Anatomical correlates for the newly discovered meningeal layer in the existing literature: A systematic review.

The existence of a previously unrecognized subarachnoid lymphatic-like membrane (SLYM) was reported in a recent study. SLYM is described as an intermediate leptomeningeal layer between the arachnoid and pia mater in mouse and human brains, which divides the subarachnoid space (SAS) into two functional compartments. Being a macroscopic structure, having missed detection in previous studies is surprising.

Alleviation of neuropathic pain with neuropeptide Y requires spinal Npy1r interneurons that coexpress Grp.

Neuropeptide Y targets the Y1 receptor (Y1) in the spinal dorsal horn (DH) to produce endogenous and exogenous analgesia. DH interneurons that express Y1 (Y1-INs; encoded by Npy1r) are necessary and sufficient for neuropathic hypersensitivity after peripheral nerve injury. However, as Y1-INs are heterogenous in composition in terms of morphology, neurophysiological characteristics, and gene expression, we hypothesized that a more precisely defined subpopulation mediates neuropathic hypersensitivity.

Endogenous μ-opioid-Neuropeptide Y Y1 receptor synergy silences chronic postoperative pain in mice.

Tissue injury creates a delicate balance between latent pain sensitization (LS) and compensatory endogenous analgesia. Inhibitory G-protein-coupled receptor (GPCR) interactions that oppose LS, including μ-opioid receptor (MOR) or neuropeptide Y Y1 receptor (Y1R) activity, persist in the spinal cord dorsal horn (DH) for months, even after the resolution of normal pain thresholds. Here, we demonstrate that following recovery from surgical incision, a potent endogenous analgesic synergy between MOR and Y1R activity persists within DH interneurons to reduce the intensity and duration of latent postoperative hypersensitivity and ongoing pain.

Contribution of µ Opioid Receptor-expressing Dorsal Horn Interneurons to Neuropathic Pain-like Behavior in Mice.

Background: Intersectional genetics have yielded tremendous advances in our understanding of molecularly identified subpopulations and circuits within the dorsal horn in neuropathic pain. The authors tested the hypothesis that spinal µ opioid receptor-expressing neurons (Oprm1-expressing neurons) contribute to behavioral hypersensitivity and neuronal sensitization in the spared nerve injury model in mice.

Methods: The authors coupled the use of Oprm1Cre transgenic reporter mice with whole cell patch clamp electrophysiology in lumbar spinal cord slices to evaluate the neuronal activity of Oprm1-expressing neurons in the spared nerve injury model of neuropathic pain.

SARS-CoV-2 Omicron Variant Genomic Sequences and Their Epidemiological Correlates Regarding the End of the Pandemic: In Silico Analysis.

Background: Emergence of the new SARS-CoV-2 variant B.1.1.

Spinal neuropeptide Y Y1 receptor-expressing neurons are a pharmacotherapeutic target for the alleviation of neuropathic pain.

Peripheral nerve injury sensitizes a complex network of spinal cord dorsal horn (DH) neurons to produce allodynia and neuropathic pain. The identification of a druggable target within this network has remained elusive, but a promising candidate is the neuropeptide Y (NPY) Y1 receptor-expressing interneuron (Y1-IN) population. We report that spared nerve injury (SNI) enhanced the excitability of Y1-INs and elicited allodynia (mechanical and cold hypersensitivity) and affective pain.

COVID-19 vaccination may enhance hippocampal neurogenesis in adults.

Emerging evidence suggests a detrimental impact of COVID-19 illness on the continued hippocampal neurogenesis in adults. In contrast, the existing literature supports an enhancing effect of COVID-19 vaccination on adult hippocampal neurogenesis. Vaccines against respiratory infections, including influenza, have been shown to enhance hippocampal neurogenesis in adult-age animals.

Postsurgical Latent Pain Sensitization Is Driven by Descending Serotonergic Facilitation and Masked by µ-Opioid Receptor Constitutive Activity in the Rostral Ventromedial Medulla.

Following tissue injury, latent sensitization (LS) of nociceptive signaling can persist indefinitely, kept in remission by compensatory µ-opioid receptor constitutive activity (MOR) in the dorsal horn of the spinal cord. To demonstrate LS, we conducted plantar incision in mice and then waited 3-4 weeks for hypersensitivity to resolve. At this time (remission), systemic administration of the opioid receptor antagonist/inverse agonist naltrexone reinstated mechanical and heat hypersensitivity.

Emerging SARS-CoV-2 variants can potentially break set epidemiological barriers in COVID-19.

