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10 Articles in Volume 16, Issue #4
Achilles Tendon Injuries
Brain Trauma in Sports
Genetic Testing: Adjunct in the Medical Management of Chronic Pain
Letters to the Editor: Sleep Apnea, SPG Blocks for Migraines, Pancreatic Pain, CDC Guidelines
Pain and Weather—A Cloudy Issue
Phulchand Prithvi Raj, MD, Pioneer in Pain Management, Dies at 84
Physical Medicine & Rehabilitation
Preventing Chronic Overuse Sports Injuries
Sports-Related Pain: Topical Treatments
The “Missing Link” in the Physiology of Pain: Glial Cells

The “Missing Link” in the Physiology of Pain: Glial Cells

Based on emerging research, it is becoming clear that glial cells release neuroactive substances that disrupt and elevate neuronal excitability, which manifests as heightened and prolonged pain.

Until recently, glial cells were thought to have a purely supportive role for neurons, providing physical and nutrition support as well as forming myelin.1 However, as the layers of confusion have been slowly peeled away, it has become clear that glial cells are active participants in a number of neurologic processes, including pain.

Interestingly, in the early 1900s, a functional glial system was proposed by Carl Ludwig Schleich.2 Since that time, glial cells and their interactions have become recognized as having a critically important role in the generation and maintenance of acute and chronic pain. Concepts of glial cell function have come a long way since 1910, and indeed 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.3

Painting by Pablo Picasso

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.3,4 This paper briefly reviews glial cells and their role in the generation of pain. It further discusses potential therapies that relate to these actions.

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.5 Researchers now propose that microglia derive from primitive macrophages in the yolk sac and during development “invade” and increase in the CNS via the pia membrane.5,6

Glia cells exist in a grid-like network and are a primary cell mediator within the CNS.7 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.5,8

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).5,9 They are known in the peripheral nervous system as satellite astrocytes and in the enteric system as enteric glia (similar to astrocytes).7 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.10 However, they are active players even under basal conditions—when they are in their basal state rather than being activated.

Figure 1. Illustration of glial cells of the central nervous system. Source: Anatomy & physiology. Connextions.

Mirroring their wide distribution centrally and peripherally, glial cells have multiple functions in a wide variety of physiological processes, including CNS development, pathogen recognition, phagocytosis, antigen presentation, cytotoxicity, extracellular matrix remodeling, repair, stem cell regulation, regulation of tumor cell proliferation, lipid transport, neuronal communication, and modulation of inflammation.11

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.12-19 The cells participate in both the initiation and maintenance of pain. The latter was demonstrated in astrocyte marker knockout mice (GFAP–/–),
in which the duration of hypersensitivity exceeded the duration of activation.13

For example, microglia in the CNS rapidly respond to nerve injury and “transform” into an activated state.20 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.21 The result of this proinflammatory milieu is magnification, maintenance, and prolongation of the response to nociceptive and neuropathic afferent input.22,23

Several of the released mediators—including cytokines (eg, tumor necrosis factor-alpha [TNFα] and interleukins), nitric oxide (NO), prostaglandins, excitatory amino acids, and others—have been associated with pain, hypersensitization, and other pain processes.24-27 Once activated, additional intracellular changes are initiated, including upregulation of a number of receptors and intracellular signaling molecules, including mitogen-activated protein kinases.28 Neurons in sensory ganglia are completely surrounded by satellite glial cells that can form a functional unit.29

The communication between sensory ganglia and satellite glial cells may be impacted by spontaneous intercellular calcium waves.30 These waves can travel over several hundred microns and may thus provide a basis for signaling over a long range.31,32 Calcium (Ca2+) triggers the release of glutamate from astrocytes and thereby modulates synaptic transmission.33 Calcium waves have been shown to influence signal propagation in facial and somatic pain.34

There is a significant amount of evidence that toll-like receptors (TLR) play a role in maintaining a balance between tissue inflammation and normal homeostasis.35 There are more than a dozen known members of the TLR family of receptors. Additionally, endotoxins cause release of cytokines via interaction with TLR on immune cells.36 These receptors activate inflammatory pathways through interleukin (IL)-1β, IL-6, IL-12, and TNFα.37 TLR4 is widely expressed on glial cells, especially microglia.38 As nociceptors are stimulated, TLR are activated. This activation in microglia is termed microgliosis.

