Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre-including this research content-immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Fig. 1. The potential mechanism of pain induced by SARS-CoV-2 in COVID-19.

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Objective. Rheumatoid arthritis (RA) is often accompanied by joint pain and inflammation. Previous studies have demonstrated that functional Fcγ receptor I (FcγRI) is expressed in dorsal root ganglion (DRG) neurons and might contribute to pain in rodent models of antigen-induced arthritis (AIA). This study was undertaken to elucidate the roles of nociceptive neuronal FcγRI-coupled signaling in the development of joint pain in AIA. Methods. RNA sequencing was used to investigate the transcriptome profile changes in the DRG in a rat model of AIA. A primary sensory neuron-specific Fcgr1a conditional-knockout (CKO) rat was established by crossing rats carrying a loxP-flanked Fcgr1a with a Pirt-specific Cre line. Behavioral, morphologic, and molecular studies were conducted to evaluate the differences between wild-type (WT) and CKO rats after AIA. Results. We first showed that AIA induced a transcriptome profile change in the DRG, involving a number of key proteins downstream of the FcγRI-related signaling pathway. Compared to the WT rats, both the IgG immune complex-induced acute pain and AIA-induced pain were alleviated in CKO rats. Moreover, the AIA-induced activation of FcγRI-related signaling in DRGs was significantly reduced in CKO rats. In addition, CKO rats showed attenuated joint swelling after AIA. Conclusion. These results indicate that activation of FcγRI-coupled signaling in DRG neurons plays an important role in the development of joint pain in AIA. Our findings may provide novel insights into the interactions between the peripheral nervous system and the immune system in pathologic conditions and might suggest potential biotargets for the treatment of pain in RA.

Background As a classic innate immunity pathway, Toll-like receptor 4 (TLR4) signaling has been intensively investigated for its function of pathogen recognition. The receptor is located not only on immune cells but also on sensory neurons and spinal glia. Recent studies revealed the involvement of neuronal TLR4 in different types of pain. However, the specific role of TLR4 signaling in the pain symptom of endometriosis (EM) remains obscure. Methods The rat endometriosis model was established by transplanting uterine horn tissue into gastrocnemius. Western blotting and/or immunofluorescent staining were applied to detect high mobility group box 1 (HMGB1), TLR4, myeloid differentiation factor-88 adaptor protein (MyD88), and nuclear factor kappa-B-p65 (NF-κB-p65) expression, as well as the activation of astrocyte and microglia. The antagonist of TLR4 (LPS-RS-Ultra, LRU) and MyD88 homodimerization inhibitory peptide (MIP) were intrathecally administrated to assess the behavioral effects of blocking TLR4 signaling on endometriosis-related pain. Results Mechanical hyperalgesia was observed at the graft site, while HMGB1 was upregulated in the implanted uterine tissue, dorsal root ganglion (DRG), and spinal dorsal horn (SDH). Compared with sham group, upregulated TLR4, MyD88, and phosphorylated NF-κB-p65 were detected in the DRG and SDH in EM rats. The activation of astrocytes and microglia in the SDH was also confirmed in EM rats. Intrathecal application of LRU and MIP alleviated mechanical pain on the graft site of EM rats, with decreased phosphorylation of NF-κB-p65 in the DRG and reduced activation of glia in the SDH. Conclusions HMGB1-TLR4-MyD88 signaling pathway in the DRG and SDH may involve in endometriosis-related hyperpathia. Blockade of TLR4 and MyD88 might serve as a potential treatment for pain in endometriosis.

Injury of peripheral nerves may quickly induce severe pain, but the mechanism remains obscure. We observed a rapid onset of spontaneous pain and evoked pain hypersensitivity after acute transection of the L5 spinal nerve (SNT) in awake rats. The outburst of pain was associated with a rapid development of spontaneous activities and hyperexcitability of nociceptive neurons in the adjacent uninjured L4 dorsal root ganglion (DRG), as revealed by both in vivo electrophysiological recording and high-throughput calcium imaging in vivo . Transection of the L4 dorsal root or intrathecal infusion of aminobutyrate aminotransferase inhibitor attenuated the spontaneous activity, suggesting that retrograde signals from the spinal cord may contribute to the sensitization of L4 DRG neurons after L5 SNT. Electrical stimulation of low-threshold afferents proximal to the axotomized L5 spinal nerve attenuated the spontaneous activities in L4 DRG and pain behavior. These findings suggest that peripheral axotomy may quickly induce hyperexcitability of uninjured nociceptors in the adjacent DRG that drives an outburst of pain.

Neuropathic pain (NP) is the cardinal symptom of neural injury, and its underlying molecular mechanism needs further investigation. Complements, especially complement 3 (C3), are involved in the pathophysiology of many neurological disorders, while the specific role of C3 in NP is still obscure. In this study, we found that both C3 and its receptor C3aR were upregulated in the spinal dorsal horn in a rat chronic constriction injury (CCI) model. In addition, C3 was mainly detected in astrocytes, while C3aR was expressed in microglia and neuron. Intrathecal injection of C3 antibody and C3aR antagonist alleviated NP in CCI model together with reduced M1 polarization of microglia. Our finding suggested that blockade of the C3/C3aR pathway might be a novel strategy for NP.

Nervous system manifestations caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are of great concern. Neurological symptoms and the neurological effects induced by SARS-CoV-2, such as the loss of various sensory perceptions, indicate direct viral invasion into sensory neurons. Therefore, it is very important to identify the distribution of angiotensin-converting enzyme 2 (ACE2), the receptor of SARS-CoV-2, in human nervous system. However, autofluorescence from lipofuscin obviously impacted immunofluorescence analysis in previous studies. We demonstrated that Sudan Black B (SBB) remarkably reduced the massive lipofuscin-like autofluorescence and the immunofluorescence signal would be sharpened following the exposure compensation. Additionally, we confirmed that ACE2 was expressed in IB4+, CGRP+, and NF200+ sensory subpopulations. The mapping of ACE2 distribution in hDRG would facilitate the understanding of sensory disorder induced by SARS-CoV-2.

A1 astrocytes are activated through M1 microglial secretion, which often be induced via 0.1 mg/kg systemic lipopolysaccharides (LPS). While a larger dose of 5 mg/kg LPS, similar to the dose used for liver injury or sepsis model, was adopted to induce A1. This study was designed to investigate a safer and effective LPS dose to induce A1, and the synchronized changes of other glial phenotypes since both astrocytes and microglia can be activated by LPS. Gene expression changes in 72 specific phenotypic markers of astrocytes and microglia were tested following the administration of systemic LPS ranging from 0.1 to 5 mg/kg, after exposure for 24 h in the cortex, hippocampus and spinal cord, using methods including RT-PCR, co-immunofluorescence, and single-cell RNA sequence. The results showed that anti-inflammatory A2 and M2 phenotypes were also activated by LPS, not the pro-inflammatory A1, M1, and A-pan phenotypes alone. But more A1 than A2 were activated even with low-dose LPS exposure. With respect to microglia, LPS induced a mild and equal level of M1 and M2 activation, indicating 24 h exposure is not proper to stimulate M1. Only several activated markers like C3, Marco and Ym1 showed good consistency among tissues with various dose of LPS. Collectively, systemic LPS induced a rather complex polarization of A1, A2, A-pan, M1, and M2. A smaller LPS dose like 1 or 3 mg/kg could be available to induce A1, and selection of phenotypic markers should be optimized by considering the LPS dose and target tissue.