Inflammatory bowel disease produces debilitating visceral pain that remains a major clinical challenge. Notably, many patients experience persistent pain even after the inflammation resolves, indicating a sustained sensitization of central neural circuits that drives enduring pain. The brainstem parabrachial nucleus integrates interoceptive signals from the gastrointestinal tract to elicit both pain perception and affective responses. Using activity-dependent mapping and an RNAscope assay, we identified a neurotensin (NT)-expressing neuronal population in the lateral PBN (PBN L ) that is selectively activated during dextran sulfate sodium-induced colitis. In vivo neural activity recordings demonstrate that PBN L NT neurons encode colon-derived nociceptive signals in an intensity-dependent manner. Silencing these neurons attenuates colonic reflexes evoked by luminal distension and normalizes aberrant gastrointestinal transit and nociceptive licking behavior in colitic mice. Pharmacological blockade of NT signaling alleviates colitis-associated hypersensitivity. These findings identify a central neural population that encodes visceral inflammation and regulates peripheral organ function, and pinpoints neurotensin as a promising therapeutic target to treat colitis-induced visceral pain.

Abstract Background Knee osteoarthritis (KOA) is a leading cause of chronic disability in the elderly population. Although electroacupuncture (EA) has shown promising anti-inflammatory effects, the central neural mechanisms underlying its therapeutic efficacy remain incompletely elucidated. Methods A mouse model of KOA was established and treated with EA at the Zusanli (ST36) acupoint. Chemogenetic manipulation and fiber photometry recording were used to investigate the role of choline acetyltransferase (ChAT)-positive neurons in the dorsal motor nucleus of the vagus (DMV). Knee joint tissues were collected for histopathological evaluation using hematoxylin and eosin staining, Safranin O/Fast Green staining, and collagen II immunohistochemistry. Synovial levels of inflammatory cytokines (TNF-α, IL-1β, and IL-6) and dopamine (DA) were quantified by enzyme-linked immunosorbent assay (ELISA). Results EA at ST36 significantly alleviated cartilage damage and suppressed the upregulation of inflammatory cytokines in KOA mice. The DMV was identified as a key brain region responsive to EA stimulation, and activation of EA-responsive DMV neurons reproduced the therapeutic effects of EA. Furthermore, EA-responsive DMV neurons were found to be predominantly ChAT-positive, and chemogenetic inhibition of DMVChAT neurons abolished the anti-inflammatory effects of EA in KOA mice. Mechanistically, both EA treatment and activation of DMVChAT neurons were associated with increased DA release into the synovial tissue. Conclusions Our findings identify a central neural mechanism underlying the therapeutic effects of EA in KOA. Specifically, EA at ST36 activates DMVChAT neurons, which subsequently promote adrenal DA release, thereby inhibiting inflammatory cytokine production in the knee joint and alleviating KOA-associated inflammation. These findings provide novel insights into the central neural mechanisms through which EA exerts its therapeutic effects in KOA.

Various populations of spinal inhibitory neurons have been implicated in itch inhibition, but the precise mechanisms underlying tonic gating of itch and its inhibition by pain remain incompletely understood. Here, we identify a subset of inhibitory interneurons that uniquely express neurokinin receptor 3 (NK3R) in the spinal cord of mice. NK3R neurons receive monosynaptic input from Tac1+ sensory neurons, which release substance P (SP) and project directly to gastrin-releasing peptide receptor (GRPR)-expressing neurons that are dedicated to itch transmission. Silencing of NK3R inhibitory neurons disinhibits GRPR neurons and induces neuropathic itch, whereas their activation profoundly impairs itch but not pain transmission. These findings suggest that spinal NK3R inhibitory neurons serve as a pivotal and specific microcircuit for tonically gating of itch, and that the SP-NK3R-GRPR pathway may underlie the inhibition of itch by pain that activates the primary afferents to release SP onto the spinal cord.

