Gut Feeling

How UTMB researchers and clinicians are joining forces to develop new
treatments that manage gastrointestinal pain

By Jennifer Reynolds-Sanchez

At mid-day, a slip of a young woman—call her Jane—sits on her bed in a darkened hospital room. She’s twenty-two years old but might pass for twelve. Tall and thin, she clutches her waist as if trying to bind her torso together. She has juvenile onset diabetes, but she’s here because she also suffers from an extreme and painful case of gastroparesis, which causes her to vomit twenty to thirty times a day. To curb her nausea, UTMB’s director of gastroenterology, P. Jay Pasricha, recently introduced a gastric pacemaker into her stomach.

Commonly found in patients with type-1 or type-2 diabetes, gastroparesis results when nerves to the stomach are damaged or stop working. The vagus nerve controls the movement of food through the digestive tract. If blood sugar levels stay high for an extended period of time, that may damage blood vessels carrying oxygen and nutrients to nerves. When the vagus nerve is damaged, muscles of the stomach and intestines do not contract normally. The movement of food is slowed or stopped. Without such contractions, food just sits, forcing the stomach to rely on acids and enzymes to digest the food and gravity to move it along.

Normal symptoms of gastroparesis consist of a feeling of fullness or bloating, a vague ache in the upper abdomen, and nausea. Jane’s symptoms are severe. When prescription medications didn’t work, Pasricha inserted the battery-operated gastric pacemaker via minimally invasive laporoscopic surgery. The small machine can fit in the palm of one’s hand and looks like a flat, black, polished stone attached to wires. It emits mild electrical pulses that regulate stomach contractions and help control nausea and vomiting.
No one really knows how the pacemaker controls symptoms like Jane’s, but Pasricha says that one important feature of the machine is its ability to stimulate the vagus nerve and modulate signals to the vomiting center of the brain.

This treatment helps relieve Jane’s pain, but it doesn’t stop it entirely. Her voice is raspy because acids from her stomach have burned her throat. She still vomits several times a day, leaving her abdomen sore.
Pasricha hopes to find better ways to manage future G.I. patients’ pain. He is teaming up with UTMB specialists from disparate fields to discover how pain is communicated between two complex nervous systems, the central nervous system (CNS) and the digestive system’s own nervous system—the enteric nervous system (ENS), which seems every bit as intricate as the central nervous system, if less thoroughly studied.

The ENS evolved earlier and consists of many of the same structures and signaling chemicals as the CNS. Like the CNS, the ENS transmits and processes messages via neuron receptors that respond to mechanical and chemical signals. Unlike the CNS, it exists within the gut walls and, Pasricha says, “is in a much more intimate relationship with the cells” to which it sends nerve impulses. The ENS is not organized into structurally discrete components such as the cerebellum, cerebral cortex, and other elements of the CNS. Still, the similarities are impressive. “Many of the neurotransmitters that we now associate with the CNS were first discovered in the ENS,” Pasricha notes. “More than 90 percent of the body’s total serotonin [an organic compound that stimulates smooth muscles and regulates cyclic body
processes] is in the gut.”

To unravel the mystery of G.I. patients’ pain, Pasricha and Javier Navarro, a professor of neuroscience and cell biology, are beginning by studying how neurons—cells within the nervous system—work in the ENS. For more than a year, the pair has been studying neurons of mice and rats through electrical recordings of nerve impulses of living creatures and by staining their cells in the lab for electrophysiology and gene expression analysis—in other words, spying on genes and recording their every move. Some of these genes are from the ENS and some are from the CNS. With Maria Micci, an assistant professor in the Division of Gastroenterology, Pasricha is doing similar work with neural stem cells from both mice and people.

As chemical or mechanical signals are received, the neuron’s receptor translates each signal and sends it to the cell. Navarro studies cell receptors to find how each unique signal is recognized and sent.

One particular receptor that Pasricha and Navarro are studying is the protease activated receptor-2, a.k.a. PAR-2, which appears to be an important receptor for sensitizing the pain-sensing neuron. In other words, after PAR-2 is activated, the neuron is more irritable and responds more readily to minor stimuli.

A few years ago, Pasricha was looking for pain signaling mechanisms in pancreatitis and stumbled upon PAR-2’s reaction to the enzyme trypsin, an ingredient of pancreatic juice that breaks down proteins into smaller units. “Because pancreatitis was associated with the activation of trypsin, we hypothesized that trypsin could directly affect pain nerves via this PAR-2 receptor,” he says. This hypothesis led to an NIH- funded project aided by the important efforts of other G.I. faculty members, particularly Sandra Hoogerwerf, John Winston, and Mohan Shenoy, to form part of a team called END Pain (for Enteric Neuromuscular Disorders and Pain Group). Other faculty members of this group include Micci, Jiande Chen, Sushil Sarna, and Peter Shi, all of whom have important NIH-funded projects in the general area of pain.

“With G.I. pain, patients tend to have severe, unrelenting pain, and they look for relief,” Baker says. “And medication is usually the first line of defense for that.”

“Once we understand the chemistry of pain, we can manage pain,” Navarro says. “The fundamental question is: How does the receptor do it? How does that receptor translate a unique signal to the response?” One chemical signal can communicate that you have less pain, “but you can have the same receptor translate another signal into more pain. We know it happens, but we don’t know how,” Navarro says. “That’s where I come into the picture. Jay Pasricha found out what activates PAR-2. Now I want to see how it works, and for that I have to visualize the action of the receptor at an atomic level.”

