Inflammation in glial cells causes them to activate and transform into immune cells. The activated glia irritate the neurons near them. This causes the neurons to become more sensitive and fire more often. This can lead to a chronic pain cycle.
Recent research shows that damaged and/or inflamed glial cells can contribute to or cause chronic pain (Hanani and Spray 2020, Du et al. 2023). Two types of glial cells, satellite glia and microglia, can initiate and maintain pain from inflammation, neuropathy, bone cancer, migraine, peripheral neuropathy and other causes.
Satellite glia: Neuroinflammatory responses from satellite glial cells may be one source of chronic or long term pain (Du et al. 2023). Satellite glia are in the peripheral nervous system (PNS). They are small flattened cells that cover and protect the bodies of neurons in ganglia. Ganglia are clusters of nerve bodies that relay or transfer nerve signals.
Satellite glia contain a lot of mitochondria and endoplasmic reticulum organelles. Due to this, satellete glia are heavily involved in neuron metabolism; calcium hemostasis; signal transmission; and synthesis and recycling of neurotransmitters and other vital molecules.
Microglia: When microglia are activated due to injury or disease, they undergo undergo morphological, transcriptional, and functional changes. In other words, they change shape, form and function. Activated glia change the types of cytokines, chemokines, and neuropeptides they produce. Many of these new chemicals are pro-inflammatory. Inflammatory compounds increase the sensitivity and firing properties of your second-order neurons. Second order neurons receive information directly from first order neurons. First order neurons directly input sensory stimuli.
For example, a first order neuron directly takes in sensory and motor signals from the skin, eyes, nose, tongue, and ears. It evaluates touch, hearing, sight, smell, taste, proprioception (tells you where body parts are in space), and vestibular (movement and balance). The first order neuron passes this information on to a second order neuron. Like a game of hot potato, the second order neuron passes the information to third order neurons in the thalamus, which is in the brain. The thalamus transmits the sensory and motor signals to the cerebral cortex to be interpreted.
When glial are activated they activate the second order neurons. Activated secondary neurons are more sensitive. They upregulate the pain (nociceptive) signaling information going to the cerebral cortex (the part of the brain responsible for higher level tasks like thinking and learning). This process, called central sensitization, seems to be a crucial step causing acute pain to become chronic (Echeverria-Villalobos et al. 2023).
Activated microglia and astrocytes can contribute to CNS dysfunction and neurodegenerative disease (Bennett and Viaene 2021).
This chronic pain cycle can be caused by opioids. Yes, you read that right. Using opioids to relieve pain can induce the proinflammatory glial cell activation that leads to MORE chronic pain (Echeverria-Villalobos et al. 2023).
If you, or someone you know, are using opioids for pain relief please see how opioids interact with glial cells to cause chronic pain.
Glial cells seem to be key players in migraine pathology. According to Vila-Pueyo et al. 2023, astrocytes and microglia are involved in initiation of the migraine aura. During this stage, a wave of neural and glial depolarization travels across the cortex. Depolarization is when the electrical charge within neurons or cells becomes less negative than the electrical charge surrounding the cell. Depolarization is followed by lower electrical activity in the brain.
Microglia from the trigeminocervical complex (this is the association between the upper neck, temporomandibular joint of the jaw, and trigeminal nerve near the brain stem) may play a role in chronic migraines. These microglia are involved in central sensitization.
Central sensitization is when nerves are on high alert and people develop an increased sensitivity to touch, pain, light, sounds and/or odors. Central sensitization causes hyperalgesia; pain feels a lot worse than normal; as well as allodynia; normal light touches or sensations feel painful.
Satellite glial cells may be involved in the headache phase of the migraine. They initiate and maintain orofacial pain (pain felt in the mouth, jaws and face) (Vila-Pueyo et al. 2023).
Cognitive behavior therapy and behavior therapy may help with migraines (Mínguez-Olaondo et al. 2024). Behavior therapy teaches people to control their physiological responses like heart rate or breathing through online feedback of these so-called involuntary body functions. This allows people to self-regulate and control these functions.
Satellite glial cells are flattened cells that wrap around and envelope neuronal cell bodies. Think of them as cozy onsies for nerve cells! They are present in peripheral ganglia and are part of the peripheral nervous system (PNS); the part of the nervous system that is outside the brain and spinal cord. Satellite glial cells maintain two way communication with neurons and produce bioactive chemicals such as ATP, glutamate and cytokines.
This close relationship with sensory nerves allows changes in satellite glial cells to contribute to chronic pain. Basically, as glia and nerve cells become more activated/sensitive/excitable they fire more often which leads to increased pain signals. This can cause a positive feedback loop with each cell influencing the other. Worse, activated cells can keep firing after the cause of the pain is gone.
Nerve damage or metainflammation can activate most glia. In particular, nerve injury leads to nitric oxide (NO) release, which causes satellite glial cell activation. Once activated, glial cells release compounds causing neuronal hyperexcitability and pain (Hanani and Spray 2020).
Astrocytes in the CNS produce GFAP, a cytoskeletal protein. Under normal circumstances, GFAP helps the blood brain barrier (BBB) function, works in cell structure and movement, and helps cell communication. GFAP is only found in the blood if neurons are injured or killed.
Increased GFAP levels are seen after brain injury (Abdelhakry et al. 2022). It can be a marker of abnormal astrocyte activation and proliferation due to nerve damage. This can cause glia activation. There is increasing evidence that measuring blood GFAP concentrations can diagnose brain injuries and even predict their severity.
Astrocytic Kir4.1 channels are used in several ways: buffering potassium (K+) (potassium helps generate nerve impulses); regulating extracellular glutamate levels by coupling with glutamate transporters; and modulating expression of brain-derived astrocyte neurotrophic factor (BDNF) (Ohno et al. 2021).
Kir4.1 potassium channels use a process called spatial potassium (K+) buffering to remove extracellular potassium (K+) from tripartite synapses.
Tripartite synapses are a three-way exchange of information involving pre-synaptic neurons, post-synaptic neurons, and astrocytes. The astrocytes are active players in this flow of information. They play a dynamic role by integrating and processing synaptic information while controlling synaptic transmission and plasticity (Arizono et al. 2020). Synaptic plasticity is the ability of the brain to alter structure and form to respond to a changing environment.
Synapses are the places where neurons connect and communicate with each other and glial cells. Most synapses use chemicals called neurotransmitters to communicate. Pre-synaptic neurons release neurotransmitters into the gap between neurons called the synaptic cleft. Post-synaptic neurons receive and read the neurotransmitters.
Astrocytic Kir4.1 channels regulate both extracellular K+ and glutamate concentrations. If this pathway is inhibited it increases both extracellular K+ and glutamate levels at nerve synapses. This increases astrocyte BDNF.
BDNF enhances neural excitability, which fosters synaptic plasticity and connectivity. This is good in normal amounts and helps the brain grow and adapt. However, in excess, it can cause extreme excitability which causes astrocyte dysfunction and activation (Méndez-González et al. 2020). It is like taking a five year old to the county fair, a few hours there fosters excitement and wonder; being there all day can trigger a meltdown.
Coupling increases after cellular damage or inflammation. This allows increased transfer of small chemicals such as NO and electrical current. This higher activity/excitement may account for the greater glia cell activation. Increased satellite glial cell coupling also contributes to acute pain; in contrast, blocking gap junctions to weaken coupling decreased pain (discussion in Hanani and Spray 2020).
Exposure to ATP causes an increase in neuronal excitation (nerve firing rate)(discussion Hanani and Spray et al. 2020). this can activate glia.
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