Implantable wireless devices trigger — and may block — pain signals
By Jim Dryden
GEREAU LAB/WASHINGTON UNIVERSITY Implanted microLED devices light up, activating peripheral nerve cells in mice. The devices are being developed and studied by researchers at Washington University School of Medicine in St. Louis and the University of Illinois at Urbana-Champaign as a potential treatment for pain that does not respond to other therapies.
Building on wireless technology that has the potential to interfere with pain, scientists have developed flexible, implantable devices that can activate — and, in theory, block — pain signals in the body and spinal cord before those signals reach the brain.
“Our eventual goal is to use this technology to treat pain in very specific locations by providing a kind of ‘switch’ to turn off the pain signals long before they reach the brain,” said co-senior investigator Robert W. Gereau IV, PhD, the Dr. Seymour and Rose T. Brown Professor of Anesthesiology and director of the Washington University Pain Center.
The study is published online Nov. 9 in the journal Nature Biotechnology.
Because the devices are soft and stretchable, they can be implanted into parts of the body that move, Gereau explained. The devices previously developed by the scientists had to be anchored to bone.
“But when we’re studying neurons in the spinal cord or in other areas outside of the central nervous system, we need stretchable implants that don’t require anchoring,” he said.
The new devices are held in place with sutures. Like the previous models, they contain microLED lights that can activate specific nerve cells. Gereau said he hopes to use the implants to blunt pain signals in patients who have pain that cannot be managed with standard therapies.
The researchers experimented with mice that were genetically engineered to have light-sensitive proteins on some of their nerve cells. To demonstrate that the implants could influence the pain pathway in nerve cells, the researchers activated a pain response with light. When the mice walked through a specific area in a maze, the implanted devices lit up and caused the mice to feel discomfort. Upon leaving that part of the maze, the devices turned off, and the discomfort dissipated. As a result, the animals quickly learned to avoid that part of the maze.
Robert W. Gereau IV, PhD
The experiment would have been very difficult with older optogenetic devices, which are tethered to a power source and can inhibit the movement of the mice.
Because the new, smaller, devices are flexible and can be held in place with sutures, they also may have potential uses in or around the bladder, stomach, intestines, heart or other organs, according to co-principal investigator John A. Rogers, PhD, professor of materials science and engineering at the University of Illinois.
“They provide unique, biocompatible platforms for wireless delivery of light to virtually any targeted organ in the body,” he said.
Rogers and Gereau designed the implants with an eye toward manufacturing processes that would allow for mass production so the devices could be available to other researchers. Gereau, Rogers and Michael R. Bruchas, PhD, associate professor of anesthesiology at Washington University, have launched a company called NeuroLux to aid in that goal.
Funding for this research comes from a National Institutes of Health (NIH) Director’s Transformative Research Award, as well as the National Institute of Neurological Disorders and Stroke, the National Institute of General Medical Sciences, an NIH Ruth I Kirschstein Predoctoral Fellowship, a Howard Hughes Medical Institute Medical Research Fellowship, and a W.M. Keck Fellowship in Molecular Medicine. NIH grant numbers NS081707, 1F31 NS078852, NS076324 and TR32 GM108539.
Park SI, et al. Soft, stretchable, fully implantable miniaturized optoelectronic systems for wireless optogenetics. Nature Biotechnology, published online Nov. 9, 2015.
Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation, currently ranked sixth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.
Moron-Concepcion Joins the Washington University Pain Center
Dr. Jose Moron-Concepcion has recently joined the department as Associate Professor of Anesthesiology. His primary appointment is in the Washington University Pain Center in the basic research section.
After completing his PhD in Biochemistry at the University of Barcelona (Spain) Dr. Moron-Concepcion was awarded a fellowship to join the intramural program at NIDA to work in the laboratory of Dr Toni Shippenberg, a pioneer in the field of opioid pharmacology. Then, he continued his postdoctoral training in the laboratory of Dr. Lakshmi Devi at Mount Sinai, where he continued his studies on the mechanisms of opioid dependence. After completing his training, he was recruited as a Faculty member in the Department of Pharmacology at University of Texas Medical Branch. He then moved Columbia University in New York, where he was on the faculty of the Department of Anesthesiology for 6 years. Dr. Moron-Concepcion joined the faculty of Washington University on October 1, 2015.
