Formalin-induced astrocyte glutamate-glutamine cycle involved in rat spinal cord central sensitization

BACKGROUND： Central sensitization, a state of increased excitability of nociceptive neurons in the spinal dorsal horn following peripheral tissue injury and/or inflammation, is an important mechanism underlying hyperalgesia and neuropathic pain. Participation of the glutamate-glutamine cycle in central sensitization of the spinal cord remains poorly understood. OBJECTIVE： To determine whether the astrocyte-neuronal glutamate-glutamine cycle is involved in formalin-induced central sensitization in the spinal cord. DESIGN, TIME AND SETTING： A randomized, controlled, animal experiment was performed at the Institute of Orthopedics, Second Hospital, Lanzhou University, China from September 2007 to August 2008. MATERIALS： Methionine sulfoximine （MSO, 0.1 mmol/L）, glutamine （0.25 mmol/L）, and formalin were used for this study. METHODS： A total of 43 male, Sprague Dawley rats, aged 4 months, were randomly assigned to a sham operation group （n = 6） and a model group （n = 37）. Rats in the model group received intrathecal infusion in the spinal cord. 7 days later, 37 model rats were randomly divided into PBS, MSO, glutamine, MSO ＋ glutamine and formalin subcutaneous injection alone groups. The PBS, MSO, glutamine, MSO ＋ glutamine groups were respectively intrathecally injected with PBS, MSO, glutamine, MSO ＋ glutamine （50 μL each）, and then infused with 10 μL of saline. Rats from the sham operation group were not subjected to intrathecal infusion in the spinal cord. At 15 minutes after intrathecal injection, a rat model of formalin-induced inflammatory pain was established by subcutaneous injection of 5% formalin （50 μL） in the left hindpaw. MAIN OUTCOME MEASURES： Changes in spontaneous nociceptive behavior （licking/biting or flinching） were observed following formalin injection into the rat hindpaw. RESULTS： Compared with the PBS group, duration of licking/biting was significantly shortened, and flinching frequency was significantly diminished in the MSO group （P 〈 0.05）. Compared with the MSO group, duration of licking/biting was significantly prolonged, and flinching frequency was significantly increased in the MSO ＋ glutamine group （P 〈 0.05）. There was no significant difference in inflammatory pain behaviors among the sham operation, PBS, glutamine, MSO ＋ glutamine, and formalin subcutaneous injection alone groups （P 〉 0.05）. CONCLUSION： The astrocyte-neuronal glutamate-glutamine cycle in the spinal cord was shown to be involved in central sensitization induced by formalin subcutaneous injection into the hindpaw.

Correlation between self-reported recovery and central sensitization in whiplash patients

Central sensitization has been associated with chronic pain in whiplash patients.Methods:Consecutive whiplash patients were assessed at 3 months post-whiplash injury with the brachial plexus provocation test(BPPT)as a sign of central sensitization.Self-reported recovery was assessed by the response to the question ‘Do you feel you have recovered fully from your accident injuries?'Results:Sixty-nine subjects(32 males,37 females,age 37.5±13.0 years(mean±SD),range 18-71)were included.Of these,34 reported a lack of recovery,and 35 reported recovery at 3 months post-injury.The mean BPPT elbow extension(from 180°)was 41.5±23.0°,and the mean VAS score for the BPPT was 2.2 ± 1.2(out of 10).Those who reported recovery had a mean BPPT elbow extension angle of 25.1±15.8 while those who did not report recovery had a mean BPPT angle of 58.4 ± 15.9(P＜0.05).The visual analogue scale(VAS)score for recovered subjects was 1.8 ± 1.1 and 2.7 ± 1.1(P＜0.05)for non-recovered.There was a moderate correlation between self-reported recovery and BPPT elbow extension angle(-0.44)and a lower correlation between self-reported recovery and VAS score(-0.30).Conclusion:Self-reported recovery correlates well with a lower likelihood of signs of central sensitization.Copyright(c)2012,Shanghai University of Sport.Production and hosting by Elsevier B.V.All rights reserved.

突发性聋患者中枢敏化因素分析及临床干预

目的探讨突发性聋的可能机制,以及中枢敏化因素临床干预在突发性聋患者中的应用分析。方法选取2020年1月~2023年1月在解放军总医院第三医学中心耳鼻咽喉头颈外科住院治疗且合并偏头痛或其他中枢敏化因素的37例突发性聋患者作为治疗组,随机选取同期无偏头痛及其他中枢敏化因素的30例突发性聋患者作为对照组。两组患者均参照突发性聋指南进行规范化分型治疗,对合并偏头痛或其他中枢敏化因素的患者进行抗偏头痛治疗,比较两组的治疗效果。结果治疗组总有效率为81.1%(30/37),其中痊愈13例、显效10例、有效7例、无效7例;对照组总有效率66.7%(20/30),其中痊愈6例、显效6例、有效8例、无效10例。治疗组痊愈及显效比例高于对照组,两组总有效率差异无统计学意义(χ^(2)=1.1364,P>0.05)。结论偏头痛是中枢敏化的一种表现形式,中枢敏化可能参与到一部分突发性聋患者的发病机制中,对突发性聋患者进行中枢敏化评估,合并偏头痛或其他中枢敏化因素的突发性聋患者可以考虑配合抗偏头痛药物进行治疗,有可能改善患者预后。

