How Glial Cells Both Prevent and Cause Pain
The mysterious glial cells (glia): home town heros or home grown terrorists?
Over half of your brain cells are glia; they include astrocytes, radial glia, ependymal cells, oligodendrocytes, Schwann cells, Bergmann glia, satellite cells, and microglial cells. Glia are not nerve cells; they do not partake in electrical signaling or synaptic interactions.
Glia is Latin for glue. When glial cells were first discovered scientists thought their role was to hold or glue the nervous system together. However, we now know that glia are so much more intriguing.
★ Glia guide, care for, and heal brain neurons.
★ Glia make myelin and provide scaffolding for nerve development.
★ Glia direct and modulate nerve cell signals.
★ Glia can transform into their alter egos, immune cells.
Under stress these peaceful cells are activated and transformed into poorly trained soldiers that fire on friend and foe.
Under stress, these healing cells can trigger chronic pain, migraines and brain disorders.
- The dark side of glia: chronic pain can be caused by activated glial cells.
- Learn more about how glia heal the brain here.
Train to be a Nurse poster from WWI UK.
What are the National Guard duties of glia cells?
Think of glia as the Brain's National Guard. As mentioned above; in their day to day civilian life glial cells have important jobs to do around the brain. However, glia can be activated and called up to Guard duty in an instant to assist as immune cells. Activation occurs when the glial cells sense danger in the form of chronic inflammation, invading pathogens, and/or injury. Basically, glia are activated, issued a uniform and a weapon, and told to report to duty as immune cells.
Activated glia transform into several immune cell forms (phenotypes) depending on what causes the transformation. These forms include classical activation (M1), alternative activation (M2), or a range of different intermediate phenotypes somewhere between M1 and M2. Interestingly, glia can also transform from one M phenotype to another (discussion in Guo et al. 2022).
This is important because M1 are pro-inflammatory and M2 are anti-inflammatory. M1 glial cells (microglia) release inflammatory mediators which increase inflammation and cause neurotoxicity. They fight viral infections. Like immune cells, M1 glial cells attack viruses, bacteria or other perceived threats by releasing pro-inflammatory cytokines. These chemicals can cause you pathological pain as well.
M2 glial cells (microglia) release anti-inflammatory mediators which reduce inflammation and protect the brain. They stimulate also tissue repair (Guo et al. 2022).
What are the civilian job duties of glia cells?
★ Internet and phone providers: Regulate communication links (neurotransmission) and carry signals from brain to rest of body.
★ Strategy and operation advisors: Glia talk to individual neurons and influence how those neurons respond to environmental factors like smell, temperature, and touch (Ray et al. 2024). They help decide what senses your neuron prioritize. Are you going to pay attention to sound, smell or sight first? When two neurons communicate, the glia modulate their synaptic activity to help guide neuron activity.
★ Confidential advisors: When communicating with neurons about environmental signals, glial cells use different clusters of cells for each neuron to keep communications private (Ray et al. 2024).
★ City planners and builders: Glia guide neuron axonal growth by putting down signposts for axons to follow.
★ Nurses and physical therapists: These healing cells help regenerate new axons on neurons, repair damaged brain cells, and modulate inflammation.
★ 3-D Model Makers: Glia make and install myelin (a fatty layer that wraps around nerves and increases nerve transmission speed) and remodels extracellular matrix (a network of protein and cells that supports cells and tissues). They help form synapses.
★ Chemists: Some glial cell regulate brain pH.
★ Sanitation workers: Glial cells clean up dead cells and other trash.
★ Infrastructure Specialists: Glia regulate brain blood flow, transport cerebrospinal fluid (CSF), transport lipids, and form the blood-brain barrier.
★ Supply Line Specialist: Some glial cells store glucose for fuel.
★ Guard Reservist: Glia act as immune cells when called to duty (activated).
There are several catches to glia activation:
Glia are untrained immune cells: Unlike the regular human National Guard who are trained, these newly pressed glia National Guard personnel are raw recruits and totally untrained. They have no idea what they are doing and tend to fire wildly in all directions - hitting friend as well as foe. Their weapons fire inflammatory chemicals (cytokines).
Imagine this, you are a nerve cell getting a warm soft cuddle from a friendly healing glial cell. Suddenly, the glia goes crazy, changes shape and starts firing off acid chemicals from an automated weapon in all directions. You start screaming for help but your friends are all in the same boat. This is how chronic pain can start and continue in a positive feedback loop. Activated glia transform, fire on and freak out nerve cells; nerve cells start screaming in pain; immune cells rush in releasing more inflammatory chemicals; inflammation increases; glia stay activated and freak out nerve cells more... More on how glia activation can result in chronic pain here.