Dr. Moron-Concepcion is a world leader in the study of the nervous system’s adaptive responses to chronic opioid exposure. Research in his laboratory is focused in understanding the mechanisms underlying opioid addiction and the intersection with pain. In addition, his lab is interested in elucidating mechanisms underlying pain in the central nervous system and in the periphery.
Clinical Studies for Chronic Pain
Diabetic peripheral neuropathy [DPN] is caused by diabetes-related damage to the nerves (neuropathy), mainly in the feet, and sometimes in the legs and the hands. It affects more than 3 million Americans and is leading cause of nerve damage-associated pain (neuropathic pain) worldwide. Currently approved drugs such as gabapentin, pregabalin, and duloxetine provide pain relief only in 1 out of 4 or 5 people with DPN.
If you are suffering from peripheral neuropathy in your legs and feet as a result of diabetes, you may be eligible to participate in a study that is taking place in the Pain Center. The purpose of this study is to evaluate a new treatment approach for painful diabetic peripheral neuropathy.
Your participation would include the study drug at no cost and about three visits to the Pain Management Center over a period of four to five weeks. Compensation for your time and travel may be provided. To qualify, you must be a diabetic who is at least 18 years old and have had pain in your feet and/or lower legs for three months or longer.
Chemotherapy-Induced Peripheral Neuropathy (CIPN) is a common complication of certain types of cancer chemotherapy drugs – for example oxaliplatin or paclitaxel. Painful CIPN mainly affects the feet and the hands, can be quite debilitating and treatment-resistant. We are looking for people who suffer from painful neuropathy caused by chemotherapy.
The purpose of the study is to evaluate a new treatment approach for CIPN. Your participation would include the study drug at no cost and about four visits to the Pain Center over a period of ten weeks. Compensation for your time and travel may be provided. To qualify, you must be at least 18 years old, have had receives certain type(s) of chemotherapy for cancer, and have had pain in your feet and/or hands for two months or longer.
Finally, our research group is performing a study where we investigate the underlying mechanisms of a certain type of chronic pain that occurs after someone has a stroke – a condition called “Central Post-Stroke Pain” – CPSP. Determining the pain mechanisms is expected to lead to new treatment approaches for this disabling painful condition. We are looking for stroke survivors who suffer from chronic pain in one (or more) extremities as a result of the stroke. Your participation would include a single intervention visit to the Pain Center. Compensation for your time and travel may be provided.
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about our Pain Center studies please contact Karen Frey at 314-454-5980.
To learn more about Washington University’s clinical trials click here.
Translational Research at the WUPC using Human Neurons
The Gold Standard: Studies of Human Nociceptors Taking Off
Thanks to organ donors, researchers are finding ways to access coveted cells
by Stephani Sutherland on 19 Dec 2014
In the wake of failed clinical trials based on animal models, the pain field is facing what seems to be an inescapable conclusion: the success of new pain drugs in the clinic will likely require studies of human cells and tissues. But human neurons are not easy to come by. Recent work culminated in an invaluable resource: human sensory neuron-like cells reprogrammed from fibroblasts (see PRF related news story). Now, a handful of academic researchers have made the move to acquire and study native human sensory neurons by tapping into organ-donor networks to access prized dorsal root ganglion (DRG) tissue. Their work promises to help validate—or invalidate—important pain mechanisms discovered in animal models.
Linda Porter, NIH
“For years we have been working with transfected cells from animals and in animal models of pain, not under the assumption that things would be the same, but with the hope that they would,“ said Linda Porter, pain policy advisor at the National Institute of Neurological Disorders and Stroke (NINDS).
“And they are certainly similar,” Porter told PRF, but it is important to understand where differences lie. Together, the native and reprogrammed human cells “hopefully will move us forward toward better translational success.”
Steve Davidson (left) and Bryan Copits
This year, Robert Gereau and colleagues at Washington University in St. Louis, US, published the first electrophysiological characterization of DRG neurons from healthy adults (Davidson et al., 2014). Gereau and co-first authors Steve Davidson and Bryan Copits made patch-clamp recordings from 141 neurons from five donors, focusing mainly on small neurons, which include nociceptors. The overwhelming majority of cells displayed a “shoulder” on the falling phase of the action potential, a feature that in rodent neurons defines them as nociceptors. The team also saw many cells respond to compounds that cause pain—adenosine triphosphate (ATP) and allyl isothiocyanate (AITC)—and itch—histamine and chloroquine. Also similar to rodent cells—and to the reprogrammed human neurons recently described by Clifford Woolf and colleagues (Wainger et al., 2014)—some human neurons became more excitable following exposure to the inflammatory mediators bradykinin and prostaglandin E2 (PGE2).
