SARS-CoV-2 Rapidly Infects Peripheral Sensory and Autonomic Neurons, Contributing to Central Nervous System Neuroinvasion before Viremia.

Neurological symptoms associated with COVID-19, acute and long term, suggest SARS-CoV-2 affects both the peripheral and central nervous systems (PNS/CNS). Although studies have shown olfactory and hematogenous invasion into the CNS, coinciding with neuroinflammation, little attention has been paid to susceptibility of the PNS to infection or to its contribution to CNS invasion. Here we show that sensory and autonomic neurons in the PNS are susceptible to productive infection with SARS-CoV-2 and outline physiological and molecular mechanisms mediating neuroinvasion. Our infection of K18-hACE2 mice, wild-type mice, and golden Syrian hamsters, as well as primary peripheral sensory and autonomic neuronal cultures, show viral RNA, proteins, and infectious virus in PNS neurons, satellite glial cells, and functionally connected CNS tissues. Additionally, we demonstrate, in vitro, that neuropilin-1 facilitates SARS-CoV-2 neuronal entry. SARS-CoV-2 rapidly invades the PNS prior to viremia, establishes a productive infection in peripheral neurons, and results in sensory symptoms often reported by COVID-19 patients.

5-HT1F agonists.

5-Hydroxytryptamine (HT)/serotonin receptor agonism has been a long-recognized property of triptan medications, and more recently, the study and development of medications with selective binding to the 1F receptor subtype have been explored. While the exact mechanism contributing to decreased symptoms of an acute migraine attack remains unclear, selective 5-HT1F agonists have demonstrated clinical efficacy with lasmiditan as the only approved medication from this class to date. Lasmiditan lacks vasoconstrictive properties, giving it utility in specific patient populations in whom triptans should be avoided. Availability, central nervous system (CNS) side effects, and 8-hour driving restriction may affect its clinical use.

Potential mechanisms for osteopathic manipulative treatment to alleviate migraine-like pain in female rats.

Introduction: Migraines are the leading cause of disability in the United States, and the use of non-pharmaceutical treatments like osteopathic manipulative treatment (OMT) has shown promise. Despite its potential, the lack of mechanistic understanding has hindered widespread adoption. This study aims to investigate the efficacy of OMT in treating acute migraines and unravel its underlying mechanisms of action. Methods: Female rats were subjected to a "two-hit" approach to induce migraine-like pain. This involved bilateral injections of Complete Freund's Adjuvant (CFA) into the trapezius muscle (1st hit) followed by exposure to Umbellulone, a human migraine trigger, on Day 6 post-CFA (2nd hit). Soft tissue and articulatory techniques were applied to the cervical region for acute abortive or repeated prophylactic treatment. Cutaneous allodynia and trigeminal system activation were assessed through behavioral tests and immunohistochemical staining. Results: Following Umbellulone inhalation, CFA-primed rats exhibited periorbital and hind paw allodynia. Immediate application of OMT after Umbellulone inhalation as an abortive treatment partially alleviated cutaneous allodynia. With OMT applied thrice as a prophylactic measure, complete suppression of tactile hypersensitivity was observed. Prophylactic OMT also prevented the increase of c-fos signals in the trigeminal nucleus caudalis and the elevation of calcitonin gene-related peptide expression in trigeminal ganglia induced by CFA and Umbellulone exposure at 2 h post-inhalation. Discussion: These findings provide mechanistic insights into OMT's migraine-relief potential and underscore its viability as a non-pharmacological avenue for managing migraines.

Oxytocin Receptors on Calvarial Periosteal Innervation: Therapeutic Target for Post-Traumatic Headache?

