Drug Discovery
UF Pharmacy leads the way in researching novel opioid addiction, alternate pain treatments.
rug overdoses from illicit and prescription drugs caused 64,000 deaths in 2016, according to the National Institute on Drug Abuse. That outnumbers Americans who died in the Vietnam War: 58,220.
The opioid epidemic has caught the nation’s attention with a demand to reduce the over-prescribing of highly addictive painkillers.
But beside the fact that opioids are addictive and can be abused, they still fulfill their basic function extremely well: They’re the gold standard of pain relief. And halting prescriptions alone won’t solve the problem for those already addicted who turn to street equivalents, like heroin and highly potent novel synthetic opioids.
Researchers at the University of Florida College of Pharmacy are investigating various methods to treat pain and addiction, including weaning addicts off opioids with safer substances, manipulating receptors to reduce dependence and tolerance, and uncovering new ways to diagnose pain.
WEANING ADDICTS OFF OPIOIDS
Buprenorphine and methadone are the classically accepted drugs for weaning addicts off opioids. Though less dangerous, they’re narcotics with the potential to be abused.
Even when addicts have everything going for them — a strong support group and access to buprenorphine or methadone — they relapse 90 percent of the time. “Opioid withdrawal may be the worst experience a human being can endure. It won’t kill you, but it feels like it will,” said Jay McLaughlin, Ph.D., an associate professor of pharmacodynamics.
In comes kratom, or Mitragyna speciosia, a tropical tree from southeast Asia. For generations, farmers there have chewed the leaves or ground them up to make a tea, giving them an extra mental and physical boost to continue working in the fields. In addition, it has been traditionally used as a substitute to avoid withdrawals when opium is not available.
More recently, researchers in the College of Pharmacy have studied its potential to wean addicts off heroin or prescription opioids. It activates the same opioid receptors and appears to satisfy the craving while lessening the risk of respiratory depression.
Respiratory depression is the most common cause of mortality when opioid users overdose. A normal breathing rate is 12–20 breaths per minute, but after an overdose, users can have their breathing slowed to one or two breaths per minute. A major goal of UF’s kratom initiative is to figure out whether kratom carries these risks.
Preclinical kratom research at UF begins with Christopher McCurdy, Ph.D., a professor of medicinal chemistry, who isolates compounds from crushed leaves in his laboratory. He passes the compounds onto Bonnie Avery, Ph.D., a clinical professor of pharmaceutics, who weighs and analyzes each compound to identify the component chemicals in each sample. She also evaluates the plant material in animals: how much is present in the body, where the compounds accumulate and how the body metabolizes and ultimately removes the compounds.
Lance McMahon, Ph.D., a professor and chair of the department of pharmacodynamics, takes the compound and tests the kratom chemicals in animal models. He and McLaughlin study the chemicals in combination with receptor blockers to help identify receptor sites of action.
McMahon’s and McLaughlin’s models explore whether kratom has the same behavioral effects as opioids, and what the effects are after chronic treatment. “We hypothesize the magnitude of kratom withdrawal is less than it is for many prescription opioids,” he said. “But the question remains, how much less?”
Just as marijuana contains cannabinoids recognized for their therapeutic benefit and tetrahydrocannabinol, or THC, known for its euphoric high, kratom too contains numerous compounds. Some are more therapeutic, others more euphoric.
McLaughlin researches kratom chemicals in mouse models to find out which have the greatest therapeutic benefit and which have the highest abuse risk.
From his models, mice do not develop tolerance to “7-OH mitragynine,” a chemical compound found in kratom, but they do experience conditioned place preference — meaning they will hang out in the test chamber where they previously received it, hoping for more. Another compound “mitragynine pseudoindoxyl” does not produce conditioned place preference, and although tolerance does develop, it does so far less than to clinical opioids like morphine.
“The hope is to find a pain killer without addiction and respiratory issues,” McLaughlin said. “I don’t think it’s a hope; I think it’s going to happen.” Kratom may fulfill this expectation.
The UF College of Pharmacy uses an interdisciplinary approach to solving pain and addiction issues. Pharmacodynamics faculty Jay McLaughlin, Ph.D., and Lance McMahon, Ph.D., collaborate with medicinal chemistry faculty Christopher McCurdy, Ph.D., Bonnie Avery, Ph.D., and Jane Aldrich, Ph.D., meet with their respective researchers and graduate students to discuss latest research.
