The “Missing Link” in the Physiology of Pain: Glial Cells – Practical Pain Management – May 2016
glial cells and their interactions have become recognized as having a critically important role in the generation and maintenance of acute and chronic pain… and may now be a “missing link” in our understanding of the conversion of acute to chronic pain and the development of chronic neuropathic pain
This conversion process has been called “chronification,” and includes
- central sensitization,
- neuroplastic changes,
- altered pain modulation, and
- changes to the “neuromatrix” of the central nervous system.
Some authors have even proposed that chronic pain could be a result of “gliopathy”—a dysregulation of glial functions in the central and peripheral nervous systems that results from glial activation during acute pain
This paper briefly reviews glial cells and their role in the generation of pain.
Glial Cells: Active Role
Microglia are the resident macrophages of the central nervous system (CNS) and are now associated with the pathogenesis of many neurodegenerative and brain inflammatory diseases
Glia cells exist in a grid-like network and are a primary cell mediator within the CNS.
They exist throughout the CNS, interacting with spinal cord nociceptive and primary neurons, and with projection neurons in the brain.
Outnumbering neurons in all areas of the brain, glial cells account for over half the volume and more than 70% of the total CNS cell population.
Glial cells are not of neural origin, but rather are neuroimmune cells, a distinct phenotype.
They are classified in the CNS as astrocytes, oligodendrocytes, and microglia, with astrocytes being the most abundant (Figure 1).
They are known in the peripheral nervous system as satellite astrocytes and in the enteric system as enteric glia (similar to astrocytes).
Astrocytes are well known for their “housekeeping” functions, such as providing physical support, a source of energy, molecules that serve as precursors to neurotransmitters, and a means of maintaining biochemical homeostasis. However, they are active players even under basal conditions—when they are in their basal state rather than being activated
Mirroring their wide distribution centrally and peripherally, glial cells have multiple functions in a wide variety of physiological processes, including
- CNS development,
- pathogen recognition,
- antigen presentation,
- extracellular matrix remodeling,
- stem cell regulation,
- regulation of tumor cell proliferation,
- lipid transport,
- neuronal communication, and
- modulation of inflammation.
Multiple studies in the literature have demonstrated an association of activated glia/astrocyte response (increased expression of astrocyte markers) in models of
- acute pain,
- inflammatory pain,
- neuropathic pain,
- bone cancer pain,
- migraine, and
- peripheral neuropathy.
The cells participate in both the initiation and maintenance of pain.
For example, microglia in the CNS rapidly respond to nerve injury and “transform” into an activated state. As these cells activate, they are capable of transforming from their resting phenotype into an active phenotype (ie, activated glia).
Other immune cells also release proinflammatory cytokines that stimulate and further activate glial cells in the brain and spinal cord to release additional proinflammatory and other substances that attract other immune cells and can lead to neuroinflammation and even neuronal cell death.
The result of this proinflammatory milieu is magnification, maintenance, and prolongation of the response to nociceptive and neuropathic afferent input.
Several of the released mediators—including
- cytokines (eg, tumor necrosis factor-alpha [TNFα] and interleukins),
- nitric oxide (NO),
- excitatory amino acids,
and others—have been associated with pain, hypersensitization, and other pain processes.
Once activated, additional intracellular changes are initiated, including upregulation of a number of receptors and intracellular signaling molecules
Neurons in sensory ganglia are completely surrounded by satellite glial cells that can form a functional unit
The communication between sensory ganglia and satellite glial cells may be impacted by spontaneous intercellular calcium waves.
Calcium (Ca2+) triggers the release of glutamate from astrocytes and thereby modulates synaptic transmission. Calcium waves have been shown to influence signal propagation in facial and somatic pain.
Opioid receptors are proinflammatory and this might explain the seemingly surprising data that opioid receptor antagonists (eg, naloxone) improve inflammatory pain.
The few clinical trials of opioid antagonists generally consist of small populations; however, the researchers noted that there does appear to be a trend of effectiveness of low doses
Visceral pain (pain from internal organs) is a major clinical problem, and it has been suggested that it is the “most frequent form of pain produced by disease and one of the main reasons for patients to seek medical attention.
Visceral pain turns out to be rather complex. According to a definitive review, visceral pain disorders exhibit multiple characteristics that suggest the presence of visceral hyperalgesia (discomfort, pain, and altered sensations, for example, to intraluminal contents). In addition, it has been shown that microglia may be involved in the development of arachnoiditis
Acute to Chronic Pain Transformation
Many patients will have an acute pain episode without developing a chronic pain syndrome. There are those, however, for whom chronic pain develops, and it has been unclear why this transformation from acute to chronic pain occurs.
Recent studies suggest that neuroinflammation and the release of inflammatory cytokines contribute to this transformation.
Changes occurring in the microglial system contribute both to neuroinflammation and to release of cytokines
Potential for Novel Pain Therapies
In 2012, Hesselink suggested that palmitoylethanolamide, a potent anti-inflammatory fatty acid amide, resulted in analgesia, through its action on activated glia and inflammation.
Bisphosphonates, hyperbaric oxygen, botulinum toxin, minocycline, tramadol, and cryptolepine have all been suggested as potential ways to reduce glial activation and neuroinflammation.
According to the researchers, omega-3 polyunsaturated fatty acids provide neuroprotection due to their anti-inflammatory and anti-apoptotic properties, as well as their regulatory function on growth factors and neuronal plasticity
DHA also modulated the spinal astrocyte activation.
Frrom Wikipedia: The three types of omega-3 fatty acids involved in human physiology are α-linolenic acid (ALA) (found in plant oils), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) (both commonly found in marine oils).
So perhaps a healthy lifestyle and diet contribute to better glial health and reduced pain susceptibility. This emerging concept is supported by research
Glial cells express cannabinoid receptors and signaling systems that likely also contribute to analgesic, anti-inflammatory, antioxidant, and neuroprotective effects.
controlling glial activation (possibly by TLR4 antagonistic mechanisms) could be an adjunctive approach to increase the clinical utility of opioid analgesics and achieve greater separation of pain relief from adverse effects.
Summary and Perspective
From emerging research in this new field, it is becoming clear that glial cells release cytokines, chemokines, and other neuroactive substances that disrupt the excitatory and inhibitory amino acid and neurotransmitter homeostasis and, consequently, elevate neuronal excitability, which manifests as both heightened and prolonged pain.
It has been suggested that glial cells are implicated in the onset or maintenance of multiple pain types and in the “chronification” of acute pain to chronic pain.
some substances released by these cells attenuate the response to pain-relieving therapies, particularly opioids.
For example, as Ji et al discuss, “glial activation is not well defined,” and it will be “difficult to design drugs that target only glial cells without affecting neurons.”
In the interim, pain patients might take a practical approach to improving their pain by improving their glial health through adoption of a healthier lifestyle and diet, losing weight, and maintaining a regular exercise program.