Background Hepatic ischemia-reperfusion injury (HIRI) is a pathologic process commonly encountered during liver surgery, which seriously threatens patient prognosis. Currently, effective interventions or preventive measures are still lacking. Notably, patients with liver disease commonly experience brief acute stress prior to surgery; however, the impact of acute stress on HIRI remains unclear.Methods A 30-min restraint stress was used to simulate acute restraint stress (ARS). Hematoxylin-eosin staining and ELISA were employed to assess HIRI. Immunofluorescence staining and electrophysiology were applied to evaluate neuronal activation. Chemogenetic manipulation was utilized to verify the role of corticotropin-releasing hormone (CRH) neurons in the hypothalamic paraventricular nucleus (PVN) in ARS-mediated attenuation of HIRI.Results The results showed that ARS significantly ameliorated liver injury, reduced the liver enzyme levels (ALT and AST), and down-regulated the inflammatory factors expression in HIRI mice. Furthermore, we found that ARS alleviated HIRI by activating the hypothalamic-pituitary-adrenal (HPA) axis to release corticosterone, rather than through the sympathetic nervous system. PVNCRH represented a critical subpopulation responding to ARS. Chemogenetic activation of PVNCRH neurons mimicked the protective effect of ARS against HIRI, whereas chemogenetic inhibition of these neurons abolished this protection.Conclusion Our findings demonstrate that PVNCRH neurons mediate the protective effect of ARS against HIRI by activating the HPA axis to release corticosterone. This work may provide key insights for developing perioperative strategies to prevent HIRI.

Background Chronic inflammatory itch is sustained by reciprocal interactions among pruriceptive circuits, scratching-induced skin injury, immune-cell infiltration, and autonomic neuroimmune signaling. Spinal cord stimulation is known to reshape dorsal horn sensory processing, but whether it modulates neuroimmune inflammation during dermatitis-associated itch remains unclear. Methods Using acute pruritogen-evoked itch and DNFB-induced chronic dermatitis models in mice, we examined the effects of low- and high-frequency spinal cord stimulation on itch-like behavior, skin inflammation, spinal GRPR-associated neuronal activation, and sympathetic-associated neuroimmune changes. Activity-dependent FosTRAP2 labeling combined with chemogenetic activation or inhibition was used to test the functional contribution of the HF-SCS/TRAP-defined neuronal ensemble. Results Spinal cord stimulation reduced pruritogen-evoked licking/biting and chronic DNFB-associated itch-like behavior, accompanied by decreased epidermal hyperplasia, T-cell infiltration, and IL-1β/TNF-α-associated inflammatory signals in lesional skin. HF-SCS increased c-Fos activity within a prominent Pax2+ inhibitory neuronal component in the dorsal horn. Chemogenetic reactivation of the HF-SCS/TRAP-defined neuronal ensemble recapitulated the behavioral and cutaneous effects associated with SCS, whereas chemogenetic inhibition impaired the protective efficacy of stimulation. Spinal cord stimulation was also associated with reduced GRPR-related neuronal activation and Grpr expression. Anatomical tracing indicated an association between the HF-SCS/TRAP-defined neuronal ensemble and ChAT+ sympathetic preganglionic neurons, while HF-SCS was accompanied by reduced sympathetic-associated markers in skin and the spinal intermediolateral region. Conclusion These findings identify spinal cord stimulation as a preclinical neuromodulatory approach that attenuates dermatitis-associated itch and cutaneous neuroinflammation. The data support a functional contribution of the HF-SCS/TRAP-defined neuronal ensemble, which is enriched in Pax2+ inhibitory neurons, while the reductions in GRPR-related activity and sympathetic-associated signaling remain associative findings.

Dorsal root ganglion (DRG) neurons are responsible for the primary detection and transmission of peripheral noxious stimuli, mainly pain and itch. However, as two distinct noxious sensations, how DRG neurons respond differently to and code pain and itch is still an attractive topic. Here, we investigate the response and activation spectrum of DRG neurons under peripheral pain and itch stimuli using in vivo two-photon calcium imaging and find differences in the response intensity to pain and itch between multisensory neurons (both pain and itch) and single-sensory neurons (either pain or itch). In addition, single-cell RNA sequencing (scRNA-seq) is used to reveal the heterogeneity of distinct subpopulations on the basis of their expressions of pain-or itch-related marker genes and to determine the similarities and differences in theirtranscriptomic changes under chronic pain and itch. Our results show that primary sensory neurons with different sensory patterns respond differently to the same nociceptive stimuli. Additionally, distinct clusters of neurons exhibit unique transcriptomic changes in the development of chronic pain and itch, which may offer new insights for treating these conditions.

