Microglial P2Y12 receptors regulate microglial activation and surveillance during neuropathic pain

Gu, Nan; Eyo, Ukpong B.; Murugan, Madhuvika; Peng, Jinrong; Matta, Sanjana; Dong, Hailong; Wu, Long Jun

doi:10.1016/j.bbi.2015.11.007

Cited by 115 publications

(114 citation statements)

References 70 publications

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“…Whether the alteration in the process morphology of SDH microglia contributes to subsequent proliferation and neuropathic pain induction remains unknown. 4) Given that PNI-induced pain hypersensitivity is blunted in mice lacking a molecule (P2Y12 receptor or transmembrane protein 16F) that regulates the shape of microglial processes, 29,30) it is possible that the first morphological change in SDH microglia by PNI may also have a role in subsequent microgliosis and neuropathic pain.…”

Section: Discussionmentioning

confidence: 99%

Temporal Kinetics of Microgliosis in the Spinal Dorsal Horn after Peripheral Nerve Injury in Rodents

Kohno

Kitano

Kohro

et al. 2018

Biological & Pharmaceutical Bulletin

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Neuropathic pain, a highly debilitating chronic pain following nerve damage, is a reflection of the aberrant functioning of a pathologically altered nervous system. Previous studies have implicated activated microglia in the spinal dorsal horn (SDH) as key cellular intermediaries in neuropathic pain. Microgliosis is among the dramatic cellular alterations that occur in the SDH in models of neuropathic pain established by peripheral nerve injury (PNI), but detailed characterization of SDH microgliosis has yet to be realized. In the present study, we performed a short-pulse labeling of proliferating cells with ethynyldeoxyuridine (EdU), a marker of the cell cycle S-phase, and found that EdU microglia in the SDH were rarely observed 32 h after PNI, but rapidly increased to the peak level at 40 h post-PNI. Numerous EdU microglia persisted for the next 20 h (60 h post-PNI) and decreased to the baseline on day 7. These results demonstrate a narrow time window for rapidly inducing a proliferation burst of SDH microglia after PNI, and these temporally restricted kinetics of microglial proliferation may help identify the molecule that causes microglial activation in the SDH, which is crucial for understanding and managing neuropathic pain.Key words proliferation; microgliosis; spinal dorsal horn; neuropathic pain; peripheral nerve injury Neuropathic pain is a debilitating chronic pain state caused by damage to the nervous system incited by cancer, diabetes, chemotherapy and trauma. One of the hallmark symptoms is mechanical allodynia (non-nociceptive mechanical stimuli elicit pain), and neuropathic pain is often resistant to currently available therapies. 1) Injury to peripheral nerves of rodents, which are frequently used as models of neuropathic pain, produces mechanical pain hypersensitivity and alterations at molecular and cellular levels that result in multiple forms of neuronal plasticity and structural reorganization, not only in the affected sensory ganglion cell body, but also in the spinal dorsal horn (SDH). 2,3) The peripheral nerve injury (PNI)-induced alterations in the SDH are observed not only in neurons, but also in glial cells, especially microglia, which are known as resident immune cells in the central nervous system (CNS). Following PNI, SDH microglia become activated through a progressive series of changes in their morphology, expression of a variety of genes and cell number. 4) One of the most prominent features of microglial activation is an increase in the number of microglia (called microgliosis). Since PNI-induced microgliosis in the SDH was recorded in 1970s 5) and the rodent models of neuropathic pain were established in 1990s, 6-9) studies have investigated the mechanism for microgliosis in the SDH after PNI. Two possible mechanisms (proliferation of resident microglia 10,11) and infiltration of bone marrow-derived monocytes 12) ) have been considered, but it is now thought that local expansion of resident microglia by proliferation is the primary cellular basis for SDH microgliosis after PNI...

