Astrocyte - Astrocytes in Chronic Pain Sensitization

Astrocytes in Chronic Pain Sensitization

Under normal conditions, pain conduction begins with some noxious signal followed by an action potential carried by nociceptive (pain sensing) afferent neurons, which elicit excitatory postsynaptic potentials (EPSP) in the dorsal horn of the spinal cord. That message is then relayed to the cerebral cortex, where we translate those EPSPs into "pain". Since the discovery of astrocytic influence, our understanding of the conduction of pain has been dramatically complicated. Pain processing is no longer seen as a repetitive relay of signals from body to brain, but as a complex system that can be up- and down-regulated by a number of different factors. One factor at the forefront of recent research is in the pain-potentiating synapse located in the dorsal horn of the spinal cord and the role of astrocytes in encapsulating these synapses. Garrison and co-workers (Garrison, 1991) were the first to suggest association when they found a correlation between astrocyte hypertrophy in the dorsal horn of the spinal cord and hypersensitivity to pain after peripheral nerve injury, typically considered an indicator of glial activation after injury. Astrocytes detect neuronal activity and can release chemical transmitters, which in turn control synaptic activity (Volters and Meldolesi, 2005; Haydon, 2001; Fellin, et al., 2006). In the past, hyperalgesia was thought to be modulated by the release of substance P and excitatory amino acids (EAA), such as glutamate, from the presynaptic afferent nerve terminals in the spinal cord dorsal horn. Subsequent activation of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid), NMDA (N-methyl-D-aspartate) and kainate subtypes of ionotropic glutamate receptors follows. It is the activation of these receptors that potentiates the pain signal up the spinal cord. This idea, although true, is an oversimplification of pain transduction. A litany of other neurotransmitter and neuromodulators, such as calcitonin gene-related peptide (CGRP), adenosine triphosphate (ATP), brain-derived neurotrophic factor (BDNF), somatostatin, vasoactive intestinal peptide (VIP), galanin, and vasopressin are all synthesized and released in response to noxious stimuli. In addition to each of these regulatory factors, several other interactions between pain-transmitting neurons and other neurons in the dorsal horn have added impact on pain pathways.