Gereau’s team presented more recent experiments at Neuroscience 2014, the annual meeting for the Society for Neuroscience in Washington, DC, in November showing that neuronal sensitization by PGE2 was blocked by activation of metabotropic glutamate receptors (mGluRs). Gereau’s lab previously identified and characterized group II mGluRs as a potential analgesic target based on work in rodents (Yang and Gereau, 2002).
Gereau had set his sights on moving toward clinical trials involving that target, but he wanted to test the pathway in human cells before making that leap. “It’s quite comforting to see exactly the same type of modulation in human cells,” he said.
In a commentary accompanying Gereau’s paper, Sulayman Dib-Hajj, Yale University, New Haven, and Veterans Administration Connecticut Healthcare System, West Haven, US, said Gereau’s data “begin to establish a baseline and a benchmark” for more representative human neuron physiology (Dib-Hajj, 2014).
Confocal image of a human sensory neuron cultured from a healthy donor without chronic pain. Neurons were immunolabeled for βIII-tubulin (red) and nuclei were visualized with Hoechst staining (blue). Credit: Bryan Copits, Washington University.
To better understand the human sensory neurons, Gereau has future plans to use calcium imaging to study populations of neurons in the dish, and to genetically analyze individual cells following physiological characterization.
With rare exceptions, sensory neurons cannot be harvested from a healthy person—neurons are not exactly a renewable resource like skin cells, nor are they so readily accessible. Many scientists simply assumed that human sensory neurons from the dorsal root ganglia (DRG) were out of reach, but through perseverance and networking, several groups have conquered the logistical challenges of procuring DRG tissue from organ donors.
Andre Ghetti, AnaBios
Gereau made the decision to pursue human neurons when he ran into his former colleague Andre Ghetti, now Chief Executive Officer for AnaBios, a for-profit company in San Diego, US, that procures tissues for research from organ donors. When a donor is identified, AnaBios uses qualified surgical contractors or sends its own team to retrieve needed tissues. Back in San Diego, they prepare the human cells for research using proprietary protocols. Operational since 2011, AnaBios has primarily served pharmaceutical companies. Gereau was the company’s first academic collaborator, and Ghetti told PRF they are now working with a growing number of academic labs.
AnaBios sometimes also performs experiments in-house for clients, but Gereau wanted to record from the cells himself. He and several lab members were essentially on call—when cells became available, they hopped a flight to San Diego and stayed for several days at a time, experimenting on the cultured neurons practically around the clock in AnaBios’ labs. “The work was intensified because of the preciousness of the resource,” Gereau told PRF. The experiments felt “quite different from usual, knowing that this gift is from a person.”
Human dorsal root ganglia neurons in culture (day 5, magnification 200x). Credit: AnaBios
Dib-Hajj and Stephen Waxman are also working with human DRG neurons, which they obtain from the nonprofit National Disease Research Interchange (NDRI). NDRI works with 56 of the 58 US federally designated organ procurement organizations, or OPOs, to obtain donor tissues for research and to get them into the hands of researchers. NDRI works with researchers to develop a plan based on the lab’s specific aims and then acquires the appropriate tissues. Researchers are responsible for dissociating and preparing cells for experiments. That is a project in and of itself, said Dib-Hajj. “Even if you can get the tissue, it is a lot of work to get functional, viable cells,” he told PRF.
Sulayman Dib-Hajj, Yale University School of Medicine and VA Connecticut
Dib-Hajj and Waxman have not published any results yet but presented some preliminary findings in a poster at Neuroscience 2014. Their data suggest that species variation in voltage-gated sodium channels cause marked differences in action potential profiles between human and rodent cells.
