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.

This diagram shows how NK cell function could in theory result in the resolution of neuropathic pain in the context of peripheral nerve injury by directed cytotoxicity against a number of pathological cellular targets. CREDIT Kim et al./Trends in Neurosciences

In the midst of a global opioid epidemic, a team of scientists is exploring natural killer (NK) cells as an alternative treatment for neuropathic pain. In an Opinion piece published June 27^th in the journal Trends in Neurosciences, the researchers gather existing evidence for the impact of NK cells in pain, pointing to their ability to prune the damaged nerve cells that may cause it. They urge the scientific community to explore biological mechanisms underlying NK cell activity to move towards a realistic pain therapy that is both effective and safe.

Neuropathic pain is a chronic condition experienced as a recurring shooting or stabbing sensation. It is caused by nerve damage, which may occur because of trauma, a disease such as diabetes, or after chemotherapy.

“The prevalence of neuropathic pain is unfortunately only likely to increase over time,” says co-author Alexander Davies, a neurophysiologist with the Neural Injury Group at Oxford University. “As we get better at treating diseases like cancer, we have survivors who may be left with pain from either the cancer treatment or the surgery that was used to remove it.”

While therapies such as opioids and antidepressants are currently used to address these pain symptoms, they do not treat the underlying cause of pain and have their own risks and side effects. The authors point out that 564,000 people overdosed on opioids in the United States between 1999 and 2020.

“The main approach is silencing the neurons,” Davies says. “While we certainly need anesthetics to deal with pain in the short term, if we use them in the long term, we can become addicted to the sensation of removing pain, which is in itself pleasurable.”

Alongside T cells and B cells, NK cells are a type of white blood cell called lymphocytes. Their existing role in the body includes attacking tumors or viruses. NK cells increase activity during acute pain. However, they appear to decline in frequency or potency in people who experience chronic pain. Not having a fully functional NK cell population may therefore prevent people from resolving neuropathic pain in the long term.

“We first became interested in this idea when one of my colleagues found a T cell response after nerve injury, but I noticed that NK cells were also involved,” says senior author Seog Bae Oh, a neurobiologist at Seoul National University. “NK cells are typically explored in the context of cancer, but I thought it was worth looking at them in pain as well.”

NK cells may resolve pain because they are involved in the process by which neurons are pruned. Injury and disease can cause neurons to become incorrectly wired or to stop functioning as intended, resulting in pain symptoms. Introducing NK cells could help to remove these anomalies. Experiments in mice have shown that if a neuron is in distress, its axon, the segment responsible for transmitting messages, displays a molecule called the RAE1 stress ligand. This could alert the NK cells to their need for pruning. A similar ligand, belonging to what is known as the ULBP family, is also seen in sensory neurons in humans with pain.

Conversely, NK cells may have a negative effect in the central nervous system, such as the brain and spinal cord, where neurons cannot regenerate so easily if they are removed. Their impact here should be considered carefully in the design of any possible therapies.

The authors stress that our understanding of the processes by which NK cells support pain relief is still limited, and their potential viability as a future treatment depends on further research. Both Davies and Oh are continuing to explore their NK cells in pain. Oh and his colleagues are investigating the therapeutic potential of NK cells in a range of preclinical models as well as their activity in patients who experience pain, while Davies is working to identify the cellular targets of NK cells following nerve injury.

“We need to have a better mechanistic understanding of how NK cells work and what they can target before we can develop realistic therapies, and we need to minimize their side effects,” Davies says. “However, the more prongs we have to treat neuropathic pain, the more likely we are ultimately to be able to address it.”