TRPC通道阻断剂SKF-96365对蜜蜂毒肽诱发初级感觉细胞内向电流和胞内钙增高的作用(英文)

目的蜜蜂毒肽是蜜蜂粗毒中的主要物质。外周皮下注射蜜蜂毒肽可导致持续性自发痛和痛觉过敏。本研究旨在研究瞬时受体电势C(transient receptor potential canonical,TRPC)通道在蜜蜂毒肽诱致的初级感觉神经元活化中的介导作用。方法运用全细胞膜片钳和激光共聚焦测钙技术,检测TRPC通道抑制剂SKF-96365对蜜蜂毒肽诱致的急性分离大鼠背根神经节细胞胞内钙和内向电流升高的影响。结果电压钳记录的91个背根神经节细胞中,蜜蜂毒肽可诱发43.9%(40/91)的细胞产生内向电流,而不同浓度的SKF-96365(1,5,10μmol/L)均明显抑制了背根神经节细胞的内向电流,且呈剂量相关性。应用激光共聚焦钙成像技术记录的210个背根神经节细胞中,67.6%的细胞对蜜蜂毒肽敏感,产生胞内钙离子浓度的升高,而SKF-96365能抑制这种胞内钙浓度的升高,抑制率为46.5%。结论 SKF-96365能够抑制蜜蜂毒肽引起的背根神经节中小神经元的活化,提示TRPC通道介导了蜜蜂毒肽对初级感觉神经元的激活作用。     

Endogenous Inhibition of the Nociceptive Flexion Reflex (NFR) and Pain Ratings During the Menstrual Cycle in Healthy Women

Background

The menstrual cycle influences pain, with symptoms often increasing during the premenstrual (late-luteal) phase. Deficiencies in endogenous inhibition of afferent nociception at the spinal level might contribute to menstrual phase-related changes in pain.

Purpose

This study assessed whether conditioned pain modulation (CPM) of spinal nociception differs between mid-follicular and late-luteal phases.

Methods

CPM was evoked by a blood pressure cuff affixed to the right forearm and inflated to induce ischemia in 41 healthy women during both menstrual phases. Suprathreshold electric stimuli were delivered to the left sural nerve to evoke pain and the nociceptive flexion reflex (NFR) before, during, and after forearm ischemia.

Results

Forearm ischemia produced CPM of electrocutaneous pain and NFR, but inhibition did not differ across mid-follicular and late-luteal phases.

Conclusions

Mechanisms contributing to changes in experimental pain across mid-follicular and late-luteal phases in healthy women are not due to deficits in CPM of spinal nociception.     

Emotional Modulation of Pain and Spinal Nociception in Persons with Severe Insomnia Symptoms

Background

Impaired sleep enhances pain, perhaps by disrupting pain modulation.

Purpose

Given that emotion modulates pain, the present study examined whether emotional modulation of pain and nociception is impaired in persons with severe insomnia symptoms relative to controls.

Methods

Insomnia group (n?=?12) met the International Classification of Diseases, tenth revision symptoms for primary insomnia and controls (n?=?13) reported no sleep impairment. Participants were shown emotionally evocative pictures (mutilation, neutral, and erotica) during which suprathreshold pain stimuli were delivered to evoke pain and the nociceptive flexion reflex (NFR; physiological correlate of spinal nociception).

Results

Emotional responses to pictures were similar in both groups, except that subjective valence/pleasure ratings were blunted in insomnia. Emotional modulation of pain and NFR was observed in controls, but only emotional modulation of NFR was observed in insomnia.

Conclusions

Consistent with previous findings, pain modulation is disrupted in insomnia, which might promote pain. This may stem from disrupted supraspinal circuits not disrupted brain-to-spinal cord circuits.     

Anticipatory activity in rat medial prefrontal cortex during a working memory task

Objective Working memory is a key cognitive function in which the prefrontal cortex plays a crucial role. This study aimed to show the firing patterns of a neuronal population in the prefrontal cortex of the rat in a working memory task and to explore how a neuronal ensemble encodes a working memory event.Methods Sprague-Dawley rats were trained in a Y-maze until they reached an 80%correct rate in a working memory task.Then a 16-channel microelectrode array was implanted in the prefrontal cortex.After recovery,neuronal population activity was recorded during the task, using the Cerebus data-acquisition system.Spatio-temporal trains of action potentials were obtained from the original neuronal population signals.Results During the Y-maze working memory task,some neurons showed significantly increased firing rates and evident neuronal ensemble activity.Moreover,the anticipatory activity was associated with the delayed alternate choice of the upcoming movement.In correct trials,the averaged pre-event firing rate(10.86±1.82 spikes/ bin) was higher than the post-event rate(8.17±1.15 spikes/bin)(P <0.05).However,in incorrect trials,the rates did not differ.Conclusion The results indicate that the anticipatory activity of a neuronal ensemble in the prefrontal cortex may play a role in encoding working memory events.     