Young age, female sex, absence of comorbidities, and prior infection or vaccination are known epidemiological barriers for contracting the new infection and/or increased disease severity. Demographic trends from the recent coronavirus disease 2019 waves, which are believed to be driven by newer severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, indicate that the aforementioned epidemiological barriers are being breached and a larger number of younger and healthy individuals are developing severe disease. The new SARS-CoV-2 variants have key mutations that can induce significant changes in the virus-host interactions.

COVID-19 Mechanisms in the Human Body-What We Know So Far.

More than one and a half years have elapsed since the commencement of the coronavirus disease 2019 (COVID-19) pandemic, and the world is struggling to contain it. Being caused by a previously unknown virus, in the initial period, there had been an extreme paucity of knowledge about the disease mechanisms, which hampered preventive and therapeutic measures against COVID-19. In an endeavor to understand the pathogenic mechanisms, extensive experimental studies have been conducted across the globe involving cell culture-based experiments, human tissue organoids, and animal models, targeted to various aspects of the disease, , viral properties, tissue tropism and organ-specific pathogenesis, involvement of physiological systems, and the human immune response against the infection.

Sex Differences in Protein Kinase A Signaling of the Latent Postoperative Pain Sensitization That Is Masked by Kappa Opioid Receptors in the Spinal Cord.

Latent sensitization (LS) of pain engages pronociceptive signaling pathways in the dorsal horn that include NMDA receptor (NMDAR)→adenylyl cyclase-1 (AC1)→protein kinase A (PKA), and exchange proteins directly activated by cyclic AMP (Epacs). To determine whether these pathways operate similarly between males and females or are under the inhibitory control of spinal κ opioid receptors (KOR), we allowed hyperalgesia to resolve after plantar incision and then blocked KOR with intrathecal administration of LY2456302, which reinstated hyperalgesia and facilitated touch-evoked immunoreactivity of phosphorylated extracellular signal-regulated kinase (pERK) in neurons (NeuN) but not astrocytes (GFAPs) nor microglia (Iba1). LY2456302 reinstated hyperalgesia even when administered 13 months later, indicating that chronic postoperative pain vulnerability persists for over a year in a latent state of remission.

COVID-19 pandemic: insights into molecular mechanisms leading to sex-based differences in patient outcomes.

Recent epidemiological studies analysing sex-disaggregated patient data of coronavirus disease 2019 (COVID-19) across the world revealed a distinct sex bias in the disease morbidity as well as the mortality - both being higher for the men. Similar antecedents have been known for the previous viral infections, including from coronaviruses, such as severe acute respiratory syndrome (SARS) and middle-east respiratory syndrome (MERS). A sound understanding of molecular mechanisms leading to the biological sex bias in the survival outcomes of the patients in relation to COVID-19 will act as an essential requisite for developing a sex-differentiated approach for therapeutic management of this disease.

Endogenous µ-opioid receptor activity in the lateral and capsular subdivisions of the right central nucleus of the amygdala prevents chronic postoperative pain.

Tissue injury induces a long-lasting latent sensitization (LS) of spinal nociceptive signaling that is kept in remission by an opposing µ-opioid receptor (MOR) constitutive activity. To test the hypothesis that supraspinal sites become engaged, we induced hindpaw inflammation, waited 3 weeks for mechanical hypersensitivity to resolve, and then injected the opioid receptor inhibitors naltrexone, CTOP or β-funaltrexamine subcutaneously, and/or into the cerebral ventricles. Intracerebroventricular injection of each inhibitor reinstated hypersensitivity and produced somatic signs of withdrawal, indicative of LS and endogenous opioid dependence, respectively.

Fast A-type currents shape a rapidly adapting form of delayed short latency firing of excitatory superficial dorsal horn neurons that express the neuropeptide Y Y1 receptor.

Key Points: Neuropeptide Y Y1 receptor-expressing neurons in the dorsal horn of the spinal cord contribute to chronic pain. For the first time, we characterized the firing patterns of Y1-expressing neurons in Y1eGFP reporter mice. Under hyperpolarized conditions, most Y1eGFP neurons exhibited fast A-type potassium currents and delayed, short-latency firing (DSLF).

Expression of SARS-CoV-2 Host Cell Entry Factors in Immune System Components of Healthy Individuals and Its Relevance for COVID-19 Immunopathology.