BACKGROUND:Depression has become a global public health problem. In recent years, transcranial magnetic stimulation (TMS) has gained considerable attention as a non-invasive treatment for depression. AIM:To investigate the research hotspots and trends in the field of TMS-based depression treatment from a bibliometric perspective. METHODS:Using the Web of Science Core Collection, articles published between 2003 and 2022 on TMS-based depression treatment were retrieved from the science citation index expanded. The publication trends and research hotspots were analyzed using VOSviewer, CiteSpace, and the bibliometric online analysis platform. Regression analysis was performed using Microsoft Excel 2021 to predict publication growth trends. RESULTS:We identified a total of 702 articles on TMS-based depression treatment with a predominance of clinical studies. Analysis of collaborative networks showed that the United States, the University of Toronto, and Daskalakis ZJ were identified as the most impactful country, institution, and researcher, respectively. In keyword burst analysis, it was found that theta burst stimulation (TBS), functional connectivity, and frequency were the most recent research hotspots. CONCLUSION:TMS provides a novel therapeutic option for patients with treatment-resistant depression. Neuroimaging technology enables more precise TMS treatment, while the novel TMS modality, TBS, enhances both therapeutic efficacy and patient experience in TMS-based depression treatment. The integration of neuroimaging techniques with TBS represents a promising research direction for advancing TMS-based depression treatment. This study presents systematic information and recommendations to guide future research on TMS-based depression treatment.

Background Hepatocellular carcinoma (HCC), the most common form of liver cancer, presents a challenging malignancy with scarce treatment options. Liver progenitor cells (LPCs) play a pivotal role in both liver regeneration and the progression of liver cancer, yet the specific functions of LPCs from different origins in liver cancer remain to be fully elucidated. Methods We explored the liver progenitor-like cells derived from human hepatocytes (HepLPCs) on the proliferation of HCC both in vitro and in vivo. The mitochondrial function was assessed through electron microscopy and functional experiments. Transcriptomic sequencing and western blot unveiled the fundamental mechanisms at play, whereas metabolomic sequencing pinpointed crucial effector molecules involved in the paracrine secretion of HepLPCs. Results By employing a co-culture system of HepLPCs and HCC cells, we found that HepLPCs markedly inhibited HCC growth by prompting mitochondrial dysfunction, which further led to the co-inhibition of the Notch1 and JAK1/STAT3 signaling pathways through paracrine actions involving S-adenosylmethionine (SAM) and Nicotinic acid (NA). Conclusions This study has uncovered that HepLPCs have a suppressive influence on the proliferation of HCC cells. This is achieved through the impairment of mitochondrial function and the inhibition of key signaling pathways, namely, Notch1 and JAK1/STAT3, which are critical drivers of cancer progression. The secretion of the metabolites SAM and NA by HepLPCs appears to be instrumental in mediating these effects. These findings provide a solid foundation for identifying new therapeutic targets and clarifying the mechanisms through which HepLPCs can be harnessed to effectively treat HCC.

Hepatocellular carcinoma (HCC), an incurable malignancy with limited therapeutic options, exhibits mitochondrial dysfunction upon co-treatment with S-adenosylmethionine (SAM) and nicotinic acid (NA); however, the underlying mechanisms were undefined. Transcriptomic analysis identified dysregulation of the solute carrier (SLC) family gene SLC25A4. Subsequent experiments confirmed that SAM-NA co-treatment upregulates SLC25A4 (ANT1) expression and nicotinamide adenine dinucleotide (NAD+) levels. Molecular docking and surface plasmon resonance (SPR) analyses suggest direct SLC25A4-NAD+ interaction. Elevated NAD+ activates sirtuin 1 (SIRT1) and AMP-activated protein kinase (AMPK), leading to remodeling of lipid metabolism. This remodeling impairs mitochondrial lipid transport and results in neutral lipid accumulation, thereby suppressing HCC proliferation. In situ xenograft models validate the safety of the treatment. This study proposes a stratified therapeutic approach: targeting the SLC25A4-NAD+-SIRT1-AMPK axis may benefit HCC patients with preserved SLC25A4 expression.