Another important player is purinergic P2X4 receptors (P2X4R), a ligand-gated ion channel member of the family of purinoceptors for adenosine triphosphate (ATP).15 Bidirectional communication between glial cells and ganglion neurons is thought to be mediated by purinergic receptors. In fact, the purinergic receptor P2X4R microglial phenotype has a literary canon indicating its important role in the development of neuropathic pain.7

In addition, opioid receptors are upregulated during inflammation and are agonists of TLR.39 Opioid receptors are proinflammatory and this might explain the seemingly surprising data that opioid receptor antagonists (eg, naloxone) improve inflammatory pain. For example, Taylor et al conducted a meta-analysis that found the benefit of opioid antagonists in reducing inflammatory pain.40

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 (higher doses antagonize opioid agonist effects). This finding might be explained by mechanisms that are related to the interactions between TLR and opioid receptors.40

Acute to Chronic Pain Transformation

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.”29 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).41 In addition, it has been shown that microglia may be involved in the development of arachnoiditis.42

Because hyperalgesia typically arises in the absence of tissue insult or inflammation, visceral hyperalgesia differs from somatic hyperalgesia, which is commonly associated with tissue injury and inflammation. Visceral hyperalgesia could develop and be maintained by peripheral or central mechanisms (eg, sensitization, “chronification,” etc), contributing to the altered sensations associated with functional visceral pain disorders (ie, irritable bowel syndrome, pelvic pain, renal colic, appendicitis). The complex pathophysiology has meant, unfortunately, that treatment for visceral pain has been limited. Recognition of the role of glial cells in this disorder might shed light on the underlying problem and, therefore, on potential treatment strategies.

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.4 Changes occurring in the microglial system contribute both to neuroinflammation and to release of cytokines.36 In fact, “all experimental neuropathic pain models are characterized by a degree of spinal microglial response” (ie, microgliosis).43 Critically, a peripheral nerve injury model has suggested that the hyperexcitability induced may not be related to nerve changes, but rather to a number of changes in glial cells.28 Further, there is a clear relationship between glial activation and stress, a known contributor to pain and its sequelae.44 Because of this, it has been suggested that the lack of efficacy of current approaches to chronic pain is a result of the focus on neurons. However, as early as 2002, it was postulated that glia would be better targets.45

Potential for Novel Pain Therapies

Although there has been a rapid and significant evolution in the understanding of the basic science concerning glial activation and its role in pain, specific targets are still poorly understood, and effective pharmacotherapeutics are still lacking. However, there is now sufficient data to suggest some intriguing clues and directions for drug discovery and development.

In 2012, Hesselink suggested that palmitoylethanolamide, a potent anti-inflammatory fatty acid amide, resulted in analgesia, through its action on activated glia and inflammation.46 Bisphosphonates, hyperbaric oxygen, botulinum toxin, minocycline, tramadol, and cryptolepine have all been suggested as potential ways to reduce glial activation and neuroinflammation.24,47-49 Some recent research on neuroinflammation and activated glial cells has focused on omega-3 polyunsaturated fatty acids. For example, Zendedel and colleagues found that rats given omega-3 fared better than controls in a model of stroke.50 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.50

Perhaps by a related mechanism, omega-3 fatty acids reduced pain and provided analgesia in a rat model of hemorrhagic cystitis.51 A study by Freitas et al investigated the effects of the long-term dietary fish oil supplementation or the acute administration of the omega-3 fatty acid docosahexaenoic acid (DHA) in a mouse model of hemorrhagic cystitis induced by the anticancer drug cyclophosphamide (CYP). The investigators found that either fish oil supplementation or DHA treatment “markedly prevented visceral pain, without affecting CYP-evoked bladder inflammatory changes. Moreover, systemic DHA significantly prevented the neutrophilia/lymphopenia caused by CYP, whereas this fatty acid did not significantly affect serum cytokines. DHA also modulated the spinal astrocyte activation.”51 In addition, Layé et al reviewed the use of omega-3 in the treatment of Alzheimer’s disease, finding it beneficial.52

So perhaps a healthy lifestyle and diet contribute to better glial health and reduced pain susceptibility. This emerging concept is supported by research. For example, tau-transgenic mice, which over-expresses human Tau23 in their brain, that were placed on a regimen of chronic endurance exercise (1 h/d treadmill, 5 d/wk for 3 months) showed reduction in neuroinflammation.53,54 Likewise, osteoarthritis improves with proper changes in diet and exercise.55 Reduced caloric intake, coenzyme Q10, and resveratrol have also been suggested to reduce neuroinflammation and improve analgesia.56-58 Glial cells express cannabinoid receptors and signaling systems that likely also contribute to analgesic, anti-inflammatory, antioxidant, and neuroprotective effects.59-61

In addition to improved lifestyle and diet, glial-targeted drugs could be used as adjuncts to existing analgesic mechanisms. For example, evidence now suggests that non-neuronal mechanisms that oppose opioid-induced analgesia and contribute to opioid tolerance and opioid-induced hyperalgesia involve glial cells that are activated in response to opioids—suggesting that 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.62,63 As previously mentioned, opioids are proinflammatory and cause neuroinflammation, and the administration of low-dose antagonists has been shown to result in analgesia.40,64,65

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.66,67 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.68 What is worse is that some substances released by these cells attenuate the response to pain-relieving therapies, particularly opioids.

The good news is that exciting new research is uncovering the role of glial cells (the “missing link”) in the understanding of the pathophysiology of pain initiation, transmission, and maintenance—and may point to potential new targets that might disrupt the negative contribution of glial cells in these processes (“gliopathies”).4,28,69-77

However, a number of questions still remain. 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.”4 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.

Last updated on: May 18, 2016
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