Varicella zoster virus, also known as human herpesvirus 3, causes chickenpox and shingles.
Image credit:©iStock.com, PonyWang
Shingles can cause pain that is notoriously difficult to manage and can persist for months or even years in some patients. The pain can be so severe that it significantly diminishes quality of life and may be accompanied by suicidal thoughts and emotional distress.
When pain lingers beyond three months, clinicians refer to the condition as post-herpetic neuralgia. Because the underlying mechanisms driving this persistent pain remain poorly understood, treatment options focus largely on symptom relief and often fall short, with fewer than half of patients achieving meaningful improvement.
However, new research from our team, published in the journal Annals of Neurology, has revealed that microparticles circulating in the blood called exosomes may help explain some of the most puzzling features of this neuropathic pain condition—and could point toward promising new therapeutic targets.
Chickenpox Reawakens As Shingles
The varicella zoster virus, which causes chickenpox, has infected over 90 percent of the world’s population. Most people encounter the virus during early childhood in temperate regions, though in tropical areas initial infection typically occurs later in adolescence or early adulthood.
Following the initial infection, the virus enters a dormant state within pain-sensing neurons. Even individuals vaccinated against varicella—such as those in the United States since 1995—still carry dormant virus in their neurons, as the vaccine uses a live but weakened strain.
In roughly one-third of the world’s population, the virus reactivates decades later to cause the notoriously painful shingles rash; for reasons still unclear, shingles rates are rising globally. For most people, the pain resolves within a few weeks. Yet approximately 10 to 18 percent of patients go on to develop post-herpetic neuralgia months after the rash has cleared, and in some cases the pain persists for years or even a lifetime.
While anyone who develops shingles is at risk of post-herpetic neuralgia, that risk increases substantially with age.
Exosomes And Irritated Neurons
The precise cause of post-herpetic neuralgia is not yet fully understood. In affected patients, the shingles rash typically heals with skin that appears normal, yet skin biopsies reveal a striking reduction in sensory nerve fibers in the painful areas. Paradoxically, this loss of nerve fibers in the skin can lead to heightened pain in many patients. What prevents these nerve fibers from repairing after the infection has cleared remains unknown.
Some researchers have proposed that ongoing or intermittent viral replication within sensory neurons continues to damage or destroy these cells long after reactivation. However, antiviral treatments that halt viral replication do not reliably prevent or reduce post-herpetic neuralgia. As a result, neurovirologists have been searching for noninfectious contributors to this condition.
In our newly published research, my team and I investigated the role that exosomes—noninfectious microscopic particles circulating in the blood—may play in the development of post-herpetic neuralgia. Exosomes are released from virtually every cell type in the body and carry bioactive cargo, including proteins and nucleic acids capable of altering a recipient cell’s behavior or specific cellular processes. They shuttle these molecules between cells, facilitating communication that is essential for normal bodily functions.
Our laboratory had previously discovered that exosomes in the blood of patients with an active shingles rash can elevate stroke risk and inflammation. This led us to hypothesize that circulating exosomes in the blood of post-herpetic neuralgia patients might also be contributing to their severe pain.
We isolated exosomes from the blood of seven patients with post-herpetic neuralgia and compared them with those from seven patients without the condition. The exosomes from post-herpetic neuralgia patients contained significantly higher concentrations of proteins known to suppress neuronal growth. This raised a compelling question: do patients with post-herpetic neuralgia carry particles in their blood that are blocking the regeneration of their pain-sensing neurons?
To test this, we exposed human sensory neurons in a petri dish to exosomes isolated from individuals with or without post-herpetic neuralgia. Using live-cell imaging, we tracked and measured the neurons’ ability to extend and form connections with one another. As expected, neurons exposed to exosomes from post-herpetic neuralgia patients were significantly stunted and unable to establish robust networks with neighboring neurons. In contrast, neurons exposed to exosomes from unaffected individuals showed no measurable disruption to their function.
When we examined the genetic activity of pain-sensing neurons after exposure to post-herpetic neuralgia exosomes, we found that these neurons underwent changes that actively inhibited the formation of growth cones—structures neurons require to grow and repair themselves. Moreover, we found evidence that these exosomes kept pain-sensing neurons in an overactive state, rendering them hypersensitive to pain signaling.
Future Of Neuropathy Treatment
Our findings suggest that targeting the underlying cause of nerve irritation and failed regeneration could pave the way for more effective treatments for post-herpetic neuralgia by addressing the source of the pain rather than merely its symptoms.
Furthermore, we believe this phenomenon may not be unique to post-herpetic neuralgia. It could likely extend to other painful neuropathies, such as diabetic neuropathy, which is similarly associated with failed nerve regeneration.
Currently, our team is collecting sequential blood samples over periods of up to a year from patients with shingles who later develop post-herpetic neuralgia, as well as from patients whose shingles resolves without lingering pain. This comparison will be crucial for determining precisely what cargo exosomes carry that contributes to this debilitating chronic pain condition.