Corticofugal influences on thalamic neurons during nociceptive transmission in awake rats

Pain is a multidimensional phenomenon and processed in a neural network. The supraspinal, brain mechanisms are increasingly recognized in playing a major role in the representation and modulation of pain. The aim of the current study is to investigate the functional interactions between cortex and thalamus during nociceptive processing, by observing the pain-related information flow and neuronal correlations within thalamo-cortical pathways. Pain-evoked, single-neuron activity was recorded in awake Sprague-Dawley rats with a Magnet system. Eight-wire microarrays were implanted into four different brain regions, i.e., the primary somatosensory (SI) and anterior cingulate cortex (ACC), as well as ventral posterior (VP) and medial dorsal thalamus (MD). Noxious radiant heat was delivered to the rat hind paws on the side contralateral to the recording regions. A large number of responsive neurons were recorded in the four brain areas. Directed coherence analysis revealed that the amount of information flow was significantly increased from SI cortex to VP thalamus following noxious stimuli, suggesting that SI cortex has descending influence on thalamic neurons during pain processing. Moreover, more correlated neuronal activities indicated by crosscorrelation histograms were found between cortical and thalamic neurons, with cortical neurons firing ahead of thalamic units. On basis of the above findings, we propose that nociceptive responses are modulated by corticothalamic feedback during nociceptive transmission, which may be tight in the lateral pathway, while loose in the medial pathway.     

Development of melanopsin-based irradiance detecting circuitry

Background

Neuronal phenotypes associated with hemizygosity of individual genes within the 22q11.2 deletion syndrome locus hold potential towards understanding the pathogenesis of schizophrenia and autism. Included among these genes is Dgcr8, which encodes an RNA-binding protein required for microRNA biogenesis. Dgcr8 haploinsufficient mice (Dgcr8+/-) have reduced expression of microRNAs in brain and display cognitive deficits, but how microRNA deficiency affects the development and function of neurons in the cerebral cortex is not fully understood.

Results

In this study, we show that Dgcr8+/- mice display reduced expression of a subset of microRNAs in the prefrontal cortex, a deficit that emerges over postnatal development. Layer V pyramidal neurons in the medial prefrontal cortex of Dgcr8+/- mice have altered electrical properties, decreased complexity of basal dendrites, and reduced excitatory synaptic transmission.

Conclusions

These findings demonstrate that precise microRNA expression is critical for the postnatal development of prefrontal cortical circuitry. Similar defects in neuronal maturation resulting from microRNA deficiency could represent endophenotypes of certain neuropsychiatric diseases of developmental onset.     

Transient Amnesia After Coiling of a Posterior Circulation Aneurysm

Background

Acute amnesia can be caused by medication effect, transient global amnesia, ischemia, metabolic abnormalities, and seizures.

Methods

Case report.

Results

A 56-year-old woman developed acute amnesia resembling transient global amnesia (TGA) after aneurysm coiling. She was started on abciximab for possible thromboembolic complications related to coiling. Abciximab was discontinued after she developed chest pain. Her chest pain resolved after discontinuing abciximab. She was subsequently found to have small medial temporal lobe strokes on diffusion weighted MRI.

Conclusions

Ischemia in the posterior circulation should be considered in the differential diagnosis of TGA, especially in situations predisposing to thromboembolism such as coiling.     

Effects of multiple intrathecal administration of L-arginine with different doses on formalin-induced nociceptive behavioral responses in rats

Objective

To investigate the effects of nitric oxide (NO) with different doses on modulation of inflammatory pain, and its possible mechanisms.

Methods

NO precursor L-arginine (L-Arg) was intrathecally administered in rats at a dose of 10 μg per day (low dose group) or 250 μg per day (high dose group) for a succession of 4 d. Normal saline was applied as a control. Then the rats were subcutaneously injected with formalin (100 μL, 2%) into the right hindpaw, and the nociceptive behavioral responses within 1 h were observed. At 4 h after formalin injection, neuronal NO synthase (nNOS) and c-Fos expression in spinal dorsal horn was examined with immunocytochemistry method.

