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