Metabolic dysfunction-associated steatohepatitis (MASH) is one of the most common chronic liver diseases worldwide, and specific treatment modalities are lacking. Accumulating evidence suggests that hepatic inflammation plays a key role in the progression from hepatic steatosis to MASH. Macrophages, especially anti-inflammatory macrophages, serve as natural immune cells that maintain homeostasis in the immune microenvironment. Here, we aimed to reveal the role of anti-inflammatory macrophages in MASH and investigate the underlying mechanism involved. Extracellular vesicles (EVs) were isolated from the supernatant of anti-inflammatory bone marrow-derived macrophages (BMDMs) by ultracentrifugation, and their protein profile was characterized by liquid chromatography–tandem mass spectrometry (LC‒MS/MS) analysis. Murine hepatocytes were stimulated with palmitic acid (PA) followed by treatment with EVs or oxysterol-binding protein-related protein 8 (ORP8/Osbpl8) shRNA. C57BL/6 mice were fed a methionine- and choline-deficient (MCD) diet for 3 weeks to establish MASH. The mice were then treated with EVs or shRNA-encoding AAV. In vitro and ex vivo experiments revealed that extracellular vesicles derived from anti-inflammatory BMDMs inhibited inflammatory responses and alleviated lipotoxicity during MASH. We identified Osbpl8 as a vital component of M2-BMDMs by LC–MS/MS analysis and found that Osbpl8 remodels lipid metabolism by inhibiting excessive IRE1α-XBP1-related ER stress. Furthermore, Osbpl8-enriched M2-BMDM-EVs promoted anti-inflammatory and antilipotoxic effects and could be a novel therapeutic target for the clinical treatment of MASH. Our findings indicate that Osbpl8 derived from EVs secreted by anti-inflammatory BMDMs plays important roles in intercellular communication between macrophages and hepatocytes, revealing a novel regulatory mechanism of macrophage homoeostasis in MASH.

Precise anesthesia is essential to ensure perioperative safety in patients with hepatic encephalopathy (HE) due to severe liver injuries. Hyperammonemia has been implicated as a possible trigger for HE. However, anesthetic sensitivity in HE and the role of hyperammonemia, in the context of anesthetic sensitivity of HE both remain uncertain. We injected male Sprague Dawley rats with thioacetamide (TAA) to induce acute HE. The time to lose and recover the righting reflex induced by either the inhalation anesthetic isoflurane or the intraperitoneal anesthetic propofol, as well as the 50

Hepatocyte-derived liver progenitor-like cells (HepLPCs) exhibit a remarkable capacity to support liver function by detoxifying ammonia, promoting native liver regeneration, and suppressing inflammation, which leads to improvements in the recovery and survival of animals with acute liver failure (ALF). However, the mechanism through which HepLPCs promote liver regeneration is unclear. Here, we isolated HepLPC-derived extracellular vesicles (HepLPC-EVs) from conditioned media and performed microRNA sequencing analysis. Our results showed HepLPC-EVs promoted liver regeneration in mice with carbon tetrachloride or acetaminophen induced ALF. Cell cycle progression and proliferation of primary human hepatocytes were promoted after coculture with HepLPC-EVs. Exosomal miRNA sequencing confirmed that HepLPC-EVs were enriched with miR-183-5p, which played an essential role in ameliorating ALF. Mechanistically, HepLPC-derived exosomal miR-183-5p negatively regulated the expression of the target gene FoxO1, activated the Akt/GSK3β/β-catenin signaling pathway, and thereby promoted liver regeneration and restoration of normal liver function. These results indicate that during ALF, HepLPC-Exos mediate liver regeneration mainly through a paracrine exosome-dependent mechanism and these effects accelerate liver regeneration and lead to the restoration of normal liver function.

