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Microglia and chronic pain

Malcangio, Marzia

doi: 10.1097/j.pain.0000000000000509
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Supplemental Digital Content is Available in the Text.

Corresponding author. Address: Wolfson CARD, Guy’s Campus, King’s College, London, London, United Kingdom. E-mail address:, (M. Malcangio).

Supported by the Wellcome Trust (WT081553AIA and Travel fellowship to Anna Clark, WT093173/Z/10/Z); MRC grant MR/M023893/1, ARUK grants MP/18277 and 20020, ncRNAPAIN FP7/2007-2014 under grant agreement 602133; PAINCAGE FP7/2007-2013 under grant agreement 603191.

The author has no conflicts of interest to declare.

Wolfson Centre for Age Related Diseases, IoPPN, King’s College London, Wolfson CARD, Guy’s Campus, United Kingdom. Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Noxious stimuli received in the periphery of the body are conveyed by nociceptive primary afferent fibres (Paf) to the spinal cord, which is the first relay station for sensory signalling on its way to the somatosensory cortex where pain is perceived. Under acute nociceptive transmission, pain is perceived as transient, and glutamate and substance P are released by Paf central terminals where activation of AMPA and NK1 receptors engages projection neurons at the first sensory synapse in the dorsal horn of the spinal cord12 (panel A).

Damage to peripheral nerves and peripheral infl ammation are well-defined causes of chronic pain which is defined as pain lasting longer than the initial harmful stimulus.18 Under sensitised pain state, sustained activation of primary afferents in the periphery is matched by an increased activity of their central terminals in the dorsal horn and enhanced excitability of dorsal horn neurons (first sensory synapse facilitation). However, the first synapse changes are specific to the type of damage. Dorsal horn microglia respond promptly to synaptic activity and proliferate, alter morphology and secrete factors which sensitise the sensory synapse thereby establishing a positive feedback which contributes to chronic pain states.7,10,13 Intriguingly, microglia may be more relevant in males than in females, and microglial response is more evident after nerve damage than infl ammation.15–17

Peripheral nerve injury is associated with downregulation of peptides in Paf and expression and secretion of novel mediators such as chemokine CCL2 and glycoprotein CSF1 which activate neuron and/or microglia8,9,15 (panel B). A major player in neuron– microglia communication is adenosine triphosphate (ATP) (some ATP derives from damaged neurons) which activates microglial P2X4 and P2X7 receptors to promote the release of BDNF and cathepsin S and IL-1β.5,4,6 In projection neurons, BDNF through TrkB receptor reduces the degree of neuronal inhibition after GABAA receptor activation (panel B). Extracellular cathepsin S enzymatically cleaves neuronal fractalkine which activates microglial CX3CR1 receptors and promotes IL-1β release. This chemokine can facilitate NMDA receptor in dorsal horn neurons.3 The newly identified sensory neuron–derived CSF1 through activation of CSF1R, which is restricted to microglia, upregulates both BDNF and CatS levels.15

In a different way, after peripheral infl ammation, Paf peptides are upregulated and released with activity from central terminals alongside glutamate, BDNF, and ATP, and they activate neurons and microglia (panel C). Evidence indicates that calcitonin gene–related peptide and the CatS-FKN system do activate microglia.2,14 In addition, high-mobility group box 1 is released from dorsal horn neurons and activates TLR4 on neurons and microglia1 (panel C).

Further studies comparing and contrasting microglial mechanisms in peripheral nerve injury and infl ammation will help delineate shared and specific pathways for chronic pain conditions. At the same time, this line of research will yield innovative targets for the development of analgesic therapies for patients’ benefit.

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