Glutamate‐mediated astrocyte‐to‐neuron signalling in the rat dorsal horn

Abstract

By releasing neuroactive agents, including proinflammatory cytokines, prostaglandins and neurotrophins, microglia and astrocytes are proposed to be involved in nociceptive transmission, especially in conditions of persistent, pathological pain. The specific action on dorsal horn neurons of agents released from astrocytes, such as glutamate, has been, however, poorly investigated. By using patch-clamp and confocal microscope calcium imaging techniques in rat spinal cord slices, we monitored the activity of dorsal horn lamina II neurons following astrocyte activation. Results obtained revealed that stimuli that triggered Ca 2+ elevations in astrocytes, such as the purinergic receptor agonist BzATP and low extracellular Ca 2+ , induce in lamina II neurons slow inward currents (SICs). Similarly to SICs triggered by astrocytic glutamate in neurons from other central nervous system regions, these currents (i) are insensitive to tetrodotoxin (TTX), (ii) are blocked by the NMDA receptor (NMDAR) antagonist d-AP5, (iii) lack an AMPA component, and (iv) have slow rise and decay times. Ca 2+ imaging also revealed that astrocytic glutamate evokes NMDAR-mediated episodes of synchronous activity in groups of substantia gelatinosa neurons. Importantly, in a model of peripheral inflammation, the development of thermal hyperalgesia and mechanical allodynia was accompanied by a significant increase of spontaneous SICs in dorsal horn neurons. The NMDAR-mediated astrocyte-to-neuron signalling thus represents a novel pathway that may contribute to the control of central sensitization in pathological pain.

An ultrastructural evidence for the expression of transient receptor potential ankyrin 1 (TRPA1) in astrocytes in the rat trigeminal caudal nucleus

“…That TRPA1 is also expressed in astrocytes suggests a novel TRPA1-mediated central mechanism for inflammatory mechanical-and cold hyperalgesia via activation by endogenous TRPA1 agonists. These may include arachidonic acid and/or products of oxidative stress, released during inflammation and other pathophysiological conditions (Bandell et al, 2004;Andersson et al, 2008), known to trigger Ca 2+ influx and subsequent release of glutamate from astrocytes, which in turn, evokes extrasynaptic NMDA receptormediated synchronous activation of multiple dorsal horn neurons, and induces potentiation of central sensitization (Fellin et al, 2004;Bardoni et al, 2010). Concurrently, glutamate, through activation of extrasynaptic glutamate receptors on nociceptive PATs, induces long-lasting enhancement of synaptic transmission and strong activation of dorsal horn neurons (Fiacco and McCarthy, 2004;Jourdain et al, 2007).…”

Glia and pain: Is chronic pain a gliopathy?

“…Interestingly, astrocytic glutamate release can be detected as slow inward currents, via patch-clamp recordings in nearby neurons. Slow inward currents are mediated by extrasynaptic NR2B receptors and induced in spinal dorsal horn neurons after inflammation [10]. …”

Spatial and temporal activation of spinal glial cells: Role of gliopathy in central neuropathic pain following spinal cord injury in rats

“…For example, activated microglia release glutamate, proinflammatory cytokines and ROS followed by activation of NMDA and P2X1/5 receptors that result in astrocytic calcium signaling (Palygin et al, 2010). The facilitation of calcium signaling in astrocytes releases glutamate extracellularly, followed by NMDA receptor-mediated facilitation of neuronal excitability, a substrate of pain transmission (Bardoni et al, 2010). …”