AIMS:The parabrachial nucleus (PBN) promotes wakefulness states under general anesthesia. Recent studies have shown that glutamatergic neurons within the PBN play a crucial role in facilitating emergence from anesthesia. Our previous study indicates that vesicular glutamate transporter 2 (vglut2) expression neurons of the PBN extend into the extended amygdala (EA). However, the modulation of PBNvglut2-EA in general anesthesia remains poorly understood. This study aims to investigate the role of PBNvglut2-EA in alterations of consciousness during sevoflurane anesthesia. METHODS:We first validated vglut2-expressing neuron projections from the PBN to the EA using anterograde tracing. Then, we conducted immunofluorescence staining of c-Fos to investigate the role of the EA involved in the regulation of consciousness during sevoflurane anesthesia. After, we performed calcium fiber photometry recordings to determine the changes in PBNvglut2-EA activity. Lastly, we modulated PBNvglut2-EA activity under sevoflurane anesthesia using optogenetics, and electroencephalogram (EEG) was recorded during specific optogenetic modulation. RESULTS:The expression of vglut2 in PBN neurons projected to the EA, and c-Fos expression in the EA was significantly reduced during sevoflurane anesthesia. Fiber photometry revealed that activity in the PBNvglut2-EA pathway was suppressed during anesthesia induction but restored upon awakening. Optogenetic activation of the PBNvglut2-EA delayed the induction of anesthesia. Meanwhile, EEG recordings showed significantly decreased δ oscillations and increased β and γ oscillations compared to the EYFP group. Furthermore, optogenetic activation of the PBNvglut2-EA resulted in an acceleration of awakening from anesthesia, accompanied by decreased δ oscillations on EEG recordings. Optogenetic inhibition of PBNvglut2-EA accelerated anesthesia induction. Surprisingly, we found a sex-specific regulation of PBNvglut2-EA in this study. The activity of PBNvglut2-EA was lower in males during the induction of anesthesia and decreased more rapidly during sevoflurane anesthesia compared to females. Photoactivation of the PBNvglut2-EA reduced the sensitivity of males to sevoflurane, showing more pronounced wakefulness behavior and EEG changes than females. CONCLUSIONS:PBNvglut2-EA is involved in the promotion of wakefulness under sevoflurane anesthesia. Furthermore, PBNvglut2-EA shows sex differences in the changes of consciousness induced by sevoflurane anesthesia.

As the ability of liver regeneration is pivotal for liver disease patients, it will be of high significance and importance to identify the missing piece of the jigsaw influencing the liver regeneration. Here, we report that chronic stress impairs the liver regeneration capacity after partial hepatectomy with increased mortality in male mice. Anatomical tracing and functional mapping identified a neural circuit from noradrenergic neurons in the locus coeruleus (LC) to serotonergic neurons in the rostral medullary raphe region (rMR), which critically contributes to the inhibition of liver regeneration under chronic stress. In addition, hepatic sympathetic nerves were shown to be critical for the inhibitory effects on liver regeneration by releasing norepinephrine (NE), which acts on adrenergic receptor beta 2 (ADRB2) to block the proinflammatory macrophage activation. Collectively, we reveal a "brain-to-liver" neural connection that mediates chronic stress-evoked deficits in liver regeneration, thus shedding important insights into hepatic disease therapy. Whether and how chronic stress, often experienced by patients with chronic liver disease, affects liver regeneration remains mysterious. Here, authors show a "brain-to-liver" neural connection that mediates chronic stress-evoked deficits in liver regeneration.

Pain sensitivity varies depending on both the state and age of an individual. For example, chronic pain is more common in older individuals, but the underlying mechanisms remain unknown. This study revealed that 18-month-old mice (aged) experienced more severe and long-lasting allodynia and hyperalgesia in the chronic constriction injury (CCI)-induced pain state compared to 2-month-old mice. Interestingly, the aged mice had a higher baseline mechanical pain threshold than the adult mice. The expression of spinal receptor-active modification protein 1 (RAMP1), as a key component and regulator of the calcitonin gene-related peptide (CGRP) receptor for nociceptive transmission from the periphery to the spinal cord, was reduced in the physiological state but significantly increased after CCI in the aged mice compared to the adult mice. Moreover, when RAMP1 was knocked down using shRNA, the pain sensitivity of adult mice decreased significantly, and CCI-induced allodynia in aged mice was reduced. These findings suggest that spinal RAMP1 is involved in regulating pain sensitivity in a state- and age-dependent manner. Additionally, interfering with RAMP1 could be a promising strategy for alleviating chronic pain in older individuals.

