A soft hydrogel fibre enables optogenetic pain inhibition during locomotion.  CREDIT Credit: Sabrina Urbina Villafranca

Scientists have a new tool to precisely illuminate the roots of nerve pain. 

Engineers at MIT have developed soft and implantable fibres that can deliver light to major nerves throughout the body. When these nerves are genetically manipulated to respond to light, the fibres can send pulses of light to the nerves to inhibit pain. The optical fibres are flexible and stretch with the body. 

The new fibres are meant as an experimental tool that can be used by scientists to explore the causes and potential treatments for peripheral nerve disorders in animal models. Peripheral nerve pain can occur when nerves outside the brain and spinal cord are damaged, resulting in tingling, numbness, and pain in affected limbs. Peripheral neuropathy is estimated to affect more than 20 million people in the United States. 

“Current devices used to study nerve disorders are made of stiff materials that constrain movement so that we can’t really study spinal cord injury and recovery if pain is involved,” says Siyuan Rao, assistant professor of biomedical engineering at the University of Massachusetts at Amherst, who carried out part of the work as a postdoc at MIT. “Our fibres can adapt to natural motion and do their work while not limiting the subject’s motion. That can give us more precise information.”

“Now, people have a tool to study the diseases related to the peripheral nervous system, in very dynamic, natural, and unconstrained conditions,” adds Xinyue Liu PhD ’22, an assistant professor at Michigan State University (MSU). 

Details of their team’s new fibres will be reported in a study appearing in Nature Methods. Rao’s and Liu’s MIT co-authors include Atharva Sahasrabudhe, a graduate student in chemistry; Xuanhe Zhao, professor of mechanical engineering and civil and environmental engineering; and Polina Anikeeva, professor of materials science and engineering, along with others at MSU, UMass-Amherst, Harvard Medical School, and the National Institutes of Health.

Beyond the brain

The new study grew out of the team’s desire to expand the use of optogenetics beyond the brain. Optogenetics is a technique by which nerves are genetically engineered to respond to light. Exposure to that light can either activate or inhibit the nerve, which can give scientists information about how the nerve works and interacts with its surroundings. 

Neuroscientists have applied optogenetics in animals to precisely trace the neural pathways underlying a range of brain disorders, including addiction, Parkinson’s disease, and mood and sleep disorders — information that has led to targeted therapies for these conditions. 

To date, optogenetics has been primarily employed in the brain, which lacks pain receptors, allowing for the relatively painless implantation of rigid devices. However, the rigid devices can still damage neural tissues. The MIT team wondered whether the technique could be expanded to nerves outside the brain. Just as with the brain and spinal cord, nerves in the peripheral system can experience a range of impairments, including sciatica, motor neuron disease, and general numbness and pain. 

Optogenetics could help neuroscientists identify specific causes of peripheral nerve conditions and test therapies to alleviate them. However, the main hurdle to implementing the technique beyond the brain is motion. Peripheral nerves experience constant pushing and pulling from the surrounding muscles and tissues. If rigid silicon devices were used peripherally, they would constrain an animal’s natural movement and potentially cause tissue damage.  

Crystals and light

The researchers looked to develop an alternative that could work and move with the body. Their new design is a soft, stretchable, transparent fibre made from hydrogel — a rubbery, biocompatible mix of polymers and water, the ratio of which they tuned to create tiny, nanoscale crystals of polymers scattered throughout a more Jell-O-like solution. 

The fibre embodies two layers — a core and an outer shell or “cladding.” The team mixed the solutions of each layer to generate a specific crystal arrangement. This arrangement gave each layer a specific, different refractive index, and together the layers kept any light travelling through the fiber from escaping or scattering away. 

The team tested the optical fibres in mice whose nerves were genetically modified to respond to blue light that would excite neural activity or yellow light that would inhibit their activity. They found that mice could run freely on a wheel even with the implanted fibre in place. After two months of wheel exercises, amounting to 30,000 cycles, the researchers found the fibre was still robust and resistant to fatigue, and could also transmit light efficiently to trigger muscle contraction. 

The team then turned on a yellow laser and ran it through the implanted fiber. Using standard laboratory procedures for assessing pain inhibition, they observed that the mice were much less sensitive to pain than rodents that were not stimulated with light. The fibers were able to significantly inhibit sciatic pain in those light-stimulated mice. 

The researchers see the fibers as a new tool that can help scientists identify the roots of pain and other peripheral nerve disorders.

“We are focusing on the fiber as a new neuroscience technology,” Liu says. “We hope to help dissect mechanisms underlying pain in the peripheral nervous system. With time, our technology may help identify novel mechanistic therapies for chronic pain and other debilitating conditions such as nerve degeneration or injury.”

