Pivotal role of the gut microbiota in congenital insensitivity to pain with anhidrosis.

BACKGROUND: Increasing evidence has shown that the occurrence and development of various human diseases are closely related to the gut microbiota. We compared the gut microbial communities of human subjects with congenital insensitivity to pain with anhidrosis (CIPA) and healthy controls (HCs) to assess whether fecal microbiota transplantation (FMT) into germ-free mice and mice in acute pain influenced the behaviors of the host. METHODS: We utilized 16 s rRNA analysis to compare the gut microbial communities of CIPA subjects and HCs and assessed whether FMT into germ-free mice and mice in acute pain influenced the behaviors of the host. RESULTS: In a 16 s RNA analysis, the CIPA group had significant decreases in the relative abundance of 11 bacteria, whereas 7 bacteria were significantly increased. In further animal experiments, the transplantation of fecal samples from CIPA patients to healthy mice significantly increased their scores on both the mechanical withdrawal test and the tail flick test; in an acute plantar incision model, scores were also significantly increased on the mechanical withdrawal test at 4 and 5 days after the operation. Moreover, pseudo-germ-free mice receiving fecal bacteria from patients with CIPA took significantly longer to escape and had a significantly longer path length on training days 1, 2, and 5 and also had fewer platform crossings and spent less time in the target quadrant in the probe trial. CONCLUSIONS: Our results suggest that the gut microbiota in CIPA subjects plays a key role in behaviors. Therapeutic strategies for improving the gut microbiota might alleviate CIPA symptoms.

Angiotensin II type 1 receptor blockade attenuates posttraumatic stress disorder-related chronic pain by inhibiting glial activation in the spinal cord.

Clinically, posttraumatic stress disorder (PTSD) and chronic pain are highly comorbid conditions, but the underlying mechanisms of and therapeutic strategies against PTSD-related pain remain unclear. Our previous studies suggested that dysregulation of neuroinflammation contributes to the development of stress-induced hyperalgesia. Recent studies reported that angiotensin II was a 'stress-related hormone', and could induce glial activation by stimulating the type 1 receptor (AT1R). In the present study, we aimed to investigate whether AT1R blockade could attenuate mechanical allodynia induced by PTSD-like stress. Adult male rats were exposed to single prolonged stress (SPS) to establish a model of PTSD-pain comorbidity. Our results showed that SPS exposure increased the levels of angiotensin II in the hippocampus, prefrontal cortex (PFC) and spinal cord; intraperitoneal injection of losartan attenuated SPS-induced mechanical allodynia, and suppressed SPS-induced glial activation (both microglia and astrocytes) and proinflammatory cytokine expression in the PFC and spinal cord, but not in the hippocampus. We further showed that intrathecal injection of losartan also exerted anti-hyperalgesic effect and suppressed SPS-induced glial activation and proinflammatory cytokine expression in the spinal cord. These results indicated that AT1R blockade by losartan attenuated mechanical allodynia induced by PTSD-like stress, and this may be attributed to the suppression of glial activation and proinflammatory cytokine expression in the spinal cord. Although further research is warranted to verify our findings in female rodents and to assess pharmacological effects of AT1R blockade in PFC and hippocampus, our study suggested the therapeutic potential of targeting AT1R in the treatment of PTSD-related chronic pain.

Effect of dexmedetomidine on delirium during sedation in adult patients in intensive care units: A systematic review and meta-analysis.

STUDY OBJECTIVE: To compare the effect of sedation protocols with and without dexmedetomidine on delirium risk and duration in adult patients in intensive care units (ICUs). DESIGN: A meta-analysis of randomized controlled trials. REVIEW METHODS: We searched the Cochrane Central Register of Controlled Trials, PubMed, EMBASE, and ISI Web of Science from inception to September 3, 2020. We included studies comparing the effect of dexmedetomidine-based sedation on delirium risk with non-dexmedetomidine-based sedation in adult patients in ICUs. We pooled the data using a random-effects model using Review Manager 5.2, and assessed publication bias using Stata 11.0. The quality of evidence was rated using the Grading of Recommendations, Assessment, Development and Evaluation system. MAIN RESULTS: We included 36 studies involving 9623 participants. The use of dexmedetomidine was associated with reduced risk of delirium (risk ratio [RR], 0.63; 95% confidence interval [CI], 0.54-0.75; very low-quality evidence), but higher incidences of hypotension and bradycardia during hospital stay. Dexmedetomidine was also associated with shorter durations of ICU stay, hospital stay and mechanical ventilation. Dexmedetomidine did not affect ICU mortality (RR, 1.01; 95% CI, 0.89-1.14; low-quality evidence), hospital mortality (RR, 1.01; 95% CI, 0.91-1.12; very low-quality evidence), or 30-day mortality (RR, 0.77; 95% CI, 0.58-1.01; moderate-quality evidence), or duration of delirium (mean difference, -0.74 days; 95% CI, -1.83 to 0.36 days; very low-quality evidence). We identified publication bias for risk and duration of delirium, length of ICU stay, and hospital stay. CONCLUSIONS: Low- or very low-quality evidence suggests that dexmedetomidine was associated with a clinically-small reduction of delirium risk, ICU/hospital stay and mechanical ventilation duration, but were not associated with improved mortality or shorter delirium duration in ICU patients. These findings were inconclusive because of publication bias, heterogeneity, and limited sample size. Significant adverse effects of dexmedetomidine include hypotension and bradycardia. PROSPERO registration number: CRD42018095358.