Results

The subcutaneous injection of formalin evoked biphasic behaviors of licking or biting the injected paw. There was no difference in acute phase of formalin test among the 3 groups, while in tonic phase, the licking and biting time, and the protein levels of nNOS and c-Fos in spinal dorsal horn were significantly decreased in low dose group and increased in high dose group, compared with those in control group.

Conclusion

These results suggest that multiple administration of NO with different doses may produce different effects. On one hand, the low dose of NO can induce antinociception. On the other hand, the high dose of NO can induce pronociception.     

Avoidance of Activities in Early Symptomatic Knee Osteoarthritis: Results from the CHECK Cohort

Background

Pain-related avoidance of activities is hypothesized to lead to lower muscle strength and thereby activity limitations. Negative affect (e.g., low vitality, depression) is thought to strengthen the tendency to avoid activities.

Purpose

The aim of this study was to assess the validity of this ??avoidance model?? in patients with early symptomatic knee osteoarthritis (OA).

Methods

Cross-sectional data (n?=?151) were used. The associations between pain, negative affect, avoidance, muscle strength, and activity limitations were modeled using structural equation modeling.

Results

Pain and negative affect were associated with lower muscle strength via avoidance (mediation by avoidance). Avoidance was associated with activity limitations via lower muscle strength (mediation by muscle strength). There were also direct associations between pain, negative affect, avoidance, muscle strength, and activity limitations.

Conclusions

The results support the validity of the avoidance model, which explains the associations between pain, negative affect, avoidance, muscle strength, and activity limitations in patients with early symptomatic knee OA.     

Site- and stage-dependent differences in vascular density of the human fetal brain

Background and purpose

Less information is available about site-dependent differences in fetal intrabrain angiogenesis. Quantitative evaluation is especially limited, with the measured area limited to the cerebral gray and white matters and the periventricular germinal matrix.

Patients and methods

We measured vascular density (number of vessels per square millimeter) and percent vascular area (percentage of areas occupied by vessels) of CD34-positive microvessels in 14 human fetal brains, including 4 fetuses at 14–16 weeks of gestation, 5 at 25–28 weeks, and 5 at 35–37 weeks. Site-dependent differences were examined among the cerebral cortex, thalamus, internal capsule, corpus callosum, ganglionic eminence, midbrain, and cerebellar cortex and nuclei.

Results

The parameters examined tended to be high in the cerebral germinal matrix, thalamus, midbrain, and cerebellum. Significant site-dependent differences were observed: lower vascular densities were observed in the internal capsule and corpus callosum than in other parts of the brain (p?<?0.05) and a larger percent area was observed in the cerebellar nuclei than in other areas. Vascular density was higher during the early than late stage because of the larger numbers of CD34-positive islands of cells in the early stage, although there were several exceptions. Percent area was not stage dependent but was almost constant at many sites.

Conclusion

Consequently, except for developing nuclei, the prenatal development of intrabrain vessels after 15 weeks may proceed without any significant changes in density.     

Sevoflurane exposure in 7-day-old rats affects neurogenesis, neurodegeneration and neurocognitive function

Objective Sevoflurane is widely used in pediatric anesthesia and former studies showed that it causes neurodegeneration in the developing brain. The present study was carried out to investigate the effects of sevoflurane on neurogenesis, neurodegeneration and behavior. Methods We administered 5-bromodeoxyuridine, an S-phase marker, before, during, and after 4 h of sevoflurane given to rats on postnatal day 7 to assess dentate gyrus progenitor proliferation and Fluoro-Jade staining for degeneration. Spatial reference memory was tested 2 and 6 weeks after anesthesia. Results Sevoflurane decreased progenitor proliferation and increased cell death until at least 4 days after anesthesia. Spatial reference memory was not affected at 2 weeks but was affected at 6 weeks after sevoflurane administration. Conclusion Sevoflurane reduces neurogenesis and increases the death of progenitor cells in developing brain. This might mediate the lateonset neurocognitive outcome after sevoflurane application.     

Stress-Related Clinical Pain and Mood in Women with Chronic Pain: Moderating Effects of Depression and Positive Mood Induction

Background

Chronic pain with comorbid depression is characterized by poor mood regulation and stress-related pain.

Purpose

This study aims to compare depressed and non-depressed pain patients in mood and pain stress reactivity and recovery, and test whether a post-stress positive mood induction moderates pain recovery.

Methods

Women with fibromyalgia and/or osteoarthritis (N?=?110) underwent interpersonal stress and were then randomly assigned by pain condition and depression status, assessed via the Center for Epidemiological Studies-Depression scale, to positive versus neutral mood induction.

