Assuntos
Sepse , Humanos , Pessoa de Meia-Idade , Feminino , Sepse/diagnóstico , Sepse/etiologia , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/efeitos adversos , Bacteriemia/diagnóstico , Bacteriemia/microbiologia , Bacteriemia/tratamento farmacológico , Insuficiência de Múltiplos Órgãos/etiologia , Insuficiência de Múltiplos Órgãos/diagnóstico , Evolução Fatal , Pró-Calcitonina/sangueAssuntos
Hérnia Inguinal , Intestino Delgado , Humanos , Masculino , Hérnia Inguinal/diagnóstico , Hérnia Inguinal/complicações , Hérnia Inguinal/cirurgia , Hérnia Inguinal/diagnóstico por imagem , Intestino Delgado/patologia , Intestino Delgado/diagnóstico por imagem , Pessoa de Meia-Idade , Ruptura/etiologia , Traumatismos Abdominais/complicações , Patologia Legal/métodos , Ultrassonografia , Períneo/lesões , Escroto/diagnóstico por imagem , Escroto/lesões , Escroto/patologia , Tomografia Computadorizada por Raios XAssuntos
Laparoscopia , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/cirurgia , Gastrectomia/efeitos adversos , Duodeno/cirurgia , Laparoscopia/efeitos adversos , Estudos Retrospectivos , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/cirurgiaRESUMO
K+-Cl- cotransporter-2 (KCC2) critically controls neuronal chloride homeostasis and maintains normal synaptic inhibition by GABA and glycine. Nerve injury diminishes synaptic inhibition in the spinal cord via KCC2 impairment. However, how KCC2 regulates nociceptive input to spinal excitatory and inhibitory neurons remains elusive. Here, we show that basal GABA reversal potentials were significantly more depolarized in vesicular GABA transporter (VGAT)-expressing inhibitory neurons than those in vesicular glutamate transporter-2 (VGluT2)-expressing excitatory neurons in spinal cords of male and female mice. Strikingly, inhibiting KCC2 with VU0463271 increased currents elicited by puff NMDA and the NMDAR-mediated frequency of mEPSCs in VGluT2, but not in VGAT, dorsal horn neurons. Notably, VU0463271 had no effect on EPSCs monosynaptically evoked from the dorsal root in VGluT2 neurons. Furthermore, VU0463271 augmented α2δ-1-NMDAR interactions and their protein levels in spinal cord synaptosomes. In Cacna2d1 KO mice, VU0463271 had no effect on puff NMDA currents or the mEPSC frequency in dorsal horn neurons. Disrupting α2δ-1-NMDAR interactions with α2δ-1 C-terminus mimicking peptide diminished VU0463271-induced potentiation in the mEPSC frequency and puff NMDA currents in VGluT2 neurons. Additionally, intrathecal injection of VU0463271 reduced mechanical and thermal thresholds in wild-type mice, but not in Cacna2d1 KO mice. VU0463271-induced pain hypersensitivity in mice was abrogated by co-treatment with the NMDAR antagonist, pregabalin (an α2δ-1 inhibitory ligand), or α2δ-1 C-terminus mimicking peptide. Our findings suggest that KCC2 controls presynaptic and postsynaptic NMDAR activity specifically in excitatory dorsal horn neurons. KCC2 impairment preferentially potentiates nociceptive transmission between spinal excitatory interneurons via α2δ-1-bound NMDARs.Significance statementImpaired function of potassium-chloride cotransporter-2 (KCC2), a key regulator of neuronal inhibition, in the spinal cord plays a major role in neuropathic pain. This study unveils that KCC2 controls spinal nociceptive synaptic strength via NMDA receptors in a cell type- and synapse type-specific manner. KCC2 inhibition preferentially augments presynaptic and postsynaptic NMDA receptor activity in spinal excitatory interneurons via α2δ-1 (previously known as a calcium channel subunit). Importantly, spinal KCC2 impairment triggers pain hypersensitivity through α2δ-1-coupled NMDA receptors. These findings pinpoint the cell and molecular substrates for the reciprocal relationship between spinal synaptic inhibition and excitation in chronic neuropathic pain. Targeting both KCC2 and α2δ-1NMDA receptor complexes could be an effective strategy in managing neuropathic pain conditions.
Assuntos
Receptores de N-Metil-D-Aspartato , Simportadores , Animais , Feminino , Masculino , Camundongos , Ácido gama-Aminobutírico/metabolismo , N-Metilaspartato/farmacologia , Peptídeos/farmacologia , Células do Corno Posterior/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Medula Espinal/metabolismo , Simportadores/genética , Simportadores/metabolismo , Sinapses/metabolismoRESUMO
Leishbuviridae is a family of negative-sense RNA viruses with genomes of about 8.0 kb that have been found in protists. The leishbuvirid genome consists of three monocistronic RNA segments with open reading frames (ORFs) that encode a nucleoprotein (NP), a glycoprotein (GP), and a large (L) protein containing an RNA-directed RNA polymerase (RdRP) domain. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the family Leishbuviridae, which is available at ictv.global/report/leishbuviridae.