Purinergic system, microglia and neuropathic pain.
ABSTRACT Extracellular nucleotides play pivotal roles in the regulation of neuronal and glial functions in the nervous system through P2X receptors (P2XRs) and P2Y receptors (P2YRs). A growing body of evidence shows that microglia express several subtypes of P2XRs and P2YRs, and that these receptors play a key role in pain signaling in the spinal cord under pathological conditions, such as following peripheral nerve injury (neuropathic pain). Following peripheral nerve injury, dorsal horn microglia become activated and show upregulated expression of purinergic receptors, and interference with the function or expression of these receptors strongly suppresses neuropathic pain. This article highlights recent advances that further increase our understanding of the mechanisms by which microglial purinergic receptors contribute to the pathogenesis of neuropathic pain.
- SourceAvailable from: Michael Salter[show abstract] [hide abstract]
ABSTRACT: ATP has been proposed as a possible chemical mediator of synaptic transmission in the spinal dorsal horn on the basis that it is released in dorsal horn synaptosomes in a Ca(2+)-dependent manner and that its effects mimic those of synaptic inputs to dorsal horn neurons. In the present study we examined the actions of ATP on neurons and glia in cell culture using optical and electrophysiological recording techniques. We found that ATP increased intracellular Ca2+ concentration ([Ca2+]i) in > 99% of astrocytes. In contrast, only 35% of neurons and 20% of oligodendrocytes responded to ATP. The prevalence of the ATP-evoked response in astrocytes led us to characterize the type of receptor mediating the response, the source of Ca2+, and the membrane currents activated by ATP. We found that ADP was approximately equipotent with ATP in increasing [Ca2+]i whereas AMP and adenosine had no effect. In addition, responses to ATP were blocked in a concentration-dependent manner by the P2 purinergic receptor antagonist suramin. Furthermore, as it was found that 2-methylthio-ATP was more potent than ATP and that beta, gamma-methylene-ATP was ineffective, the responses were mediated via the P2 gamma subtype of purinergic receptor. The increase in [Ca2+]i evoked by ATP persisted in extracellular medium with no added Ca2+ and containing EGTA, indicating that this increase was due to release of Ca2+ from intracellular stores. Release of Ca2+ by ATP was blocked by thapsigargin but was unaffected by caffeine. ATP had several effects on membrane current activating inward, outward, and mixed currents despite uniformly causing increases in [Ca2+]i. These observations indicate that ATP has diverse electrophysiological effects on astrocytes as well as increasing [Ca2+]i in these cells. We speculate that ATP released from synaptic terminals in the dorsal horn might act not only on postsynaptic neurons but also on perisynaptic astrocytes. Thus, a physiological role for ATP may be as a neuronal-glial signaling molecule within the spinal dorsal horn.Journal of Neuroscience 03/1994; 14(3 Pt 2):1563-75. · 6.91 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Microglial cells express a peculiar plasma membrane receptor for extracellular ATP, named P2Z/P2X7 purinergic receptor, that triggers massive transmembrane ion fluxes and a reversible permeabilization of the plasma membrane to hydrophylic molecules of up to 900 dalton molecule weight and eventual cell death (Di Virgilio, F. 1995. Immunol. Today, 16:524-528). The physiological role of this newly cloned (Surprenant, A., F. Rassendren, E. Kawashima, R. A. North and G. Buell, 1996. Science (Wash. DC). 272:735-737) cytolytic receptor is unknown. In vitro and in vivo activation of the macrophage and microglial cell P2Z/P2X7 receptor by exogenous ATP causes a large and rapid release of mature IL-1 beta. In the present report we investigated the role of microglial P2Z/P2X7 receptor in IL-1 beta release triggered by LPS. Our data suggest that LPS-dependent IL-1 beta release involves activation of this purinergic receptor as it is inhibited by the selective P2Z/P2X7 blocker oxidized ATP and modulated by ATP-hydrolyzing enzymes such as apyrase or hexokinase. Furthermore, microglial cells release ATP when stimulated with LPS. LPS-dependent release of ATP is also observed in monocyte-derived human macrophages. It is suggested that bacterial endotoxin activates an autocrine/paracrine loop that drives ATP-dependent IL-1 beta secretion.Journal of Experimental Medicine 03/1997; 185(3):579-82. · 13.21 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Pain after nerve damage is an expression of pathological operation of the nervous system, one hallmark of which is tactile allodynia-pain hypersensitivity evoked by innocuous stimuli. Effective therapy for this pain is lacking, and the underlying mechanisms are poorly understood. Here we report that pharmacological blockade of spinal P2X4 receptors (P2X4Rs), a subtype of ionotropic ATP receptor, reversed tactile allodynia caused by peripheral nerve injury without affecting acute pain behaviours in naive animals. After nerve injury, P2X4R expression increased strikingly in the ipsilateral spinal cord, and P2X4Rs were induced in hyperactive microglia but not in neurons or astrocytes. Intraspinal administration of P2X4R antisense oligodeoxynucleotide decreased the induction of P2X4Rs and suppressed tactile allodynia after nerve injury. Conversely, intraspinal administration of microglia in which P2X4Rs had been induced and stimulated, produced tactile allodynia in naive rats. Taken together, our results demonstrate that activation of P2X4Rs in hyperactive microglia is necessary for tactile allodynia after nerve injury and is sufficient to produce tactile allodynia in normal animals. Thus, blocking P2X4Rs in microglia might be a new therapeutic strategy for pain induced by nerve injury.Nature 09/2003; 424(6950):778-83. · 38.60 Impact Factor