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Section: Discussionmentioning

confidence: 99%

Temporal Kinetics of Microgliosis in the Spinal Dorsal Horn after Peripheral Nerve Injury in Rodents

Kohno

Kitano

Kohro

et al. 2018

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

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“…Neuropathic pain is a chronic pain caused by a lesion or disease of the somatosensory nervous system and characterized by hyperalgesia and allodynia [1,2]. It is an unpleasant sensory consequence of neuronal activities in specific nociceptive pathways that is triggered by noxious stimuli, inflammation, or damage to the nervous system [3].…”

Section: Introductionmentioning

confidence: 99%

Microvesicles shed from microglia activated by the P2X7-p38 pathway are involved in neuropathic pain induced by spinal nerve ligation in rats

Jiang

et al. 2016

Purinergic Signalling

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Microglia are critical in the pathogenesis of neuropathic pain. In this study, we investigated the role of microvesicles (MVs) in neuropathic pain induced by spinal nerve ligation (SNL) in rats. First, we found that MVs shed from microglia were increased in the cerebrospinal fluid and dorsal horn of the spinal cord after SNL. Next, MVs significantly reduced paw withdrawal threshold (PWT) and paw withdrawal latency (PWL). In addition, the P2X7-p38 pathway was related to the bleb of MVs after SNL. Interleukin (IL)-1β was found to be significantly upregulated in the package of MVs, and PWT and PWL increased following inhibition with shRNA-IL-1β. Finally, the amplitude and frequency of spontaneous excitatory postsynaptic currents increased following stimulation with MVs. Our results indicate that the P2X7-p38 pathway is closely correlated with the shedding of MVs from microglia in neuropathic pain, and MVs had a significant effect on neuropathic pain by participating in the interaction between microglia and neurons.

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“…P2Y12R plays a vital role in microglia activation, as they act as the primary site at which nucleotides act to induce microglial chemotaxis in response to local CNS injury (Haynes et al, 2006, De Simone et al, 2010). It has been shown that enhanced P2Y12R-mediated purinergic signaling was responsible for microglial activation and the resultant increase in voltage-activated potassium currents in hippocampal microglia following status epilepticus (Avignone et al, 2008) and in spinal microglia following peripheral nerve injury (Gu et al, 2015). P2Y12R activation has also been shown to mediate microglial process extension and convergence towards dendrites following neuronal hyperactivity (Eyo et al, 2014, Eyo et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Activation of microglial P2Y12 receptor is required for outward potassium currents in response to neuronal injury

et al. 2016

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Microglia, the resident immune cells in the central nervous system, constantly survey the surrounding neural parenchyma and promptly respond to brain injury. Activation of purinergic receptors such as P2Y12 receptors (P2Y12R) in microglia has been implicated in chemotaxis towards ATP that is released by injured neurons and astrocytes. Activation of microglial P2Y12R elicits outward potassium current that is associated with microglial chemotaxis in response to injury. This study aimed at investigating the identity of the potassium channel implicated in microglial P2Y12R-mediated chemotaxis following neuronal injury and understanding the purinergic signaling pathway coupled to the channel. Using a combination of two-photon imaging, electrophysiology and genetic tools, we found the ATP-induced outward current to be largely dependent on P2Y12R activation and mediated by G-proteins. Similarly, P2Y12R-coupled outward current was also evoked in response to laser-induced single neuron injury. This current was abolished in microglia obtained from mice lacking P2Y12R. Dissecting the properties of the P2Y12R-mediated current using a pharmacological approach revealed that both the ATP and neuronal injury-induced outward current in microglia was sensitive to quinine (1 mM) and bupivacaine (400 μM), but not TEA (10 mM) and 4-AP (5 mM). These results suggest that the quinine/bupivacaine-sensitive potassium channels are the functional effectors of the P2Y12R–mediated signaling in microglia activation following neuronal injury.

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Microglial P2Y12 receptors regulate microglial activation and surveillance during neuropathic pain

Cited by 115 publications

References 70 publications

Temporal Kinetics of Microgliosis in the Spinal Dorsal Horn after Peripheral Nerve Injury in Rodents

Temporal Kinetics of Microgliosis in the Spinal Dorsal Horn after Peripheral Nerve Injury in Rodents

Microvesicles shed from microglia activated by the P2X7-p38 pathway are involved in neuropathic pain induced by spinal nerve ligation in rats

Activation of microglial P2Y12 receptor is required for outward potassium currents in response to neuronal injury

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