Michael Gold at the Center for Pain Research at the University of Pittsburgh, US, has just wrapped up a year of intensive experiments on human sensory neurons. Gold obtained the cells by working directly with the Center for Organ Recovery & Education (CORE), a US federally designated organ procurement organization, or OPO, that serves the 155 hospitals in Gold’s west Pennsylvania region. Gold and his team trained technicians from the CORE tissue recovery team, who then extracted the ganglia and handed them over to Gold’s lab technician to dissociate and plate the cells for experiments. When preparing neurons in his lab, Gold adapted his protocol from that used by Thomas Baumann at Oregon Health and Sciences University to isolate neurons from pain patients who received a ganglionectomy as a last resort treatment. Gold worked in collaboration with Eli Lilly, who funded the project.
Michael Gold, University of Pittsburgh
Gold told PRF he has three manuscripts in preparation detailing his findings. “Some things were comfortingly similar between rodent and human neurons, but we also saw things that were clearly very different,” he said. Michael Gold, University of Pittsburgh
Inspired by his experience working with the human cells, and by Gold’s success at getting human tissues locally, Gereau has also forged a relationship with a transplant service in his home town of St. Louis, so that human neurons will become “a more standard resource” in his lab. All three groups had access to donors’ medical records, with varying degrees of detail. While the initial focus has been on studying cells from healthy donors, the researchers eventually intend to investigate neurons from patients with chronic pain conditions.
At what cost? Gereau said although he knew that cells had been available for several years, he believed that he could not afford human cells in his academic lab. “But I could. I just had to work it into my funding concept.” Porter encouraged pain researchers to follow Gereau’s lead and write grants for funding to study human cells, which face no particular hurdles at the NIH, she told PRF.
Thomas Bell, National Disease Research Interchange
What kind of funding is required to get human DRG cells? Of course it is illegal to buy or sell human tissue in the US, but there are significant costs associated with the cells, from the specialized team trained to extract the ganglia to the courier service used to transport the tissue. Thomas Bell, Director of Scientific Services at NDRI, estimates the cost of a pair of DRGs at $1,200, plus several hundred dollars in shipping costs. “It is absolutely our goal to make this resource as affordable as possible so that any lab can use it.” Considering the cost of animal housing, Bell told PRF, human cells might not be much more expensive than rodents.
AnaBios’ Ghetti estimates their cost at a bit higher—perhaps several thousand dollars for a pair of DRG, each of which contains thousands of cells, although researchers end up patch-clamping only a fraction of these. Gold, who recovers four ganglia from each donor, said he typically uses one for studying physiology, fixes one for histology, and freezes the other two for genetic testing.
“All these findings support the idea that there are important species differences,” Gold said, “and this is why it is critical to study human neurons. We can learn interesting biology, but we are focused most heavily on validating targets.”
Porter agreed that the cells will be invaluable for target validation. “These cells give us better drug screening tools that we did not have before. These are critical tools for the pain field.”
Stephani Sutherland, PhD, is a neuroscientist, yogi, and freelance writer in Southern California, US.
Shingles (herpes zoster), an often a very painful disease, is caused by the same virus that causes chickenpox. After you have chickenpox, the virus remains inactive in certain nerves of your body. If the virus becomes active again when you are an adult, you get shingles.
For some people the nerve pain persists well after resolution of the rash. This condition is called postherpectic neuralgia. Most often, the symptom is one-sided pain and has been described as:
Shooting and/or sharp
Symptoms usually disipitate in 2 to 3 weeks. However, when postherpetic neuralgia occurs after having shingles, the pain can may persist for months or even years.
Additional symptoms may include:
Difficulty moving some muscles in the face
Drooping eyelid/loss of eye motion/vision problems
Joint pain/muscle weakness
Swollen lymph nodes
Prevention and Causes
If you have never had the chickenpox or the chickenpox vaccine, avoid touching the rash and blisters of someone who has the virus. The chickenpox vaccine may be reccommended for teenagers or adults who have never had chickenpox. Adults over the age of sixty, should consider receiving the chickenpox vaccine. Medical evidence has shown that older adults who receive the vaccine are less likely to have complications from the virus.
After you get the chickenpox, the virus becomes dormant in certain nerves in the body. Shingles occurs after the virus becomes active again in these nerves. The virus can remain inactive for several years. The reason for the virus to become active again is unclear.
Shingles may develop at any age, however, one is likely to develop the virus if:
You had chickenpox before the age of one
You are over the age of 60
Your immune system is weakend by medications or disease
Our pain management specialists can offer you options to help manage the pain caused by shingles and postherpectic neuralgia. Lidocaine patches and steroid injections into the affected nerve root are two methods we frequently use to block the pain of shingles and postherpectic neuralgia.