Results

Depression did not predict stress-related reactivity in despondency, joviality, or clinical pain. However, depression × mood condition predicted recovery in joviality and clinical pain; depressed women recovered only in the positive mood condition, whereas non-depressed women recovered in both mood conditions.

Conclusions

Depression does not alter pain and mood stress reactivity, but does impair recovery. Boosting post-stress jovial mood ameliorates pain recovery deficits in depressed patients, a finding relevant to chronic pain interventions.     

Pain Hypervigilance is Associated with Greater Clinical Pain Severity and Enhanced Experimental Pain Sensitivity Among Adults with Symptomatic Knee Osteoarthritis

Background

Pain hypervigilance is an important aspect of the fear-avoidance model of pain that may help explain individual differences in pain sensitivity among persons with knee osteoarthritis (OA).

Purpose

The purpose of this study was to examine the contribution of pain hypervigilance to clinical pain severity and experimental pain sensitivity in persons with symptomatic knee OA.

Methods

We analyzed cross-sectional data from 168 adults with symptomatic knee OA. Quantitative sensory testing was used to measure sensitivity to heat pain, pressure pain, and cold pain, as well as temporal summation of heat pain, a marker of central sensitization.

Results

Pain hypervigilance was associated with greater clinical pain severity, as well as greater pressure pain. Pain hypervigilance was also a significant predictor of temporal summation of heat pain.

Conclusions

Pain hypervigilance may be an important contributor to pain reports and experimental pain sensitivity among persons with knee OA.     

Salivary Cortisol and Cold Pain Sensitivity in Female Twins

Background

There is a dearth of knowledge about the link between cortisol and pain sensitivity.

Purpose

We examined the association of salivary cortisol with indices of cold pain sensitivity in 198 female twins and explored the role of familial confounding.

Methods

Three-day saliva samples were collected for cortisol levels and a cold pressor test was used to collect pain ratings and time to threshold and tolerance. Linear regression modeling with generalized estimating equations examined the overall and within-pair associations.

Results

Lower diurnal variation of cortisol was associated with higher pain ratings at threshold (p?=?0.02) and tolerance (p?<?0.01). The relationship of diurnal variation with pain ratings at threshold and tolerance was minimally influenced by familial factors (i.e., genetics and common environment).

Conclusions

Understanding the genetic and non-genetic mechanisms underlying the link between HPA axis dysregulation and pain sensitivity may help to prevent chronic pain development and maintenance.     

Fear-Avoidance,Pain Acceptance and Adjustment to Chronic Pain: A Cross-Sectional Study on a Sample of 686 Patients with Chronic Spinal Pain

Background

Prior studies found a range of psychological factors related to the perception of pain, maintenance of pain and disability.

Purpose

The aim of this study was to investigate the role of pain fear-avoidance and pain acceptance in chronic pain adjustment. The influence of two diathesis variables (resilience and experiential avoidance) was also analyzed.

Methods

The sample was composed of 686 patients with chronic spinal pain. Structural equation modelling analyses were used to test the hypothetical model.

Results

Experiential avoidance was associated with pain fear-avoidance, and resilience was strongly associated with pain acceptance. Pain acceptance was negatively associated with negative mood, functional impairment and pain intensity. However, pain fear-avoidance was positively and significantly associated with negative mood but had no association with pain intensity. There was a path from functional impairment to pain fear-avoidance.

Conclusions

Resilience and experiential avoidance appear as variables which could explain individual differences in pain experience.     

Pain Fear Avoidance and Pain Acceptance: A Cross-Sectional Study Comparing Their Influence on Adjustment to Chronic Pain Across Three Samples of Patients

Background

Prior studies found that pain fear avoidance and pain acceptance are significantly associated with adjustment to chronic pain.

Purpose

The purpose of this study is to compare the influence of pain fear avoidance and pain acceptance on adjustment to chronic pain across three samples: patients with chronic back pain treated at primary care centres, patients with heterogeneous pain conditions treated at a pain clinic and patients with pain associated with inflammatory bowel disease.

Methods

Structural equation modelling was used to test for differences between groups in the linear relationships between variables.

Results

The model had the best fit for the group of patients with back pain. Three significant relationships were equal across the groups: experiential avoidance on pain fear avoidance, pain intensity on pain fear avoidance, and pain fear avoidance on negative mood.

Conclusions

The associations between both pain fear avoidance and pain acceptance and adjustment to chronic pain vary depending on the pain condition and the type of health care centres where the patients are treated.     

