STING recognition of viral dsDNA by nociceptors mediates pain in mice.

Pain is often one of the initial indicators of a viral infection, yet our understanding of how viruses induce pain is limited. Immune cells typically recognize viral nucleic acids, which activate viral receptors and signaling, leading to immunity. Interestingly, these viral receptors and signals are also present in nociceptors and are associated with pain. Here, we investigate the response of nociceptors to nucleic acids during viral infections, specifically focusing on the role of the viral signal, Stimulator of Interferon Genes (STING). Our research shows that cytosolic double-stranded DNA (dsDNA) from viruses, like herpes simplex virus 1 (HSV-1), triggers pain responses through STING expression in nociceptors. In addition, STING agonists alone can elicit pain responses. Notably, these responses involve the direct activation of STING in nociceptors through TRPV1. We also provided a proof-of-concept showing that STING and TRPV1 significantly contribute to the mechanical hypersensitivity induced by HSV-1 infection. These findings suggest that STING could be a potential therapeutic target for relieving pain during viral infections.

A mimetic peptide of ACE2 protects against SARS-CoV-2 infection and decreases pulmonary inflammation related to COVID-19.

Since human angiotensin-converting enzyme 2 (ACE2) serves as a primary receptor for SARS-CoV-2, characterizing ACE2 regions that allow SARS-CoV-2 to enter human cells is essential for designing peptide-based antiviral blockers and elucidating the pathogenesis of the virus. We identified and synthesized a 25-mer mimetic peptide (encompassing positions 22-46 of the ACE2 alpha-helix α1) implicated in the S1 receptor-binding domain (RBD)-ACE2 interface. The mimetic (wild-type, WT) ACE2 peptide significantly inhibited SARS-CoV-2 infection of human pulmonary Calu-3 cells in vitro. In silico protein modeling predicted that residues F28, K31, F32, F40, and Y41 of the ACE2 alpha-helix α1 are critical for the original, Delta, and Omicron strains of SARS-CoV-2 to establish the Spike RBD-ACE2 interface. Substituting these residues with alanine (A) or aspartic acid (D) abrogated the antiviral protective effect of the peptides, indicating that these positions are critical for viral entry into pulmonary cells. WT ACE2 peptide, but not the A or D mutated peptides, exhibited significant interaction with the SARS-CoV-2 S1 RBD, as shown through molecular dynamics simulations. Through identifying the critical amino acid residues of the ACE2 alpha-helix α1, which is necessary for the Spike RBD-ACE2 interface and mobilized during the in vitro viral infection of cells, we demonstrated that the WT ACE2 peptide protects susceptible K18-hACE2 mice against in vivo SARS-CoV-2 infection and is effective for the treatment of COVID-19.

Jararhagin, a snake venom metalloproteinase, induces mechanical hyperalgesia in mice with the neuroinflammatory contribution of spinal cord microglia and astrocytes

Jararhagin is a hyperalgesic metalloproteinase from Bothrops jararaca venom. In rodents, jararhagin induces nociceptive behaviors that correlate with an increase in peripheral cytokine levels. However, the role of the spinal cord glia in pain processing after peripheral stimulus of jararhagin has not been investigated. Aiming to explore this proposal, mice received intraplantar (i.pl.) injection of jararhagin and the following parameters were evaluated: hyperalgesia, spinal cord TNF-α, IL-1β levels, and CX3CR1, GFAP and p-NFκB activation. The effects of intrathecal (i.t.) injection of TNF-α soluble receptor (etanercept), IL-1 receptor antagonist (IL-1Ra), and inhibitors of NFκB (PDTC), microglia (minocycline) and astrocytes (α-aminoadipate) were investigated. Jararhagin inoculation induced cytokine production (TNF-α and IL-1β) in the spinal cord, which was reduced by treatment with PDTC (40% and 50%, respectively). Jararhagin mechanical hyperalgesia and cytokine production were inhibited by treatment with etanercept (67%), IL-1Ra (60%), PDTC (70%), minocycline (60%) and α-aminoadipate (45%). Furthermore, jararhagin induced an increase in p-NFκB, CX3CR1 and GFAP detection in the spinal cord indicating activation of NFκB, microglia and astrocytes. These results demonstrate for the first time that jararhagin-induced mechanical hyperalgesia is dependent on spinal cord activation of glial cells, consequent NFκB activation, and cytokine production in mice.

Non-peptidergic nociceptive neurons are essential for mechanical inflammatory hypersensitivity in mice

Small nerve fibers that bind the isolectin B4 (IB4+ C-fibers) are a subpopulation of primary afferent neurons that are involved in nociceptive sensory transduction and do not express the neuropeptides substance P and calcitonin-gene related peptide (CGRP). Several studies have attempted to elucidate the functional role of IB4+-nociceptors in different models of pain. However, a functional characterization of the non-peptidergic nociceptors in mediating mechanical inflammatory hypersensitivity in mice is still lacking. To this end, in the present study, the neurotoxin IB4-Saporin (IB4-Sap) was employed to ablate non-peptidergic C-fibers. Firstly, we showed that intrathecal (i.t.) administration of IB4-Sap in mice depleted non-peptidergic C-fibers, since it decreased the expression of purinoceptor 3 (P2X3) and transient receptor potential cation channel subfamily V member 1 (TRPV1) in the dorsal root ganglia (DRGs) as well as IB4 labelling in the spinal cord. Non-peptidergic C-fibers depletion did not alter the mechanical nociceptive threshold, but it inhibited the mechanical inflammatory hypersensitivity induced by glial cell-derived neurotrophic factor (GDNF), but not nerve growth factor (NGF). Depletion of non-peptidergic C-fibers abrogated mechanical inflammatory hypersensitivity induced by carrageenan. Finally, it was found that the inflammatory mediators PGE2 and epinephrine produced a mechanical inflammatory hypersensitivity that was also blocked by depletion of non-peptidergic C-fibers. These data suggest that IB4-positive nociceptive nerve fibers are not involved in normal mechanical nociception but are sensitised by inflammatory stimuli and play a crucial role in mediating mechanical inflammatory hypersensitivity.