Dr. DP Mohapatra, an expert in bone pain associated with cancer, joins the faculty of the Washington University Pain Center
Durga P. (DP) Mohapatra, PhD has joined the faculty of the Department of Anesthesiology as an Associate Professor in the Washington University Pain Center. DP joins us from the University of Iowa where he was on faculty for seven years.
The major research focus of Dr. Mohapatra’s laboratory is to define the precise tumor-nerve signaling crosstalk that underlie the initiation and maintenance of chronic pain associated with prostate/breast cancer bone metastases. The Mohapatra group is developing rodent models of chronic ongoing/un-evoked pain behaviors associated with prostate/breast cancer bone metastasis, as well as investigating the precise tumor-nerve signaling mechanisms underlying such chronic painful conditions. The Mohapatra group also works on mechanisms underlying peripheral pain sensitization under conditions of tissue injury, inflammation and development of obesity. Their work seeks to identify and validate specific targets for the development of novel and efficacious pharmacotherapeutics for chronic pain associated with metastatic bone cancers, inflammation and obesity. In addition to pain research, the Mohapatra group is investigating the mechanisms underlying neuronal survival-death dynamics in multiple neurodegenerative conditions, such as stroke-reperfusion injury and neuro-HIV-1 infections. Their multidisciplinary research approach ranges from cellular, molecular, biochemical, live-cell ion imaging and electrophysiology to multiple behavioral assessments in rodent models of human diseases, including the utilization of mouse genetics.
Gereau named Brown professor of anesthesiology
This story was originally published in The Record.
Robert W. Gereau IV, PhD, has been named the Dr. Seymour and Rose T. Brown Professor of Anesthesiology at Washington University School of Medicine in St. Louis.
The named professorship was announced by Washington University in St. Louis Chancellor Mark S. Wrighton and Larry J. Shapiro, MD, executive vice chancellor for medical affairs and dean of the School of Medicine.
Larry J. Shapiro, MD, (left), executive vice chancellor for medical affairs and dean of the School of Medicine, congratulates Robert W. Gereau IV, PhD, at his installation as the Dr. Seymour and Rose T. Brown Professor of Anesthesiology.
The professorship honors Washington University alumni Seymour Brown, MD, a 1940 graduate of the School of Medicine who served for more than 40 years as chief of anesthesiology at what was then St. John’s Mercy Hospital, and his wife, Rose Brown, who graduated from WUSTL in 1936 with a bachelor’s degree in education and biology. After completing her degree, Mrs. Brown served on the editorial staff of C.V. Mosby Publishing Co., editing medical books and journals.
They married in 1941, and shortly after that, Seymour Brown served as a physician on a destroyer in World War II, where he lived through many legendary naval battles including the battles of Midway and Guadalcanal. During the latter battle, his ship was torpedoed and sunk. Later in his military career, Brown was named chief of anesthesiology at naval hospitals in Great Lakes, Ill., and Mare Island, Calif.
When Dr. Brown completed military service, the Browns moved to Boston, where he studied anesthesiology at the Lahey Clinic and Mrs. Brown worked at Massachusetts Institute of Technology, editing books.
When they returned to St. Louis, Dr. Brown worked briefly at Barnes Hospital before starting the anesthesiology program at St. John’s and joining the clinical teaching faculty at Saint Louis University, where he served for more than 30 years. He also served terms as president of the Missouri state and the St. Louis societies of anesthesiology. Mrs. Brown assisted hearing-impaired students for 13 years and later worked as a real estate agent. She also volunteered at St. John’s Mercy Medical Center and at St. Luke’s Hospital for 20 years.
“Over the years, the Brown family’s generosity has helped fund scholarships for medical students, and this is one of two professorships the family established in anesthesiology,” Wrighton said. “The Browns also created an endowment for research in the Division of Gastroenterology in honor of their son, who was a gastroenterology resident here. We cannot thank the Browns enough for their extremely generous support.”
Dr. and Mrs. Brown were married for 65 years prior to Dr. Brown’s death in 2006. Mrs. Brown died in 2013. The couple had two sons, Alvin R. Brown, MD, and Donald E. Brown. Alvin Brown, who was a resident in gastroenterology at the School of Medicine, died in 2000. Donald Brown, an attorney, lives in Maryland with his wife and daughter.