OBJECTIVE: Following a mild traumatic brain injury (mTBI), the most prevalent and profoundly debilitating occurrence is the emergence of an acute and persistent post-traumatic headache (PTH), for which there are presently no approved treatments. A crucial gap in knowledge exists regarding the consequences of an mTBI, which could serve as a foundation for the development of therapeutic approaches. The activation of trigeminal sensory nerve terminals that innervate the calvarial periosteum (CP)-a densely innervated tissue layer covering the calvarial skull-has been implicated in both migraines and PTHs. We have previously shown that trigeminal oxytocin receptors (OTRs) may provide a therapeutic target for PTHs. This study examined the expression of oxytocin receptors on trigeminal nerves innervating the periosteum and whether these receptors might serve as a therapeutic target for PTHs using a direct application of oxytocin to the periosteum in a rodent model of PTH. METHODS: We used retrograde tracing and immunohistochemistry to determine if trigeminal ganglion (TG) neurons innervating the periosteum expressed OTRs and/or CGRPs. To model the impact of local inflammation that occurs following an mTBI, we applied chemical inflammatory mediators directly to the CP and assessed for changes in immediate-early gene expression as an indication of neuronal activation. We also determined whether mTBI would lead to expression changes to OTR levels. To determine whether these OTRs could be a viable therapeutic target, we assessed the impact of oxytocin injections into the CP in a mouse model of PTH-induced periorbital allodynia. RESULTS: The results of these experiments demonstrate the following: (1) the cell bodies of CP afferents reside in the TG and express both OTRs and CGRPs; (2) inflammatory chemical stimulation of the periosteum leads to rapid activation of TG neurons (phospho-ERK (p-ERK) expression), (3) mTBI-induced inflammation increased OTR expression compared to the sham group; and (4) administration of oxytocin into the periosteum on day 2 and day 40 blocked cutaneous allodynia for up to one hour post-administration for both acute and persistence phases in the PTH model-an effect that was preventable by the administration of an OTR antagonist. CONCLUSION: Taken together, our observations suggest that periosteal trigeminal afferents contribute to post-TBI craniofacial pain, and that periosteum tissue can be used as a potential local target for therapeutics such as oxytocin.

Infecção latente pelo herpesvírus bovino tipo 1 em búfalos (Bubalus bubalis) no Rio Grande do Sul / Bovine herpesvirus type 1 latent infection in buffalo (Bubalus bubalis) in Rio Grande do Sul

Apesar dos bovinos serem considerados os hospedeiros naturais do BoHV-1, estudos sorológicos têm sugerido que búfalos podem ser suscetíveis ao BoHV-1 e a outros alfa-herpesvírus geneticamente relacionados. O objetivo deste estudo foi detectar a presença de DNA viral de BoHV-1 em 202 amostras de gânglios trigêmeos de búfalos, pela técnica de semi-nested PCR, para detecção de um segmento do gene codificante da glicoproteína D (gD) do BoHV-1. Além disso, 242 amostras de soro foram analisadas pela técnica de soroneutralização (SN) para a detecção de anticorpos neutralizantes contra BoHV-1, BoHV-5 e BuHV. Todas as amostras clínicas foram coletadas em um matadouro na cidade de Pelotas, RS, Brasil. O DNA de BoHV-1 foi detectado em 61 (30,1%) gânglios, e os resultados da SN demonstraram que 27,6% dos animais apresentaram anticorpos contra, pelo menos, um dos vírus testados. O sequenciamento genômico e a análise de 14 amplicons confirmaram a presença do DNA do BoHV-1 nos tecidos analisados. Em resumo, os resultados indicam que o BoHV-1 está distribuído em rebanhos bubalinos provenientes da região Sul do Brasil. Entretanto, são necessárias investigações adicionais, no sentido de elucidar o papel exato dos búfalos na epidemiologia das infecções pelo BoHV-1.(AU)