Acute effects of the intensity in the agonistantagonist paired-set on the neuromuscular performance / Efeito agudo da intensidade no sistema agonista-antagonista pareado por série sobre o desempenho neuromuscular

The intensity employed in the agonist-antagonist paired-set (AAPS) system may influence neuromuscular performance due to increased fatigue and decreased antagonist coactivation. However, it is not yet known whether performing submaximal repetitions at different intensities (i.e., wit h out m uscle failure) negatively affects agonist muscle performance. The aim of this study was to verify the acute effect of the AAPSsystem performed at different intensities with submaximal repetitions. 20 trained m ales in resistance training (RT) (21.8 [3.1] years; 76.9 [9.7] kg; 1.7 [0.0] m; 24.3 [2.6] kg/m2 ) participated of this investigation. All the participants were allocated in a randomized order in one of the two AAPS configurations: high-load (HL) or low-load (LL). In the HL condition, the individuals were submit t ed to one set of eight repetitions at 75% of one-repetition maximum (1RM) in the knee flexion (i.e., antagonist), followed by 75% 1RM knee extension (i.e., agonist) exercise until momentary concentric failure. In t he LL condition, they performed one set of 12 repetitions at 50% 1RMin the knee flexion, followed by knee extension at 75%1RM also until momentary concentric failure. Both experimental conditions p resented similar values for the number of repetitions, without significant difference (p= 0.66, ES= 0.15). Thus, our data suggest that the adoption of AAPS system without an increase of the antagonist fatigue and consequently no reduction of coactivation, acutely, may not lead to increased p erfo rm an ce o f target musculature during a resistance exercise session...(AU)

A intensidade empregada no sistema agonista-antagonista pareado por série ( AAPS) pode influenciar o desempenho neuromuscular devido ao aumento da fadiga e diminuição da co ativação do antagonista. No entanto, ainda não se sabe se realizar repetições submáximas em diferentes intensidades (i.e., sem falha muscular) afeta negativamente o desempenho muscular. O objetivo deste estudo foi verificar o efeito agudo do sistema AAPS realizado em diferentes intensidades com repetições submáximas. 20 homens treinados em treinamento resistido (TR) (21.8 ± 3.1 anos; 76.9 ± 9.7 kg; 1.7 ± 0.0 m; 24.3 ± 2.6 kg/m2 ) participaram desta investigação. Todos os participantes foram alocados, de forma aleatória, em uma das duas configurações do sistema AAPS: alta-carga (AC) ou baixa- carga (BC). Na condição AC, os indivíduos foram submetidos a uma série de oito repetições a 75% 1RMno exercício de flexão do joelho (i.e., antagonista), seguido por uma série a 75% 1RM de extensão do joelho até a falha oncêntrica momentânea. Ambas as condições experimentais apresentaram v alores sim ilares para o número de repetições, sem diferença significante (p = 0.66, TE = 0.15). Assim, nossos dados sugerem que a adoção do sistema AAPSsem aumento da fadiga do antagonista e consequentemente sem redução da coativação, agudamente, pode não levar ao aumento do desempenho da musculatura alvo durante uma sessão de exercício resistido...(AU)

Non-peptidergic nociceptive neurons are essential for mechanical inflammatory hypersensitivity in mice

Small nerve fibers that bind the isolectin B4 (IB4+ C-fibers) are a subpopulation of primary afferent neurons that are involved in nociceptive sensory transduction and do not express the neuropeptides substance P and calcitonin-gene related peptide (CGRP). Several studies have attempted to elucidate the functional role of IB4+-nociceptors in different models of pain. However, a functional characterization of the non-peptidergic nociceptors in mediating mechanical inflammatory hypersensitivity in mice is still lacking. To this end, in the present study, the neurotoxin IB4-Saporin (IB4-Sap) was employed to ablate non-peptidergic C-fibers. Firstly, we showed that intrathecal (i.t.) administration of IB4-Sap in mice depleted non-peptidergic C-fibers, since it decreased the expression of purinoceptor 3 (P2X3) and transient receptor potential cation channel subfamily V member 1 (TRPV1) in the dorsal root ganglia (DRGs) as well as IB4 labelling in the spinal cord. Non-peptidergic C-fibers depletion did not alter the mechanical nociceptive threshold, but it inhibited the mechanical inflammatory hypersensitivity induced by glial cell-derived neurotrophic factor (GDNF), but not nerve growth factor (NGF). Depletion of non-peptidergic C-fibers abrogated mechanical inflammatory hypersensitivity induced by carrageenan. Finally, it was found that the inflammatory mediators PGE2 and epinephrine produced a mechanical inflammatory hypersensitivity that was also blocked by depletion of non-peptidergic C-fibers. These data suggest that IB4-positive nociceptive nerve fibers are not involved in normal mechanical nociception but are sensitised by inflammatory stimuli and play a crucial role in mediating mechanical inflammatory hypersensitivity.

Cytokine inhibitors and pain control: [review]

The authors describe the evidences supporting the role of cytokines in experimental pain, discussing possible approaches for pain control using cytokine-targeting therapies.

Os autores fazem uma revisão sobre evidências que demonstram o papel de citocinas em modelos experimentais de dor, discutindo possíveis terapias com alvo em citocinas para controle da dor.