Peripheral nerve injury (PNI) can transform primary somatosensory neurons to a regenerative state. However, the details of the transcriptomic changes associated with the nerve regeneration of somatosensory neurons remain unclear. In this study, single-cell RNA sequencing (scRNA-seq) is conducted on mouse dorsal root ganglion (DRG) cells after the early stage of nerve injury on day 3 after chronic constriction injury (CCI). We observe that a novel CCI-induced neuronal population (CIP) emerge and express high levels of activating transcription factor (Atf3), a neuronal injury marker. CIP neurons highly express regeneration-associated genes (RAGs) and are enriched in regeneration-related gene ontology (GO) terms, suggesting that these neurons can constitute a pro-regenerative population. Moreover, intercellular communication networks show that CIP neurons closely communicate with satellite glial cells (SGCs) and specifically transmit strong Fgf3- Fgfr1 signaling to SGCs, which could initiate regeneration-associated transcriptional changes in SGCs. We also confirm that regenerative progress occurs at the early stage of nerve injury because immunohistochemistry shows that the expression of ATF3 is significantly increased beginning at 3 days post-CCI and decreased at 1 month post-CCI. Our bioinformatics analysis at single-cell resolution advances the knowledge of regenerative dynamic transcriptional changes in DRG cells after injury and the underlying molecular mechanisms involved.

Itch is a somatosensory sensation to remove potential harmful stimulation with a scratching desire, which could be divided into mechanical and chemical itch according to diverse stimuli, such as wool fiber and insect biting. It has been reported that neuropeptide Y (NPY) neurons, a population of spinal inhibitory interneurons, could gate the transmission of mechanical itch, with no effect on chemical itch. In our study, we verified that chemogenetic activation of NPY neurons could inhibit the mechanical itch as well as the chemical itch, which also attenuated the alloknesis phenomenon in the chronic dry skin model. Afterwards, intrathecal administration of NPY1R agonist, [Leu31, Pro34]-NPY (LP-NPY), showed the similar inhibition effect on mechanical itch, chemical itch and alloknesis as chemo-activation of NPY neurons. Whereas, intrathecal administration of NPY1R antagonist BIBO 3304 enhanced mechanical itch and reversed the alloknesis phenomenon inhibited by LP-NPY treatment. Moreover, selectively knocking down NPY1R by intrathecal injection of Npy1r siRNA enhanced mechanical and chemical itch behavior as well. These results indicate that NPY neurons in spinal cord regulate mechanical and chemical itch, and alloknesis in dry skin model through NPY1 receptors.

Treating psoriasis presents a major clinical challenge because of the limitations associated with traditional topical glucocorticoid therapy. This study introduced a drug delivery system utilizing zinc-doped mesoporous silica nanoparticle (Zn-MSN) and microneedle (MN), designed to enhance drug utilization for prolonged anti-inflammatory and anti-itch effects. The MN system facilitated the transdermal delivery of betamethasone dipropionate (BD), allowing its slow release. The BD@Zn-MSN-MN system promoted the polarization of macrophages towards the anti-inflammatory M2 phenotype, achieving superior anti-inflammatory effects compared to the clinically used BD cream. Additionally, this study demonstrated that BD@Zn-MSN-MN could further alleviate itching in psoriasis-afflicted mice by decreasing the excitability of the transient receptor potential vanilloid V1 (TRPV1) ion channel positive neurons and reducing the release of calcitonin gene-related peptide (CGRP) in the dorsal root ganglion (DRG). These findings offer new insights and effective therapeutic options for the future design of transdermal drug delivery for psoriasis.

Our previous clinical trial showed that etomidate requirements to reach an appropriate level of anesthesia in patients with obstructive jaundice were reduced, which means that these patients are more sensitive to etomidate. However, the mechanism is still not completely clear. The present study was aimed to investigate the mechanism by which bilirubin facilitates etomidate induced sedation.A bile duct ligation (BDL) rat model was used to simulate obstructive jaundice. Anesthesia sensitivity to etomidate was determined by the time to loss of righting reflex (LORR). Intrathecal injection of bilirubin was used to test the effects of bilirubin on etomidate induced sedation. The modulating effects of bilirubin on GABA responses were studied using the whole-cell patch clamp technique.The time to LORR induced by etomidate was significantly decreased in the BDL groups (p < 0.05), and unconjugated bilirubin in serum and cerebrospinal fluid (CSF) were markedly increased (p < 0.05). The time to LORR induced by etomidate was decreased after intrathecal injection of bilirubin (p < 0.05). A bilirubin concentration of 1.0 μM increased the GABA-induced currents of rat cortical pyramidal neurons (p < 0.05). Furthermore, 1.0 μM bilirubin enhanced GABA-induced currents modulated by etomidate (p < 0.05).Our results demonstrated that pathologic bilirubin in CSF could enhance etomidate induced sedation. The mechanism may be that bilirubin increase the GABA-induced currents of rat pyramidal neurons.