Glia activation increases inflammation: Activated glial cells increase localized inflammation. They do this by spewing inflammatory cytokines, accidently injuring innocent nerve cells, and attracting more immune cells which also emit cytokines.
Inflammation hinders nerve to nerve communication: Increased inflammation hinders nerve communication, partially by keeping the glial cells from completing their normal duties as internet and phone providers. This slows down your thinking ability by slowing the speed in which brain neurons communicate with each other.
Inflammation shuts down energy production: Excess inflammation disrupts mitochondrial energy production. When energy flow is disrupted, the available energy gets shunted to necessary functions like making sure your heart beats. Less necessary functions, like critical thinking, emotional regulation, or writing a paper on the Greater Titmouse, gets shortchanged.
The prefrontal cortex in your brain, which make decisions and controls your emotions, uses a lot of energy. When energy has to be rationed, this area gets hit hard with the energy shortage. Think about it: the body is not going to shut down the heart or the lungs - it will pick the less essential functions to shortchange. Without extra energy it is harder for your brain to concentrate, regulate emotions, think, read, or work.
Activated glia can't do their regular jobs: Activation and their new duties as immune cells prevent glia from fulfilling their primary civilian jobs of cultivating nerve pathways, healing nerve cells, removing garbage, and optimizing nerve growth in the brain. Without their support team, neurons and nerves become less functional. Think about what happens to a big city when the sanitation workers and other city workers go on strike. Garbage buildup alone makes everyday life intolerable.
Once they are activated glia are primed: This means even after glia are deactivate and return to their regular duties, they retain the memory of their glory days as immune cells. Primed glia are more responsive to stimuli (inflammation, viruses, pathogens, injury or stress) and can develop more extreme responses. That means it is easier to activate primed glial cells (León-Rodríguez et al. 2025). They are hypersensitive to any insults.
*Names and some minor identifying details in all stories in this website are changed to protect people's privacy.
This information in this website is for informational purposes only and does not constitute medical advice, diagnosis, or treatment.
Science Bite: how to deactivate glia
Glia can be deactivated naturally. However, once primed, glia remain more sensitive to future injuries and inflammation and will activate quicker. This is one reason why previous injuries can 'flare up' when you are under stress.
Scientists are investigating ways to influence activated glia to turn away from causing injury (neurodegenerative) and turns towards facilitating repair (neurorestorative) (discussion Hermann et al. 2021).
Mice studies used a compound that temporary eliminated 40%–50% of the microglial cell population. One compound used, PLX5622, inhibits colony stimulating factor 1 receptor CSF1R.
CSF1R is needed for survival, proliferation, and differentiation of many types of myeloid cells including microglia. Microglia are brain macrophages and the only myeloid cells present in the central nervous system (CNS).
The rodent brain studies found that moderate CSF1R inhibition caused microglia to revert back to a naive unprimed state with only a temporary dip in population numbers. It also prevented lipopolysaccharide (LPS) microgliosis (activation in response to injury) and inflammatory activation (discussion León-Rodríguez et al. 2024). LPS causes neuroinflammation so it is often used in studies looking at brain inflammation.
Microglia are heavily involved in directing brain synaptic plasticity. Synaptic plasticity is the superpower of neurons to adapt by either strengthening or weakening their connections to each other based on memory, learning and other brain activities.
References:
Guo S, Wang H, Yin Y. Microglia Polarization From M1 to M2 in Neurodegenerative Diseases. Front Aging Neurosci. 2022 Feb 16;14:815347. doi: 10.3389/fnagi.2022.815347. Full article.
Hermann DM, Gunzer M. Modulating Microglial Cells for Promoting Brain Recovery and Repair. Front Cell Neurosci. 2021 Jan 11;14:627987. doi: 10.3389/fncel.2020.627987. Full article.
León-Rodríguez A, Grondona JM, Marín-Wong S, López-Aranda MF, López-Ávalos MD. Long-term reprogramming of primed microglia after moderate inhibition of CSF1R signaling. Glia. 2025 Jan;73(1):175-195. doi: 10.1002/glia.24627. Full article.
Ray S, Gurung P, Manning RS, Kravchuk AA, Singhvi A. Neuron cilia restrain glial KCC-3 to a microdomain to regulate multisensory processing. Cell Rep. 2024 Mar 26;43(3):113844. doi: 10.1016/j.celrep.2024.113844. Full article.