Jesse Jones
MANIPULATING OPIOID RECEPTORS TO PREVENT ADDICTION
There are three different types of opioid receptors — kappa, mu and delta. Manipulating the kappa and mu receptors can create more desirable outcomes, but researchers stay away from delta receptors, the manipulation of which can cause epileptic seizures.
Activating kappa receptors causes dysphoria, a profound state of unease or dissatisfaction. Activating mu receptors causes euphoria, the high that keeps drug users coming back for more.
Jane Aldrich, Ph.D., a professor of medicinal chemistry, uses certain peptide agonists to stimulate kappa receptors to reduce euphoria felt from mu receptors. She can also use peptide antagonists to block receptors from being activated.
McLaughlin runs the mouse models to show with the right blend of agonists and antagonists, opioids could still treat pain while having fewer negative consequences.
The difficulty comes in finding drugs that can cross the blood-brain barrier, a semipermeable membrane that separates extracellular fluid in the central nervous system from circulating blood in the brain. Less than 2 percent of drugs can cross the barrier, but Aldrich has identified several peptides that can make the journey.
“These cyclic peptides not only reach the brain, but they can be absorbed after oral administration, a feat that’s pretty rare for peptides,” Aldrich said. “This makes them a very promising type of compound for the development of treatments, both for pain and drug abuse.”
Career Highlights
All five of these faculty joined the UF College of Pharmacy since 2015
Professor and Chair, Department of Pharmacodynamics
Career research dollars awarded: $9 million
Peer-reviewed journal articles: 81
Book chapters: 5
Patents: 1
Professor, Department of Medicinal Chemistry
Director, UF Translational Drug Development Core
Career research dollars awarded: $10 million
Peer-reviewed journal articles: 100
Book chapters: 5
Patents: 4
Professor, Department of Medicinal Chemistry
Career research dollars awarded: $15 million
Peer-reviewed journal articles: 71
Book chapters: 4
Patents: 2
Clinical Professor, Department of Pharmaceutics
Career research dollars awarded: $30 million
Peer-reviewed journal articles: 45
Book chapters: 1
Patents: 3
Associate Professor, Department of Pharmacodynamics
Career research dollars awarded: $13 million
Peer-reviewed journal articles: 62
Book chapters: 1
Patents: 2
SIGMA RECEPTORS: DIAGNOSING AND TREATING PAIN
Drugs that target sigma receptors can be used to both diagnose and treat pain. Sigma receptors are a unique protein in mammalian systems that seem to be activated during cellular stress, such as nerve injury, and modulate other protein systems involved in the disease state.
The receptors, which are highly distinct from the opioid receptors kappa, mu and delta, can be expressed in a person’s body, and they tend to gather at the site where pain originates, creating a visual map.
“A visual pain map could be extremely useful for physicians to pinpoint pain’s possible origin to prescribe a more direct approach to treatment, administered to the precise site of injury,” Avery said. “Imagine being able to find a needle in a haystack; this could be the answer.”
McCurdy and Avery conduct this diagnostic human clinical research in close collaboration with researchers, Frederick Chin, Ph.D., and Sandip Biswal, M.D., at Stanford University, using a newly developed, combined PET/MRI scanning machine. These studies have been able to selectively identify areas of nerve damage that could be the source of a patient’s pain.
There is potential for this diagnostic agent to be used in animals. In collaboration with researchers at Stanford University and the University of California Davis, UF researchers are investigating its diagnostic potential in thoroughbred racing horses.
In a separate study funded by the Department of Defense, McCurdy, McLaughlin and Avery study sigma receptors’ potential as a painkiller that won’t impair soldiers’ performance and ability to operate large machinery or their ability to perform on the battlefield.
Blocking these receptors can reverse perceived pain, without the traditional side effects other chronic pain medications cause — dependence, tolerance, respiratory depression, constipation and sedation.
FROM LAB BENCH TO HUMANS IN ONE PLACE
UF researchers are leading the way in developing better methods for treating pain and addiction, searching for alternate solutions to opioids or manipulating opioids’ mechanism of action to make them less addictive. And it’s all housed under one roof — the UF College of Pharmacy.
“It’s almost like being part of a small company,” McCurdy said. “From chemistry to just before clinical trials, we can cover the whole spectrum within the college. It’s a pretty unique place where you can take a molecule from lab bench all the way to humans without leaving the university.”
