Review
ATP receptors gate microglia signaling in neuropathic pain

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Abstract

Microglia were described by Pio del Rio-Hortega (1932) as being the ‘third element’ distinct from neurons and astrocytes. Decades after this observation, the function and even the very existence of microglia as a distinct cell type were topics of intense debate and conjecture. However, considerable advances have been made towards understanding the neurobiology of microglia resulting in a radical shift in our view of them as being passive bystanders that have solely immune and supportive roles, to being active principal players that contribute to central nervous system pathologies caused by disease or following injury. Converging lines of evidence implicate microglia as being essential in the pathogenesis of neuropathic pain, a debilitating chronic pain condition that can occur after peripheral nerve damage caused by disease, infection, or physical injury. A key molecule that modulates microglial activity is ATP, an endogenous ligand of the P2-purinoceptor family consisting of P2X ionotropic and P2Y metabotropic receptors. Microglia express several P2 receptor subtypes, and of these the P2X4, P2X7, and P2Y12 receptor subtypes have been implicated in neuropathic pain. The P2X4 receptor has emerged as the core microglia–neuron signaling pathway: activation of this receptor causes release of brain-derived neurotrophic factor (BDNF) which causes disinhibition of pain-transmission neurons in spinal lamina I. The present review highlights recent advances in understanding the signaling and regulation of P2 receptors expressed in microglia and the implications for microglia–neuron interactions for the management of neuropathic pain.

Introduction

Pain is a double-edged sword that can be protective or cause considerable suffering. Acute nociceptive pain warns against imminent or existing tissue damage, whereas chronic pain has no known defensive or beneficial function and is unremitting for those who suffer from this condition. Acute pain is produced by physiological functioning of the normal peripheral and central nervous systems. However, the processes initiated during acute pain can sometimes progress to chronic pain that is characterized as persisting long after the initiating event has healed. This transition to chronicity is highly variable between individuals and the degree of injury is not necessarily predictive of the severity or chronicity of the pain. There is mounting evidence that the transition from acute to chronic pain involves discrete pathophysiological steps that alter the cellular, molecular, and anatomical organization of nociceptive neural networks in the spinal dorsal horn (Latremoliere and Woolf, 2009, Scholz and Woolf, 2002, Voscopoulos and Lema, 2010, Woolf and Salter, 2000). In this pathologically altered system, the balance of inhibitory and excitatory control is shifted such that inhibitory mechanisms are weakened while excitatory mechanisms are strengthened. A subtle shift in this balance can have a profound effect that results in both a pathological amplification and a change in modality of sensory input and output from the spinal cord which leads to the exaggerated pain responses seen in chronic pain conditions (Costigan et al., 2009b).

Neuropathic pain is among the most debilitating type of chronic pain, which typically develops because of injury to a nerve caused by trauma, infection, or pathology (Scholz and Woolf, 2002, Zimmermann, 2001, Gwak and Hulsebosch, 2009). The cardinal symptom of neuropathic pain is hypersensitivity that can manifest spontaneously in the absence of an overt stimulus (spontaneous pain), or it can be evoked, such as in the case of allodynia (pain resulting from an innocuous stimulus) and hyperalgesia (an exaggerated pain response to a noxious stimulus). The sequelae of neuropathic pain are difficult to treat and often refractory to the current available pharmacological treatments, which are typically directed against neuronal molecular targets. The failure of these neuron-targeted drugs to alleviate neuropathic pain is consistent with accruing evidence that non-neuronal mechanisms are also major contributors to chronic neuropathic pain. Thus, a new framework for understanding the etiology of neuropathic pain is forming from a rapidly growing body of evidence that glia in the central nervous system are critical in establishing and maintaining neuropathic pain (Beggs and Salter, 2010, Grace et al., 2011, Inoue and Tsuda, 2006, Milligan and Watkins, 2009, Gwak and Hulsebosch, 2010). Microglia, in particular, have emerged as key players in the etiology of neuropathic pain (Inoue and Tsuda, 2006, Tsuda et al., 2003, Tsuda et al., 2005, Watkins et al., 2001, Watkins and Maier, 2003, Tsuda et al., 2005). The present article highlights the recent advances in our understanding of the role microglia, and particularly microglia–neuron interactions mediated through ATP-gated P2-receptors, play in the pathogenesis of nerve injury-induced neuropathic pain.

