invaluable for identifying targets for new potential treatments.” But researchers should also look to people too, since “human tissues can be used to help prioritize which drug targets should be pursued in the clinic,” according to Gereau.
However, researchers must be cautious when ruling out a drug that may have failed in tests using human tissue. For example, the finding that a drug candidate does not quiet human pain-sensing neurons in the peripheral nervous system doesn’t mean that it can’t provide pain relief by acting in a different part of the nervous system, such as the spinal cord.
Further, unlike laboratory animals, humans are genetically diverse, so it can be difficult for researchers to draw conclusions about human pain processing based on observations in tissues from a small group of organ donors.
Nevertheless, testing candidate pain drugs in human tissues has emerged as a crucial step that could help ensure that more treatments make it all the way through the drug development process.
The findings so far show that some discoveries in rodents are lost in translation, while others stand the test of evolutionary time. Knowing if it’s the former or the latter could be the difference between a leaky pipeline and one that stops dripping.
Tayler Sheahan, PhD, is a postdoctoral research fellow at the University of Pittsburgh, US.