An artistic representation of the interaction between the NaV1.7 sodium ion channel and collapsin response mediator protein 2 (CRMP2). The researchers identified a unique regulatory sequence in NaV1.7 that is required for NaV1.7 function. They found that this peptide disrupted the interaction with CRMP2 and reduced excitability in sensory neurons. The researchers then showed that this peptide relieved pain in animal models, demonstrating that this interaction can be targeted to ameliorate chronic pain. CREDIT Samantha Perez-Miller and Rajesh Khanna (New York University)

Researchers at NYU College of Dentistry’s Pain Research Center have developed a gene therapy that treats chronic pain by indirectly regulating a specific sodium ion channel, according to a new study published in the Proceedings of the National Academy of Sciences (PNAS).

The innovative therapy, tested in cells and animals, is made possible by the discovery of the precise region where a regulatory protein binds to the NaV1.7 sodium ion channel to control its activity.

“Our study represents a major step forward in understanding the underlying biology of the NaV1.7 sodium ion channel, which can be harnessed to provide relief from chronic pain,” said Rajesh Khanna, director of the NYU Pain Research Center and professor of molecular pathobiology at NYU Dentistry.

Chronic pain is a significant public health issue that affects roughly a third of the U.S. population. Scientists are eager to develop pain medications that are more effective and safer alternatives to opioids.

Sodium ion channels play a key role in the generation and transmission of pain, as they are critical for nerve cells, or neurons, communicating with each other. One particular sodium ion channel called NaV1.7 emerged as a promising target for treating pain following the discovery of its importance in people with rare, genetic pain disorders. In some families, a mutation in the gene that encodes for NaV1.7 allows large amounts of sodium to enter cells, causing intense chronic pain. In other families, mutations that block NaV1.7 result in a complete lack of pain.

Scientists have been trying for years to develop pain treatments to selectively block NaV1.7—with little success. Khanna has taken a different approach: rather than blocking NaV1.7, his goal is to indirectly regulate it using a protein called CRMP2.

“CRMP2 ‘talks’ to the sodium ion channel and modulates its activity, allowing more or less sodium into the channel. If you block the conversation between Nav1.7 and CRMP2 by inhibiting the interaction between the two, we can dial down how much sodium comes in. This quiets down the neuron and pain is mitigated,” said Khanna, the PNAS study’s senior author.

Khanna’s lab previously developed a small molecule that indirectly regulates Nav1.7 expression through targeting CRMP2. The compound has been successful in controlling pain in cells and animal models, and studies are continuing towards its use in humans. But despite the compound’s success, a key question remained: why does CRMP2 only communicate with the NaV1.7 sodium ion channel, and not the eight other sodium ion channels in the same family?

In their PNAS study, the researchers pinpointed a specific region within NaV1.7 where the CRMP2 protein binds to the sodium ion channel in order to regulate its activity. They learned that this region is specific to NaV1.7, as CRMP2 did not readily bind to other sodium ion channels.

“This got us really excited, because if we took out that particular piece of the NaV1.7 channel, the regulation by CRMP2 was lost,” said Khanna.

To limit the communication between CRMP2 and NaV1.7, the researchers created a peptide from the channel that corresponds to the region where CRMP2 binds to NaV1.7. They inserted the peptide into an adeno-associated virus in order to deliver it to neurons and inhibit NaV1.7. Using viruses to transport genetic material to cells is a leading approach in gene therapy, and has led to successful treatments for blood disorders, eye diseases, and other rare conditions.

The engineered virus was given to mice experiencing pain, including sensitivity to touch, heat, or cold, as well as peripheral neuropathy that results from chemotherapy. After a week to 10 days, the researchers’ assessed the animals and found that their pain was reversed.

“We found a way to take an engineered virus—containing a small piece of genetic material from a protein that all of us have—and infect neurons to effectively treat pain,” said Khanna. “We are at the precipice of a major moment in gene therapy, and this new application in chronic pain is only the latest example.”

The researchers replicated their findings inhibiting NaV1.7 function across multiple species, including rodents and the cells of primates and humans. While more studies are needed, this is a promising sign that their approach will translate into a treatment for humans.

“There is a significant need for new pain treatments, including for cancer patients with chemotherapy-induced neuropathy. Our long-term goal is to develop a gene therapy that patients could receive to better treat these painful conditions and improve their quality of life,” said Khanna.

Chronic pain can seriously restrict our lives, preventing us from reaching our full professional potential, enjoying hobbies, and even participating in meaningful life events with friends and family out of fear that certain activities may lead to additional pain and suffering. Avoiding experiences associated with pain can be an adaptive behavior. But, as Eveliina Glogan, Peixin Liu, and Ann Meulders (Maastricht University) demonstrate in a recent Psychological Science article, when we learn to avoid one activity that has caused pain in the past, it can also lead us to avoid conceptually related activities that we may be able to complete painlessly. 

“When avoidance generalizes to such safe movements and activities, it can become problematic,” Glogan said in an interview. “For example, needless avoidance can come at the cost of other valued activities, such as playing with one’s children, and can even culminate in disability due to reduced activity levels.” This generalization can extend not only to physically similar tasks (e.g., from mopping to vacuuming) but also across entire categories of conceptually related activities, such as cleaning or sports. 