Identifying neuropathic pain in patients with multiple sclerosis: a cross-sectional multicenter study using highly specific criteria

Background

Pain is a common and heterogeneous complication of multiple sclerosis (MS). In this multicenter, cross sectional study, we aimed at investigating the prevalence of pain in MS using highly specific criteria for distinguishing the different types of pain.

Materials and methods

After a structured interview, in patients with pain, clinical examination and DN4 questionnaire were used for distinguishing neuropathic and nociceptive pain. In subjects with neuropathic pain, the Neuropathic Pain Symptom Inventory was used for differentiating neuropathic pain symptoms.

Results

We enrolled 1249 participants (832 F, 417 M, mean age 33.9 years, mean disease duration 8 years, mean EDSS 3.2); based on clinical evaluation and DN4 score 429 patients (34.34%) were classified with pain (470 pain syndromes): 286 nociceptive pain syndromes and 184 neuropathic pain syndromes. Multivariate analysis showed that pain was associated with age, gender and disease severity and that neuropathic pain was distinctly associated with EDSS.

Conclusions

Our study, providing definite information on the prevalence, characteristics and variables associated with neuropathic pain due to MS, shows that a more severe disease course is associated with a higher risk of neuropathic pain. Our findings might, therefore, provide a basis for improving the clinical management of this common MS complication.

     

An investigation of factors associated with psychiatric hospital admission despite the presence of crisis resolution teams

Background

Evidence suggests that white matter integrity may play an underlying pathophysiological role in schizophrenia. N-acetylaspartate (NAA), as measured by Magnetic Resonance Spectroscopy (MRS), is a neuronal marker and is decreased in white matter lesions and regions of axonal loss. It has also been found to be reduced in the prefrontal and temporal regions in patients with schizophrenia. Diffusion Tensor Imaging (DTI) allows one to measure the orientations of axonal tracts as well as the coherence of axonal bundles. DTI is thus sensitive to demyelination and other structural abnormalities. DTI has also shown abnormalities in these regions.

Methods

MRS and DTI were obtained on 42 healthy subjects and 40 subjects with schizophrenia. The data was analyzed using regions of interests in the Dorso-Lateral Prefrontal white matter, Medial Temporal white matter and Occipital white matter using both imaging modalities.

Results

NAA was significantly reduced in the patient population in the Medial Temporal regions. DTI anisotropy indices were also reduced in the same Medial Temporal regions. NAA and DTI-anisotropy indices were also correlated in the left medial temporal region.

Conclusion

Our results implicate defects in the medial temporal white matter in patients with schizophrenia. Moreover, MRS and DTI are complementary modalities for the study of white matter disruptions in patients with schizophrenia.     

Oxidative damage increased in presenilin1/presenilin2 conditional double knockout mice

Objective

This report aims to describe the oxidative damage profile in brain of presenilin1 and presenilin2 conditional double knockout mice (dKO) at both early and late age stages, and to discuss the correlation between oxidative stress and the Alzheimer-like phenotypes of dKO mice.

Methods

The protein level of Aβ₄₂ in dKO cortex and free 8-OHdG level in urine were measured by ELISA. Thiobarbituric acid method and spectrophotometric DNPH assay were used to determine the lipid peroxidation and protein oxidation in cortex, respectively. SOD and GSH-PX activities were assessed by SOD Assay Kit-WST and GSH-PX assay kit, separately.

Results

Significant decrease of Aβ₄₂ was verified in dKO cortex at 6 months as compared to control mice. Although lipid peroxidation (assessed by MDA) was increased only in dKO cortex at 3 months and protein oxidation (assessed by carbonyl groups) was basically unchanged in dKO cortex, ELISA analysis revealed that free 8-OHdG, which was an indicator of DNA lesion, was significantly decreased in urine of dKO mice from 3 months to 12 months. Activities of SOD and GSH-PX in dKO and control cortices showed no statistical difference except a significant increase of GSH-PX activity in dKO mice at 9 months.

Conclusion

Oxidative damage, especially DNA lesion, was correlated with the neurodegenerative symptoms that appeared in dKO mice without the deposition of Aβ₄₂. Triggers of oxidative damage could be the inflammatory mediators released by activated microglia and astrocytes.     

Stress-Induced Neuronal Colony Stimulating Factor 1 Provokes Microglia-Mediated Neuronal Remodeling and Depressive-like Behavior

Background

Chronic stress exposure causes neuronal atrophy and synaptic deficits in the medial prefrontal cortex (PFC), contributing to development of anxiety- and depressive-like behaviors. Concomitantly, microglia in the PFC undergo morphological and functional changes following stress exposure, suggesting that microglia contribute to synaptic deficits underlying behavioral consequences.