If Navarro can understand how the receptor recognizes the pain signal, he may be able to transform the process into one that would decrease pain. “If I can see the signal bound to its receptor, I may be able to manipulate it,” he says.
Pasricha and Navarro are working to find compounds that can block PAR-2 and hence be potential pain relievers. Although they have not yet begun screening drugs for such effectiveness, Navarro’s lab is laying the groundwork by building the necessary tools for drug development. This includes the successful cloning of PAR-2 in what’s called a reporter cell line, a unique group of cells that emit light when a signaling molecule activates the receptor. Pasricha warns, however, that the end results, no matter how successful, will just control pain, not cure it.

“Even if such compounds are found, it does not mean that we have solved the problem of pain,” Pasricha cautions. “Many different stimuli and receptors converge on the pain sensing neuron. PAR-2 is only one piece, perhaps an important one.”

Pasricha and Navarro’s basic research isn’t moving fast enough to help current patients like Jane. For them, true pain relief now is out of reach; the best they can hope for is a better way to cope with their existing pain.

Medication is one option, but another alternative can often make a crucial difference: specific mental techniques that help patients deal with pain. Since coming to UTMB in 1997, Pasricha has been working with UTMB psychologist Jeff Baker to control pain associated with gastrointestinal diseases. While Pasricha and Navarro search for molecules to mitigate pain by manipulating cells, Baker, who hasn’t treated Jane, teaches other patients like her to use their minds to manage their pain.

“With G.I. pain, patients tend to have severe, unrelenting pain, and they look for relief,” Baker says. “And medication is usually the first line of defense for that.” He explained that when a patient visits the doctor to ask for a prescription to treat pain, the doctor will often ask, “What else is going on in your life?”

“He’s not trying to imply that it’s all in your head, but the fact is, what’s in your head does exacerbate your memory of pain,” Baker says. “Say you had a G.I. problem and you wake up in the morning and you say, ‘Oh gosh, here it comes again. My whole day is going to be ruined; I have to reschedule my day.’ So is that real pain or is that psychological pain? It’s usually a combination of both. One pain, or one pain memory, triggers that response.”

Medication is one option, but another alternative can often make a crucial difference: specific mental techniques that help patients deal with pain. Since coming to UTMB in 1997, Pasricha has been working with UTMB psychologist Jeff Baker to control pain associated with gastrointestinal diseases.

After being referred to Baker, who typically does an hour-long clinical interview with patients to explore the various issues that cause stress and see how the patient copes, the patient is handed a series of personality, depression, and coping skills tests. These assessment instruments give Baker a more objective measure of the levels of depression and anxiety the patient has been experiencing and how he or she deals with stress. One patient seeking Baker’s help was a professional working in a high-stress job; she suffered from G.I. cramping and chronic pain. They affected not only her professional life but her personal and social life as well. Baker says that after her evaluation and extensive clinical interview, she began to rethink her priorities.

Through cognitive behavioral therapy—a type of psychotherapy that addresses thinking patterns and how they exacerbate symptoms—she recognized that she had grown to be somewhat self-denigrating while demanding perfection from herself. As this behavior continued, her G.I. condition appeared and then worsened. Baker instructed her to substitute her denigrating statements with positive affirmations. Baker also taught her relaxation techniques, which she practiced at home. This combination of therapies appeared to help stabilize the physical difficulties she was experiencing, Baker says, and let her regain a part of her life she thought was lost.
Baker believes stress plays a significant role in G.I. conditions: “Stress is good. It gets you out of bed, helps you prepare for tests. But when stress turns into distress, it’s not quite as helpful.”

Learning to cope and adjust to living with pain, Baker says, can be a long, difficult process. A patient must accept that the excellent health he or she once had is part of the past and then learn how best to live with the pain and inconvenience of their current condition and the feelings that come with it. Learning how to do this involves self-reflection and clarification of values, he says.

“You start looking at your life and what you’ve done in your life and how you feel about your life. It does help you prioritize,” Baker says. “For instance, I work with patients in UTMB’s Acute Care for Elders (ACE) Unit. While hospitalized, some of those patients have lots of time on their hands and thoughts start coming to them. This self-reflection comes to most of us at different times, but at seventy or eighty, many people are facing the reality that you’re not going to live for fifty more years. They’ll think ‘what have I done here with my life? Am I proud of that? Am I finished with this?’”

As patients of any age work to find answers or begin to seek resolutions or finish unfinished business, their concerns about their quality of life begin to lessen, Baker suggests.

“They’re more at peace and less conflicted. They actually start enjoying life better,” he says, and can still enjoy life without fretting over what they should have done with it.

Although Jane still suffers, she rates her improvement since she’s received the gastric pacemaker as a seven on a scale of one to ten. As her recovery continues, Pasricha will continue to monitor her health to determine if she may need psychological counseling to help her manage her condition and quality of life.

Pasricha also will continue to work with Navarro to discover pain management treatments for patients who suffer from painful G.I. disorders. He hopes to someday establish a center for pain management that will encourage more collaborative research trials among scientists within UTMB, including basic researchers like Navarro and psychologists like Baker.

“We are crossing boundaries,” Baker says.“M.D.s are talking to Ph.D.s. Research is going into Jay Pasricha’s treatment team, and he’s using the science to drive his clinical practice. We’re trying to do the same thing in my area.”

The collaboration between scientists can only open more doors to solve the mysteries of pain, Navarro says, and only when that happens will he be satisfied.

“That will be the best reward you can get,” he says.