Glial Cell Activation and Neuroinflammation: How They Cause Centralized Pain
Glial cell activation and neuroinflammation are known to be one of the underlying causes of centralized pain (CP) and many of its comorbidities, including depression, fatigue, and insomnia.1-4 Activation of glial cells leads to an ongoing pathologic process in the central nervous system (CNS) that includes neuroinflammation, glial cell dysfunction (GCD), cellular destruction, hyperarousal of the sympathetic nervous system, and stimulation of the hypothalamic-pituitary complex.5-15
Pain that initially arises from a peripheral nervous system injury may become imprinted or “embedded” in the CNS. This phenomenon is called “central sensitization,” and the resulting state is CP.13-16 Phantom limb pain is the classic example. Other examples include neuropathies, including complex regional pain syndrome and diabetic neuropathies.
In this review, I will explain how glial cell activation and neuroinflammation occur and review their clinical ramifications to provide the pain practitioner with a status report on what is known about this pathologic process.
How Glial Cells Malfunction
The CNS is comprised of neurons that transmit pain signals as well as 3 basic types of glia cells: microglia, astrocytes, and oligodendrocytes (Table 1). Neurons in the CNS are surrounded by glial cells whose primary function is to support, protect, and nurture the neurons through mediators involved in energy transfer and processes essential to neural plasticity and stability.7,17,18 Microglia cells migrate to the CNS during prenatal development. They are the resident immune cells in both the brain and spinal cord and are vigilant for any type of toxic challenge, including injury, infection, and ischemia (Table 2).7-10,17,18 Once activated, they take on a role similar to that of a peripheral macrophage, in that, they enlarge, migrate, and can become phagocytic and remove toxic matter.9,10,17 If the microglia cells cannot resolve or eliminate a toxic insult in the CNS, they remain reactive and recruit astrocytes and oligodendrocytes into an ongoing inflammatory process (Table 3).4,8,19,20 Glutamate, an important neurotransmitter, and neurotoxins are released during neural injury. Even neurons may be recruited and trapped in the neuroinflammatory process. The anatomic size and site of inflammation and dysfunction that results from glial cell activation may vary in the brain; multiple anatomic areas have been implicated.14,15 Magnetic resonance imaging (MRI) scans of the brain of patients with CP show areas of varying cellular dysfunction and/or destruction.21-27 Symptoms and comorbidities may vary depending on the CNS location and severity of the inflamed site.3,28,29
After microglia activate and neuroinflammation begins, the autonomic, sympathetic nervous system is stimulated and the hypothalamic-pituitary complex is aroused5,14-16 and the CNS may become overly sensitive to pain (central sensitization).30 The CNS attempts to heal or reform itself and eliminate the pathologic process.5,6 This reformation or reshaping of CNS tissue is referred to as neuroplasticity.30 The neuroplastic response is believed by some observers to be the mechanism that captures or traps the memory of pain. Activated microglial cells and neuroinflammation can release at least 30 different molecular mediators, some pro-inflammatory and others anti-inflammatory.17,31-34 Some of these mediators enter the blood circulation and can be measured.35,36
Schwann cells are a fourth type of glial cell located in the peripheral nervous system, whose primary function is supply the myelin to surround and insulate the axons of the peripheral neurons.37 When a peripheral injury occurs, Schwann cells proliferate, migrate, and secrete numerous factors including pro-inflammatory cytokines.37 It is generally thought that various mediators and/or electrical signals from an injury site travel retrograde up neurons to activate microglia in the CNS and initiate the neuroinflammatory process. Schwann cells undoubtedly participate in signaling microglia, but the mechanism is unclear.19,37
Which Pain States are Involved?
Any pain state that becomes centralized in the CNS apparently is the product of and/or is associated with microglial activation, neuroinflammation, and GCD.11-14 Patients who have been labeled as having central pain syndrome have been victims of a lesion or injury in the spinal cord, brainstem, or cerebral hemisphere(s).15 These lesions or injuries can be caused by stroke, multiple sclerosis, Parkinson’s disease, encephalitis, and traumatic brain injury, among other neurologic diseases. Nerve injury in the periphery, such as discogenic spine degeneration, neuropathies, and arthropathies, also may activate microglial cells in the CNS to induce neuroinflammation.14,15 Even after the peripheral nerve injury is healed, CP may endure and become permanent (Figure 1). A third group of pain patients who may have neuroinflammation and GCD are those who have fibromyalgia, interstitial cystitis, and vulvodynia.25 These conditions are believed by many observers to arise, de novo, in the CNS.
Clinical Profile of CP
Depression and CP
Other Comorbidities
The realization that CP is based on neuroinflammation and GCD provides a better understanding of the close relationship of CP and depression, as well as symptoms of insomnia, fatigue, anxiety, and mental impairments. Other mood disorders, including post-traumatic stress disorder, anxiety, and manic depressive disorder, that commonly occur with chronic pain states also may be related to neuroinflammation.28,29,40,42 Although not completely clear, the close association and temporal relationship between CP and mood disorders strongly suggests that neuroinflammation and GCD are the major underlying factors in such conditions as post-traumatic stress disorder. It may well be that childhood abuse, sexual or otherwise, and other CNS insults that occur long before clinical symptoms of depression or CP may set up an inflammatory focus or propensity that contributes to these conditions in later life. This is easy to comprehend, considering that neuroinflammation is a focus of cellular dysfunction and destruction that may affect various parts of the CNS, may spread in a random, uncontrolled fashion, and may produce a variety of clinical manifestations.