Glogan, Liu, and Meulders investigated how generalized avoidance occurs in healthy individuals through a study of 40 people without chronic pain. 

To establish what they consired a painful shock, each participant wore a set of two electrodes that delivered increasingly strong electric shocks. Once the participant rated the pain as an 8 out of 10 in severity (described as “significantly painful and demanding some effort to tolerate”), the shocks stopped and the practice phase of the experiment began. 

During this phase, participants were instructed to complete digital “gardening” and “cleaning” tasks by using a joystick to move a tool, such as a wheelbarrow or a mop, toward an appropriate item, such as a pile of grass or puddle of water, across a computer screen. In the first eight practice trials, participants were able to choose one of two routes to the item: a direct, efficient route that allowed them to complete the task with one movement of the joystick and a longer, inefficient route that required them to move the tool to the item twice. 

In the subsequent acquisition trials, however, every time participants completed the tasks from one category (mopping and vacuuming for cleaning or raking and using a wheelbarrow for gardening), they were 80% likely to receive a painful shock while using the direct route. But they never received a shock while using the indirect route or while completing tasks from the other category (the “safe” category). Before each trial, participants used a scale of 0 to 100 to report how painful they expected each route to be and how fearful they were of using them. 

Once participants had the opportunity to learn about which tasks were likely to cause pain, they completed a generalization phase that included a mix of eight additional gardening and cleaning tasks and the same measures of expected pain and fear. Although mopping/vacuuming or raking/wheelbarrowing using the direct route continued to result in a painful shock, participants could complete the new tasks from both categories using either route without getting zapped. 

By the end of the acquisition phase, participants were more than 5 times more likely to choose the longer, pain-free route to complete tasks in which the direct route had previously resulted in them getting shocked. Participants also reported higher pain expectations and fear in relation to the direct route before completing these tasks, and these higher pain expectations and fear extended to tasks that had never resulted in pain, albeit to a lesser extent. This suggests that although participants had learned to fear experiencing pain on the direct route during certain tasks, they were not entirely certain that the “safe” tasks were really safe either, Glogan and colleagues wrote.

By the end of the experiment, the avoidance of previously painful actions had also generalized to other tasks in the same category even though using the direct route to complete these tasks never resulted in experiencing pain. Overall, participants were 1.8 times more likely to take the indirect route when completing new tasks from the same category as previously painful tasks—for example, cleaning activities like washing dishes or dusting if taking the direct path to mopping and vacuuming had previously caused them pain—than they were during new tasks from the safe category. 

Additionally, participants reported fearing and expecting more pain from the direct route during the new tasks from the pain-associated category than from the safe category. They also reported higher fear and pain expectations related to taking the direct route during the new tasks from the safe category than during familiar safe tasks. 

Although Glogan and colleagues’ previous research supports the view that people generalize pain expectations across categories of activities according to their perceptual similarities, this research suggests that generalized avoidance may also be based on the conceptual similarities individuals assign to tasks, Glogan explained in the interview. This amounts to the difference between perceptually linking vacuuming and mopping because they involve physically similar movements and conceptually linking mopping, dishwashing, and dusting because they are related to the same category—cleaning. 

Psychological factors, rather than physical ones like the severity of an injury, have been shown to be the best predictors of which patients will experience chronic pain, Meulders said in a separate interview, so increasing our understanding of how pain avoidance generalizes could help improve treatment outcomes. 

“Fears and avoidant behavior can spread in idiosyncratic ways, and it’s so important to tap into those semantic networks and find out the specific categories that people have if you want to treat them,” Meulders added. 

Future work is needed to explore how these findings may apply to people with chronic pain, who are thought to generalize pain avoidance more broadly than healthy individuals, Glogan and Meulders said. 

A study of commercially insured adults with chronic noncancer pain found that state medical cannabis laws did not affect receipt of opioid or nonopioid pain treatment. These findings suggest that cannabis use has not led to large shifts in pain treatment patterns at the population level. The study is published in Annals of Internal Medicine.

In the 37 states and the District of Columbia (D.C.) with medical cannabis laws, people with chronic noncancer pain are eligible to use cannabis for pain management. The concern is that state medical cannabis laws may lead patients with chronic noncancer pain to substitute cannabis in place of prescription opioid or recommended nonopioid prescription pain medications or procedures. However, the research is not clear.

Researchers from Weill Cornell Medicine studied insurance claims data from 12 states that implemented medical cannabis laws and 17 comparison states to assess the effects of such laws on receipt of prescription opioids, nonopioid prescription pain medications, and procedures for chronic noncancer pain. The researchers found that in any given month during the 3 years of law implementation, medical cannabis laws led to a negligible difference in the proportion of patients receiving any pain medication or chronic pain procedure. According to the researchers, slow implementation could contribute to the study findings. Results also may be explained by reluctance among health system leaders and individual clinicians to recommend cannabis for pain.