Intense immunological dysregulation including immune cell lesions has been characteristically observed in severe cases of coronavirus disease-2019 (COVID-19), for which molecular mechanisms are not properly understood. A study of physiological expressions of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) host cell entry-related factors in immune system components may help explain molecular mechanisms involved in COVID-19 immunopathology. We analyzed transcriptomic and proteomic expression metadata for SARS-CoV-2 host cell entry receptor and entry associated proteases (, , and ) across immune system components including the blood lineage cells.

Relevance of SARS-CoV-2 related factors ACE2 and TMPRSS2 expressions in gastrointestinal tissue with pathogenesis of digestive symptoms, diabetes-associated mortality, and disease recurrence in COVID-19 patients.

COVID-19 is caused by a new strain of coronavirus called SARS-coronavirus-2 (SARS-CoV-2), which is a positive sense single strand RNA virus. In humans, it binds to angiotensin converting enzyme 2 (ACE2) with the help a structural protein on its surface called the S-spike. Further, cleavage of the viral spike protein (S) by the proteases like transmembrane serine protease 2 (TMPRSS2) or Cathepsin L (CTSL) is essential to effectuate host cell membrane fusion and virus infectivity.

Pathogenesis guided therapeutic management of COVID-19: an immunological perspective.

Lack of standardized therapeutic approaches is arguably the significant contributor to the high burden of mortality observed in the ongoing pandemic of the Coronavirus disease, 2019 (COVID-19). Evidence is accumulating on SARS-CoV-2 specific immune cell dysregulation and consequent tissue injury in COVID-19. Currently, no definite drugs or vaccines are available against the disease; however initial results of the ongoing clinical trials have raised some hope.

SARS-CoV-2-specific virulence factors in COVID-19.

The paucity of knowledge about severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific virulence factors has greatly hampered the therapeutic management of patients with coronavirus disease 2019 (COVID-19). Recently, a cluster of studies appeared, which presented empirical evidence for SARS-CoV-2-specific virulence factors that can explain key elements of COVID-19 pathology. These studies unravel multiple structural and nonstructural specifics of SARS-CoV-2, such as a unique FURIN cleavage site, papain-like protease (SCoV2-PLpro), ORF3b and nonstructural proteins, and dynamic conformational changes in the structure of spike protein during host cell fusion, which give it an edge in infectivity and virulence over previous coronaviruses causing pandemics.

Possible routes of SARS-CoV-2 invasion in brain: In context of neurological symptoms in COVID-19 patients.

Manifestation of neurological symptoms in certain patients of coronavirus disease-2019 (COVID-19) has warranted for their virus-induced etiogenesis. SARS-CoV-2, the causative agent of COVID-19, belongs to the genus of betacoronaviruses which also includes SARS-CoV-1 and MERS-CoV; causative agents for severe acute respiratory syndrome (SARS) in 2002 and Middle East respiratory syndrome (MERS) in 2012, respectively. Studies demonstrating the neural invasion of SARS-CoV-2 in vivo are still scarce, although such characteristics of certain other betacoronaviruses are well demonstrated in the literature.

Neurotrophin mediated HPA axis dysregulation in stress induced genesis of psychiatric disorders: Orchestration by epigenetic modifications.

Apart from their established role in embryonic development, neurotrophins (NTs) have diverse functions in the nervous system. Their role in the integration of physiological and biochemical aspects of the nervous system is currently attracting much attention. Based on a systematic analysis of the literature, we here propose a new paradigm that, by exploiting a novel role of NTs, may help explain the genesis of stress-related psychiatric disorders, opening new avenues for better management of the same.

Involvement of Neuropeptide Y in Post-Incisional Nociception in Rats.

Background: Neuropeptide Y (NPY) is abundantly distributed in the mammalian nervous system. Its role in nociception arising from inflammatory and neuropathic pain conditions has been elucidated. However, its involvement in post-incisional nociception, particularly at the spinal cord level, is relatively unknown.

Comparison of the peripheral antinociceptive effect of somatostatin with bupivacaine and morphine in the rodent postoperative pain model.

Background And Objectives: Infiltration of surgical wound with local anaesthetics attenuate postoperative pain. However, side effects can also occur. Somatostatin (SST) and its analogues like octreotide reportedly reduce peripheral sensitisation.

Possible modulation of PPAR-γ cascade against depression caused by neuropathic pain in rats.

Background: Sciatic nerve ligation causes neuropathic pain with chronic constriction injury (CCI). However, there is no published report on the effect of pioglitazone as an antidepressant in the treatment of depression induced by neuropathic pain with CCI in rats. The aim of this study was to evaluate the effect of pioglitazone as an antidepressant by targeting oxidative stress by the peripheral neuropathic pain model using the CCI of the sciatic nerve.