Although bovines are natural hosts for BoHV-1, serologic studies in several countries have suggested that buffaloes (Bubalus bubalis) may be susceptible to BoHV-1 and other genetically related alphaherpesvirus. This study aimed to investigate the presence of BoHV-1 DNA in trigeminal ganglia from 202 buffaloes by a semi-nested PCR to amplify partially the glycoprotein D (gD) gene of BoHV-1. Additionally, 242 serum samples were tested by serum neutralization (SN) for the detection of antibodies against BoHV-1, BoHV-5 and BuHV. All clinical samples were collected in a slaughterhouse located in Pelotas, RS, Brazil. BoHV-1 DNA was detected in 61 (30.1%) of the samples and SN revealed 27.6% of the animals with neutralizing antibodies against at least one of the tested viruses. Nucleotide sequencing of 15 amplicons followed by BLAST analysis confirmed the presence of BoHV-1 DNA in the analyzed tissues. Taken together, these data indicate that BoHV-1 infection is distributed in buffaloes in southern Brazil. However, the role of buffaloes in the BoHV-1 epidemiology needs further investigation.(AU)

Detección de la presencia de antígeno y ADN de virus herpes simple tipo 1 en ganglios trigeminales humanos / Viral DNA and antigen detection of type 1 herpes simplex virus in human trigeminal ganglia

Antecedentes: la infección por virus herpes simple tipo 1 (VHS-1) es una de las más frecuentesen la población humana; produce infecciones en mucosa oral, piel, ojos e inclusoen el sistema nervioso, que causa encefalitis. Después de la infección en la región orofacial,este virus puede permanecer en estado de latencia en el ganglio trigémino y eventualmentereactivarse. Objetivo: determinar la presencia de VHS-1 en ganglios trigeminales humanosmediante pruebas paralelas de PCR, RT-PCR e inmunohistoquímica. Métodos: previa aprobacióndel Comité de Ética de la Facultad de Odontología de la Universidad Nacional deColombia y del Instituto de Medicina Legal y Ciencias Forenses, se recolectaron dieciséispares de ganglios trigeminales humanos, que se procesaron tanto para extracción de ácidosnucleicos como para inmunohistoquímica. Resultados: en seis de los ocho donantesanalizados por inmunohistoquímica se encontró marcaje positivo para antígeno de VHS-1.Se halló que nueve de los donantes evaluados por PCR para VHS-1 y cinco de los diezexaminados para transcritos asociados a latencia (LAT) fueron positivos. Conclusión: seencontraron ganglios trigeminales en los que no se detectó virus y otros con distintosestados de infección (activa y latente). En casi todos los ganglios fue evidente el infiltradoinflamatorio asociado. El presente es el primer trabajo en el que se busca sistemáticamentetanto genoma viral como proteínas y transcritos LAT en ganglios trigeminales humanos, locual abre puertas para la investigación tanto de la epidemiología como de los fenómenosasociados a la LAT y reactivación del VHS-1...

Background: Infection by type 1 Herpes Simplex Virus (HSV-1) is the most frequent viralinfection in human population being able to cause injuries in oral mucosa, skin, cornea,and even the central nervous system causing encephalitis. After mucosal infection, HSV-1establishes a lifespan latent infection in trigeminal ganglia where it occasionally reactivatesinfecting primary sites again. It is little known about cell and molecular events responsiblefor infection reactivation and immune response in human ganglia. Objective: To standardizethe obtaining and processing of human trigeminal ganglia to detect specific HSVantigen, DNA and RNA. Methods: After approval of the study by the Universidad NacionalIRB, 32 trigeminal ganglia were obtained from 16 cadavers from the Colombian ForensicMedicine Institute. Results: Using PCR technique to detect viral DNA, it was found that 56.3 %of ganglia (9/16) amplified specific fragment and five out of ten with suitable quality RNAwere positive for latency associated transcript. Conclusion: Some trigeminal ganglia did notshow evidence of infection and some had different HSV-1 infection status (active or latent)with inflammatory cells infiltrate in almost all samples. This is the first work that detectssimultaneously genome, proteins and LAT of HSV-1 in human trigeminal ganglia, leading toexplore findings about the latency and r eactivation pr ocess...