RESUMEN
Glycinergic neurons regulate nociceptive and pruriceptive signaling in the spinal cord, but the identity and role of the glycine-regulated neurons are not fully known. Herein, we have characterized spinal glycine receptor alpha 3 (Glra3) subunit-expressing neurons in Glra3-Cre female and male mice. Glra3-Cre(+) neurons express Glra3, are located mainly in laminae III-VI, and respond to glycine. Chemogenetic activation of spinal Glra3-Cre(+) neurons induced biting/licking, stomping, and guarding behaviors, indicative of both a nociceptive and pruriceptive role for this population. Chemogenetic inhibition did not affect mechanical or thermal responses but reduced behaviors evoked by compound 48/80 and chloroquine, revealing a pruriceptive role for these neurons. Spinal cells activated by compound 48/80 or chloroquine express Glra3, further supporting the phenotype. Retrograde tracing revealed that spinal Glra3-Cre(+) neurons receive input from afferents associated with pain and itch, and dorsal root stimulation validated the monosynaptic input. In conclusion, these results show that spinal Glra3(+) neurons contribute to acute communication of compound 48/80- and chloroquine-induced itch in hairy skin.
Asunto(s)
Prurito , Receptores de Glicina , Médula Espinal , Animales , Prurito/inducido químicamente , Prurito/metabolismo , Ratones , Receptores de Glicina/metabolismo , Masculino , Femenino , Médula Espinal/metabolismo , Médula Espinal/efectos de los fármacos , Cloroquina/farmacología , Ratones Transgénicos , Piel/inervación , Ratones Endogámicos C57BL , p-Metoxi-N-metilfenetilamina/farmacología , Neuronas/metabolismo , Neuronas/efectos de los fármacos , Neuronas/fisiologíaRESUMEN
BACKGROUND: The glycinergic system plays an important inhibitory role in the mouse central nervous system, where glycine controls the excitability of spinal itch- and pain-mediating neurons. Impairments of the glycine receptors can cause motor and sensory deficits. Glycine exerts inhibition through interaction with ligand-gated ion channels composed of alpha and beta subunits. We have investigated the mRNA expression of the glycine receptor alpha 3 (Glra3) subunit in the nervous system as well as in several peripheral organs of female and male mice. RESULTS: Single-cell RNA sequencing (scRNA-seq) data analysis on the Zeisel et al. (2018) dataset indicated widespread but low expression of Glra3 in vesicular glutamate transporter 2 (Vglut2, Slc17a6) positive and vesicular inhibitory amino acid transporter (Viaat, Slc32a1)positive neurons of the mouse central nervous system. Highest occurrence of Glra3 expression was identified in the cortex, amygdala, and striatal regions, as well as in the hypothalamus, brainstem and spinal cord. Bulk quantitative real-time-PCR (qRT-PCR) analysis demonstrated Glra3 expression in cortex, amygdala, striatum, hypothalamus, thalamus, pituitary gland, hippocampus, cerebellum, brainstem, and spinal cord. Additionally, male mice expressed higher levels of Glra3 in all investigated brain areas compared with female mice. Lastly, RNAscope spatially validated Glra3 expression in the areas indicated by the single-cell and bulk analyses. Moreover, RNAscope analysis confirmed co-localization of Glra3 with Slc17a6 or Slc32a1 in the central nervous system areas suggested from the single-cell data. CONCLUSIONS: Glra3 expression is low but widespread in the mouse central nervous system. Clear sex-dependent differences have been identified, indicating higher levels of Glra3 in several telencephalic and diencephalic areas, as well as in cerebellum and brainstem, in male mice compared with female mice.
Asunto(s)
Glicina , Receptores de Glicina , Ratones , Masculino , Femenino , Animales , Receptores de Glicina/metabolismo , Glicina/metabolismo , Neuronas/metabolismo , Encéfalo/metabolismo , Médula Espinal/metabolismo , ARN MensajeroRESUMEN
OBJECTIVE: To systematically review evidence on the efficacy and safety of sleep deprivation (SD) as a treatment option for patients with unipolar or bipolar depression. METHODS: A systematic review according to PRISMA guidelines was conducted. The certainty of evidence was assessed using the GRADE approach. Controlled trials were included in efficacy analysis, case series for evaluating complications and qualitative studies for patients' experiences. RESULTS: Eight controlled studies (368 patients), one qualitative study and seven case series (825 patients) were included. One week after treatment start, SD combined with standard treatment did not reduce depressive symptoms compared with standard treatment (standardized mean difference, SMD = -0.29, [95% confidence interval, CI: -0.84 to 0.25], p = 0.29). When excluding a study in elderly patients in a post hoc analysis, the difference was statistically significant (SMD = -0.54 ([95% CI: -0.86 to -0.22], p < 0.001)) but it diminished two weeks after treatment start. No superiority of SD was found compared with antidepressants, but SD may be superior to exercise in certain settings. It is uncertain whether SD affects quality of sleep, quality of life, everyday functioning or length of stay. Apart from switch to mania (ranging between 2.7% and 10.7%), no other serious complications were reported. CONCLUSION: Sleep deprivation has been studied in a wide range of settings resulting in divergent results for the short-term efficacy on depressive symptoms. Post hoc analyses indicated that there may be a significant but transient effect in certain populations. Further studies should focus on identifying subgroups of responders as well as examining feasibility in routine clinical care.