Similar Datasets
Project description:In settings of heightened pain sensitivity, such as following peripheral nerve injury (PNI) or opioid-induced hyperalgesia (OIH), microglia take on an activated phenotype. Functional studies have suggested that microglia activated by PNI or chronic opioids then engage common mechanisms to facilitate pain. Here we conducted RNA sequencing of acutely isolated spinal cord microglia to comprehensively interrogate commonality between PNI and OIH. By combining our results with meta-analysis of published datasets, we identify transcriptional signatures of microglial reactivity that differ between PNI models over time, opioid exposure, or CNS pathology, despite similar histological outcomes. Collectively, these results reveal a discrepancy between histological markers of activation and transcriptional response, and provide a resource of pain-associated microglial transcriptomes that caution against a universal signature of microglia activation.
2022-01-03 | GSE117320 | GEO
Project description:In settings of heightened pain sensitivity, such as following peripheral nerve injury (PNI) or opioid-induced hyperalgesia (OIH), microglia take on an activated phenotype. Functional studies have suggested that microglia activated by PNI or chronic opioids then engage common mechanisms to facilitate pain. Here we conducted RNA sequencing of acutely isolated spinal cord microglia to comprehensively interrogate commonality between PNI and OIH. By combining our results with meta-analysis of published datasets, we identify transcriptional signatures of microglial reactivity that differ between PNI models over time, opioid exposure, or CNS pathology, despite similar histological outcomes. Collectively, these results reveal a discrepancy between histological markers of activation and transcriptional response, and provide a resource of pain-associated microglial transcriptomes that caution against a universal signature of microglia activation.
2022-01-03 | GSE117319 | GEO
Project description:Distinct microglial transcriptional responses during opioid exposure or neuropathic pain
| PRJNA481747 | ENA
Project description:Distinct microglial transcriptional responses during opioid exposure or neuropathic pain [rat]
| PRJNA481754 | ENA
Project description:Distinct microglial transcriptional responses during opioid exposure or neuropathic pain [mouse]
| PRJNA481755 | ENA
Project description:Microglial cells are critical in the pathogenesis of neuropathic pain and several microglial receptors have been proposed to mediate this process. Of these receptors, the P2Y12 receptor is a unique purinergic receptor that is exclusively expressed by microglia in the central nervous system (CNS). In this study, we set forth to investigate the role of P2Y12 receptors in microglial electrophysiological and morphological (static and dynamic) activation during spinal nerve transection (SNT)-induced neuropathic pain in mice. First, we found that a genetic deficiency of the P2Y12 receptor (P2Y12(-/-) mice) ameliorated pain hypersensitivities during the initiation phase of neuropathic pain. Next, we characterised both the electrophysiological and morphological properties of microglia in the superficial spinal cord dorsal horn following SNT injury. We show dramatic alterations including a peak at 3days post injury in microglial electrophysiology while high resolution two-photon imaging revealed significant changes of both static and dynamic microglial morphological properties by 7days post injury. Finally, in P2Y12(-/-) mice, these electrophysiological and morphological changes were ameliorated suggesting roles for P2Y12 receptors in SNT-induced microglial activation. Our results therefore indicate that P2Y12 receptors regulate microglial electrophysiological as well as static and dynamic microglial properties after peripheral nerve injury, suggesting that the microglial P2Y12 receptor could be a potential therapeutic target for the treatment of neuropathic pain.
| S-EPMC4864135 | biostudies-literature
Project description:Microglia are important mediators of neuroinflammation, which underlies neuropathic pain. However, the molecular checkpoints controlling microglial reactivity are not well-understood. Here, we investigated the role of Orai1 channels for microglia-mediated neuroinflammation following nerve injury and find that deletion of Orai1 in microglia attenuates Ca2+ signaling and the production of inflammatory cytokines by proalgesic agonists. Conditional deletion of Orai1 attenuated microglial proliferation in the dorsal horn, spinal cytokine levels, and potentiation of excitatory neurotransmission following peripheral nerve injury. These cellular effects were accompanied by mitigation of pain hyperalgesia in microglial Orai1 knockout mice. A small-molecule Orai1 inhibitor, CM4620, similarly mitigated allodynia in male mice. Unexpectedly, these protective effects were not seen in female mice, revealing sexual dimorphism in Orai1 regulation of microglial reactivity and hyperalgesia. Together, these findings indicate that Orai1 channels are key regulators of the sexually dimorphic role of microglia for the neuroinflammation that underlies neuropathic pain.