NGF-Induced Nav1.7 Upregulation Contributes to Chronic Post-surgical Pain by Activating SGK1-Dependent Nedd4-2 Phosphorylation.

At present, chronic post-surgical pain (CPSP) is difficult to prevent and cure clinically because of our lack of understanding of its mechanisms. Surgical injury induces the upregulation of voltage-gated sodium channel Nav1.7 in dorsal root ganglion (DRG) neurons, suggesting that Nav1.7 is involved in the development of CPSP. However, the mechanism leading to persistent dysregulation of Nav1.7 is largely unknown. Given that nerve growth factor (NGF) induces a long-term increase in the neuronal hyperexcitability after injury, we hypothesized that NGF might cause the long-term dysregulation of Nav1.7. In this study, we aimed to investigate whether Nav1.7 regulation by NGF is involved in CPSP and thus contributes to the specific mechanisms involved in the development of CPSP. Using conditional nociceptor-specific Nav1.7 knockout mice, we confirmed the involvement of Nav1.7 in NGF-induced pain and identified its role in the maintenance of pain behavior during long-term observations (up to 14 days). Using western blot analyses and immunostaining, we showed that NGF could trigger the upregulation of Nav1.7 expression and thus support the development of CPSP in rats. Using pharmacological approaches, we showed that the increase of Nav1.7 might be partly regulated by an NGF/TrkA-SGK1-Nedd4-2-mediated pathway. Furthermore, reversing the upregulation of Nav1.7 in DRG could alleviate spinal sensitization. Our results suggest that the maintained upregulation of Nav1.7 triggered by NGF contributes to the development of CPSP. Attenuating the dysregulation of Nav1.7 in peripheral nociceptors may be a strategy to prevent the transition from acute post-surgical pain to CPSP.

The Role of Voltage-Gated Sodium Channel 1.8 in the Effect of Atropine on Heart Rate: Evidence From a Retrospective Clinical Study and Mouse Model.

Atropine is commonly used to counter the effects of the parasympathetic neurotransmitter acetylcholine on heart rate in clinical practice, such as in the perioperative period; however, individual differences in the response to atropine are huge. The association between SCN10A/voltage-gated sodium channel 1.8 (NaV1.8) and cardiac conduction has been demonstrated; however, the exact role of SCN10A/NaV1.8 in the heart rate response to atropine remains unclear. To identify the role of SCN10A variants that influence the heart rate responses to atropine, we carried out a retrospective study in 1,005 Han Chinese subjects. Our results showed that rs6795970 was associated with the heart rate response to atropine. The heart rate responses to atropine and methoctramine in NaV1.8 knockout mice were lower, whereas the heart rate response to isoproterenol was like those in wild type mice. Furthermore, we observed that the NaV1.8 blocker A-803467 alleviated the heart rate response to atropine in wild type mice. The retrospective study revealed a previously unknown role of NaV1.8 in controlling the heart rate response to atropine, as shown by the animal study, a speculative mechanism that may involve the cardiac muscarinic acetylcholine receptor M2.

Upregulation of transcription factor 4 downregulates NaV1.8 expression in DRG neurons and prevents the development of rat inflammatory and neuropathic hypersensitivity.

The voltage sodium channel 1.8 (NaV1.8) in the dorsal root ganglion (DRG) neurons contributes to the initiation and development of chronic inflammatory and neuropathic pain. However, an effective intervention on NaV1.8 remains to be studied in pre-clinical research and clinical trials. In this study, we aimed to investigate whether transcription factor 4 (TCF4) overexpression represses NaV1.8 expression in DRG neurons, thus preventing the development of chronic pain. Using chromatin immunoprecipitation (CHIP), we verified the interaction of TCF4 and sodium voltage-gated channel alpha subunit 10A (SCN10A) enhancer in HEK293 cells and rat DRG neurons. Using a dual luciferase reporter assay, we confirmed the transcriptional inhibition of TCF4 on SCN10A promoter in vitro. To investigate the regulation of TCF4 on Nav1.8, we then upregulated TCF4 expression by intrathecally delivering an overexpression of recombinant adeno-associated virus (rAAV) in the Complete Freund's adjuvant (CFA)-induced inflammatory pain model and spared nerve injury (SNI)-induced neuropathic pain model. By using a quantitative polymerase chain reaction (qPCR), western blot, and immunostaining, we evaluated NaV1.8 expression after a noxious stimulation and the application of the TCF4 overexpression virus. We showed that the intrathecal delivery of TCF4 overexpression virus significantly repressed the increase of NaV1.8 and prevented the development of hyperalgesia in rats. Moreover, we confirmed the efficient role of an overexpressed TCF4 in preventing the CFA- and SNI-induced neuronal hyperexcitability by calcium imaging. Our results suggest that attenuating the dysregulation of NaV1.8 by targeting TCF4 may be a novel therapeutic strategy for chronic inflammatory and neuropathic pain.