Section snippets

Microglial response to peripheral nerve injury

Microglia are resident cells in the central nervous system that respond to adverse physiological conditions such as trauma, ischemia, inflammation, and infection. Recent evidence suggests that almost the entire population of microglia originate from embryonic macrophages derived from the yolk sac (Ginhoux et al., 2010). In the adult central nervous system, microglia comprise 5–10% of the total glial population and they are roughly equal in number to neurons (Kreutzberg, 1996, Lawson et al., 1990

Microglia increase and transform the output of pain transmission neurons

A major ascending nociceptive (pain-related) pathway arises from neurons in lamina I of the spinal dorsal horn (Bester et al., 2000). The action potential discharge of these neurons, that is to say the output of these neurons, is normally evoked only in response to noxious peripheral stimulation, such as pinch to the skin (Keller et al., 2007) (Fig. 1). However, after peripheral nerve injury the output of these neurons is transformed such that innocuous stimulus, such as brush or touch, evokes

P2 receptor expression in microglia

Microglia–neuron communication is bidirectional and considerable evidence implicates ATP as being a critical molecular substrate for interaction between these cells (Coull et al., 2005, Jarvis, 2010, Maeda et al., 2010). ATP is an endogenous ligand of the P2 purinergic family of receptors, which consists of P2Y metabotropic receptors and P2X ionotropic receptors. P2Y receptors (P2Y1, 2, 4, 6, 11, 12, 13 and 14) are G-protein coupled, whereas P2X receptors (P2X1–P2X7) are non-selective cation

Role of microglial P2X4 receptors in neuropathic pain

The essential role of P2X4 receptors in neuropathic pain was first reported by Tsuda et al. (2003). It was demonstrated that intrathecal injection of 2′,3′-O-(2,4,6-trinitrophenyl)adenosine 5′-triphosphate (TNP-ATP), an antagonist of P2X1-4Rs, reversed tactile allodynia in nerve-injured rats. By contrast, treatment with pyridoxalphosphate-6-azophenyl-2′,4′-disulphonoic acid (PPADs), an antagonist of P2X1–3, 5, 7Rs, but not the P2X4 receptor, had no effect on tactile allodynia. Based on the

Role of microglial P2X7 receptors in neuropathic pain

In addition to P2X4 receptors, microglia express functional P2X7 receptors. Stimulation of P2X7 receptors is implicated in the microglia response to inflammation (Collo et al., 1997), microglial proliferation (Bianco et al., 2005, Monif et al., 2009), and release of proinflammatory cytokines (Brough et al., 2002, Chakfe et al., 2002, Clark et al., 2010, Ferrari et al., 1997a, Ferrari et al., 1997b). A role for P2X7 receptors in neuropathic pain is also suggested on the basis of reduced pain

Role of microglial P2Y receptors in neuropathic pain

Microglia express a wide range of P2Y receptors (P2Y1, 2, 4, 6, and 12), with P2Y6 and P2Y12 receptors mediating chemotaxis and migration of microglia towards the site of damage (Haynes et al., 2006, Honda et al., 2001, Maeda et al., 2010, Ohsawa et al., 2007). To date, only the P2Y12 receptor subtype has been explicitly implicated in the development of neuropathic pain. In response to peripheral nerve injury, P2Y12 receptor expression is upregulated on microglia and activation of these

Conclusion and future directions

Several advances in recent years have emphasized the essential role of microglial P2 receptors in the sequelae of neuropathic pain arising from peripheral nerve injury. In particular, P2X4, P2X7 and P2Y12 receptors expressed on microglia have emerged as new molecular players that are critically involved in the etiology of neuropathic pain. Activation of these P2 receptor subtypes engages distinct intracellular signaling pathways in microglia that converge onto p38 MAPK (Fig. 2). Thus, p38 MAPK

Acknowledgments

MWS is supported by grants from the Canadian Institutes of Health Research (CIHR; grant number MT-11219) and the Neuroscience Canada Brain Repair Program. MWS is an International Research Scholar of the Howard Hughes Medical Institute and holds a Canada Research Chair (Tier I) in Neuroplasticity and Pain. TT was supported by a CIHR fellowship.

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