| S-EPMC9883051 | biostudies-literature
Project description:Neuropathic pain that typically develops when peripheral nerves are damaged through surgery, bone compression in cancer, diabetes, or infection is a major factor causing impaired quality of life in millions of people worldwide. Recently, there has been a rapidly growing body of evidence indicating that spinal glia play a critical role in the pathogenesis of neuropathic pain. Accumulating findings also indicate that nucleotides play an important role in neuron-glia communication through P2 purinoceptors. Damaged neurons release or leak nucleotides including ATP and UTP to stimulate microglia through P2 purinoceptors expressing on microglia. It was shown in an animal model of neuropathic pain that microglial P2X(4) and P2X(7) receptors are crucial in pain signaling after peripheral nerve lesion. In this review, we describe the modification of neuropathic pain sensation through microglial P2X(4) and P2X(7), with the possibility of P2Y(6) and P2Y(12) involvement.
| S-EPMC2072920 | biostudies-other
Project description:Neuropathic pain is a widespread chronic pain state that results from injury to the nervous system. Spinal microglia play a causative role in the pathogenesis of neuropathic pain through secretion of growth factors and cytokines. Here, we investigated the contribution of TMEM16F, a protein that functions as a Ca(2+)-dependent ion channel and a phospholipid scramblase, to microglial activity during neuropathic pain. We demonstrate that mice with a conditional ablation of TMEM16F in microglia do not develop mechanical hypersensitivity upon nerve injury. In the absence of TMEM16F, microglia display deficits in process motility and phagocytosis. Moreover, loss of GABA immunoreactivity upon injury is spared in TMEM16F conditional knockout mice. Collectively, these data indicate that TMEM16F is an essential component of the microglial response to injury and suggest the importance of microglial phagocytosis in the pathogenesis of neuropathic pain.
| S-EPMC4921873 | biostudies-literature
Project description:Prostaglandins (PGs) are typical lipid mediators that play a role in homeostasis and disease. They are synthesized from arachidonic acid by cyclooxygenase 1 (COX1) and COX2. Although COX2 has been reported to be upregulated in the spinal cord after nerve injury, its expression and functional roles in neuropathic pain remain unclear. In this study, we investigated the expression of Cox2, PGI2 synthase (Pgis), and prostaglandin I2 receptor (IP receptor) mRNA in the rat spinal cord after spared nerve injury (SNI). Levels of Cox2 and Pgis mRNA increased in endothelial cells from 24 to 48 h after nerve injury. IP receptor mRNA was constitutively expressed in dorsal horn neurons. A COX2 inhibitor and IP receptor antagonists attenuated pain behavior in the early phase of neuropathic pain. Furthermore, we examined the relationship between COX2 and tumor necrosis factor-α (TNFα) in the spinal cord of a rat SNI model. Levels of TNFα mRNA transiently increased in the spinal microglia 24 h after SNI. The TNF receptors Tnfr1 and Tnfr2 mRNA were colocalized with COX2. Intrathecal injection of TNFα induced Cox2 and Pgis mRNA expression in endothelial cells. These results revealed that microglia-derived TNFα induced COX2 and PGIS expression in spinal endothelial cells and that endothelial PGI2 played a critical role in neuropathic pain via neuronal IP receptor. These findings further suggest that the glia-endothelial cell interaction of the neurovascular unit via transient TNFα is involved in the generation of neuropathic pain.
| S-EPMC5399753 | biostudies-literature