In addition to his appointment in anesthesiology, Gereau also is a professor of anatomy and of neurobiology and is director of the Washington University Pain Center. He studies the molecular mechanisms involved in pain sensation, and his research includes basic laboratory work and translational studies of the pain response in people.
Most recently, Gereau’s laboratory has been involved in studies using optogenetics, which uses light signals to activate or deactivate nerve cells responsible for transmitting pain signals from the periphery to the brain. He is using tiny, light-emitting devices to map the molecular and cellular properties of neural circuits to better understand how those circuits transmit pain after nerve injury. Being able to visualize how the circuits connect and transmit pain signals could allow for the development of new treatments.
“Dr. Gereau’s work is at the forefront of pain research and is helping to better understand and alleviate chronic pain,” Shapiro said. “His efforts are vital to the development of new and more effective ways to treat the large numbers of patients with pain who could not previously be helped.”
Gereau graduated summa cum laude with a bachelor’s degree in biology from what is now Missouri State University. He earned a doctorate in neuroscience from Emory University School of Medicine and then completed a postdoctoral fellowship at the Salk Institute for Biological Studies before he became an assistant professor in the Division of Neuroscience at Baylor College of Medicine in 1998. He joined the Washington University faculty in 2004.
“Rob is a very talented scientist and a wonderful mentor for our residents, students and fellows,” said Alex S. Evers, MD, the Henry E. Mallinckrodt Professor and head of the Department of Anesthesiology. “His recent work using optogenetic techniques to turn pain signals on and off could lead to major breakthroughs in both the understanding and treatment of pain.”
(From left) Chancellor Mark S. Wrighton, Robert W. Gereau IV, PhD, Alex S. Evers, MD, and Larry J. Shapiro, MD, celebrate Gereau’s installation as the Dr. Seymour and Rose T. Brown Professor of Anesthesiology.
Gereau’s research has been supported continuously by National Institutes of Health (NIH) grants for the last 15 years, and he has served as a member and chair of multiple NIH study sections. He also serves on several editorial boards for scientific journals and is a member of the board of directors of the American Pain Society.
“The support from the Brown family for research in the Department of Anesthesiology has been tremendous,” Gereau said. “It is a great honor to receive this recognition for pain research, and I am very grateful to Don Brown and his family for their generosity in establishing this professorship. This support will help make our research effort more agile and innovative, and I hope it will help us to bring new treatments to the tens of millions of people who suffer with chronic pain.”
He has authored 80 peer-reviewed scientific publications, 26 invited publications and has been invited to deliver 85 lectures. During his career, Gereau also has mentored 34 pre- and postdoctoral trainees, as well as nine undergraduates and five high school students. In 2011, he received the Outstanding Faculty Mentor Award from the Washington University Graduate Student Senate. Among his other honors is a 2012 NIH Director’s Transformative Research Award for his efforts to treat pain using optogenetics.
Light — not pain-killing drugs — used to activate brain’s opioid receptors
Despite the abuse potential of opioid drugs, they have long been the best option for patients suffering from severe pain. The drugs interact with receptors on brain cells to tamp down the body’s pain response. But now, neuroscientists at Washington University School of Medicine in St. Louis have found a way to activate opioid receptors with light.
New research at Washington University in St. Louis shows that it’s possible to activate opioid receptors with light instead of pain-killing drugs. The discovery eventually may lead to new ways to relieve severe pain without the addictive properties and side effects posed by opiate drugs, such as morphine, OxyContin and Vicodin.
In a test tube, the scientists melded the light-sensing protein rhodopsin to key parts of opioid receptors to activate receptor pathways using light. They also influenced the behavior of mice by injecting the receptors into the brain, using light instead of drugs to stimulate a reward response.
Their findings are published online April 30 in the journal Neuron.
The eventual hope is to develop ways to use light to relieve pain, a line of discovery that also could lead to better pain-killing drugs with fewer side effects.
“It’s conceivable that with much more research we could develop ways to use light to relieve pain without a patient needing to take a pain-killing drug with side effects,” said first author Edward R. Siuda, a graduate student in the laboratory of Michael R. Bruchas, PhD, an assistant professor of anesthesiology and of neurobiology.
But before that’s possible, the researchers are attempting to learn the most effective ways to activate and deactivate the opioid receptor’s pathways in brain cells. Bruchas, the study’s principal investigator, explained that working with light rather than pain-killing drugs makes it much easier to understand how the receptors function within the complex array of cells and circuits in the brain and spinal cord.
“It’s been difficult to determine exactly how opioid receptors work because they have multiple functions in the body,” Bruchas explained. “These receptors interact with pain-killing drugs called opiates, but they also are involved in breathing, are found in the gastrointestinal tract and play a role in the reward response.”
So the researchers sought a way to limit opioid receptors to performing a single task at a time, and it turned out to be almost as easy as flipping on a light switch, according to Bruchas, Siuda and their collaborators, including co-first author Bryan A. Copits, PhD, a postdoctoral research scholar in the laboratory of Robert W. Gereau, IV, PhD, the Dr. Seymour and Rose T. Brown Professor of Anesthesiology.
By combining the rhodopsin protein, which senses light in the eye’s retina, with a specific type of opioid receptor called a Mu opioid receptor, the researchers were able to build a receptor that responds to light in exactly the same way that standard opioid receptors respond to pain-killing drugs.
From left, co-first author Bryan A. Copits, PhD, Michael R. Bruchas, PhD, and co-first author Edward R. Siuda used light to activate opiod receptors in the brains of mice.
When an opioid receptor is exposed to a pain-killing drug, it initiates activity in specific chemical pathways in the brain and spinal cord. And when the researchers shone light on the receptors that contained rhodopsin, the same cellular pathways were activated.
In a test tube and in cells, Siuda exposed the receptors to light and then watched as they released the same chemicals that standard opioid receptors release. Then, in mice, the researchers implanted a light-emitting diode (LED) device the size of a human hair into a brain region linked to the reward response. They injected the light-sensing receptors they had genetically manufactured into the same brain region. Neurons in that part of the brain release chemicals such as dopamine that create feelings of euphoria.
In decades of past opioid studies, researchers have observed mice and rats to press a lever to receive a dose of morphine, for example. The morphine would activate opioid receptors and the release of dopamine, and the animals would enjoy the response and press the lever again to continue feeling that reward sensation. This is one of the reasons opiates are so often abused in patients being treated for pain — people like the way the drugs make them feel as much as the pain relief they provide — and rates of abuse have skyrocketed over the past ten years.
Working to deliver a similar reward sensation using light, the researchers put the mice into an enclosed chamber. In one part of the chamber, the lighted laser fiber-optic device stimulated the release of dopamine in the brain. When the animals left that part of the chamber, the light in the brain turned off. Soon after, the mice returned to the part of the chamber that activated the fiber-optic device so that the brain could receive more light stimulation.
“By activating the receptors with light, we are presumably causing the brain to release more dopamine,” Bruchas explained. “Rather than a drug such as morphine activating an opioid receptor, the light provides the reward.”
The researchers were able to vary the animals’ response depending on the amount and type of light emitted by the LED. Different colors of light, longer and shorter exposure to light, and whether the light pulsed or was constant all produced slightly different effects.
When a person takes an opioid drug such as Vicodin or OxyContin to relieve pain, such drugs interact with receptors in the brain to blunt pain sensations. But over time, patients develop tolerance and sometimes addiction. Opioids also can dramatically slow a person’s breathing, too, and typically cause constipation.
In theory, receptors tuned to light may not present the same danger. Siuda said it someday may be possible to activate, or deactivate, nerve cells without affecting any of the other receptors that pain-killing drugs trigger, although achieving that goal will be difficult.
Bruchas’ team is planning future studies that will use these receptors to test ways to control the brain cells that mediate pain and reward behavior with light rather than drugs.
The research was supported by a EUREKA award from the National Institute on Drug Abuse, the National Institute of Mental Health and the National Institute of General Medical Sciences of the National Institutes of Health (NIH); grant numbers R01 DA037152, F31 MH101956, K99 DA038725, TR32 GM108539 and NSTR01 NS081707. Additional funding from a W.M. Keck Fellowship in Molecular Medicine; and the Howard Hughes Medical Institute.
Siuda ER, Copits BA, Schmidt MJ, Baird MA, Al-Hasani R, Planer WJ, Funderburk SC, McCall JG, Gereau RW, Bruchas M. Spatiotemporal control of opioid signaling and behavior. Neuron, published online April 30, 2015.
Washington University School of Medicine‘s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’shospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation, currently ranked sixth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.