Systematic mechanism-orientated approach to chronic pancreatitis pain

Pain in chronic pancreatitis(CP) shows similarities with other visceral pain syndromes(i.e.,inflammatory bowel disease and esophagitis),which should thus be managed in a similar fashion.Typical causes of CP pain include increased intrapancreatic pressure,pancreatic inflammation and pancreatic/extrapancreatic complications.Unfortunately,CP pain continues to be a major clinical challenge.It is recognized that ongoing pain may induce altered central pain processing,e.g.,central sensitization or pro-nociceptive pain modulation.When this is present conventional pain treatment targeting the nociceptive focus,e.g.,opioid analgesia or surgical/endoscopic intervention,often fails even if technically successful.If central nervous system pain processing is altered,specific treatment targeting these changes should be instituted(e.g.,gabapentinoids,ketamine or tricyclic antidepressants).Suitable tools are now available to make altered central processing visible,including quantitative sensory testing,electroencephalograpy and(functional) magnetic resonance imaging.These techniques are potentially clinically useful diagnostic tools to analyze central pain processing and thus define optimum management approaches for pain in CP and other visceral pain syndromes.The present review proposes a systematic mechanism-orientated approach to pain management in CP based on a holistic view of the mechanisms involved.Future research should address the circumstances under which central nervous system pain processing changes in CP,and how this is influenced by ongoing nociceptive input and therapies.Thus we hope to predict which patients are at risk for developing chronic pain or not responding to therapy,leading to improved treatment of chronic pain in CP and other visceral pain disorders.

High-intensity swimming alleviates nociception and neuroinflammation in a mouse model of chronic postischemia pain by activating the resolvin E1-chemerin receptor 23 axis in the spinal cord

Physical exe rcise effectively alleviates chronic pain associated with complex regional pain syndrome type-Ⅰ.However,the mechanism of exe rcise-induced analgesia has not been clarified.Recent studies have shown that the specialized pro-resolving lipid mediator resolvin E1 promotes relief of pathologic pain by binding to chemerin receptor 23 in the nervous system.However,whether the resolvin E1-chemerin receptor 23 axis is involved in exercise-induced analgesia in complex regional pain syndrome type-Ⅰ has not been demonstrated.In the present study,a mouse model of chronic post-ischemia pain was established to mimic complex regional pain syndrome type-Ⅰ and subjected to an intervention involving swimming at different intensities.Chronic pain was reduced only in mice that engaged in high-intensity swimming.The resolvin E1-chemerin receptor 23 axis was clearly downregulated in the spinal cord of mice with chronic pain,while high-intensity swimming restored expression of resolvin E1 and chemerin receptor 23.Finally,shRNA-mediated silencing of chemerin receptor 23in the spinal cord reve rsed the analgesic effect of high-intensity swimming exercise on chronic post-ischemic pain and the anti-inflammato ry pola rization of microglia in the dorsal horn of the spinal cord.These findings suggest that high-intensity swimming can decrease chronic pain via the endogenous resolvin E1-chemerin receptor 23 axis in the spinal cord.

Emerging pharmacological strategies for the treatment of fibromyalgia

Fibromyalgia(FM) has been described as a chronic clinical condition related to multisensory hypersensitivitypresenting with a complex of symptoms dominated by chronic widespread pain associated with the existence of a range of co-morbidities, such as fatigue, sleep disturbance, cognitive impairment, anxiety and depression. Current treatments include drugs that target serotonin and noradrenaline levels within the central nervous system, e.g., tricyclic antidepressants, serotonin noradrenaline reuptake inhibitors, and voltage-gated calcium channel subunit ligands, e.g., gabapentin and pregabalin. Investigation of a range of novel targets, such as melatoninergic, cannabinoid, dopamine, NMDA, angiotensin, orexin and opioid receptors, and ion channels, in addition revisiting bioamine modulation and subunits has provided efficacy outcomes that improve the health status of patients with FM. Nevertheless, modest and limited efficacy is often observed reflecting the heterogeneity of FM with existence of subpopulations of patients, the contribution of peripheral and central components to the pathophysiology, and the extensive range of accompanying co-morbidities. The complexity and multidimensional nature of FM is emphasized by the diversity of pharmacological targets gaining interest. Clues to underlying mechanisms which offer themselves as novel and potential targets for new medications are being provided by advances in the understanding of the pathophysiology of FM.

Astroglial glutamate-glutamine cycle is involved in the modulation of inflammatory nociception in rats

Our previous behavioral studies have indicated that the astroglial glutamate-giutamine cycle is involved in the process of formalin-induced spinal cord central sensitization, but there was little morphological evidence. In this study, double-labeling immunofluorescence techniques showed that after rats were intrathecally injected with PBS and plantarly injected with formalin, glial fibrillary acidic protein （GFAP） and glutamine synthesase （GS） expression were increased and GFAP/GS coexpression was changed to include layers III and IV. After intrathecal injection of methionine sulfoximine, a GS specific inhibitor, the formalin-induced change in expression and coexpression of GFAP and GS in spinal cord dorsal horns was inhibited. The morphology, distribution and quantity of astrocytes recovered to normal levels. An intrathecal glutamine injection reversed the inhibitory effect of methionine sulfoximine. Astrocytes showed significant activation and distribution extended to layers V and VI. The present study provides morphological evidence that the astroglial glutamateglutamine cycle is involved in the process of formalin-induced spinal cord central sensitization.

TNF-αTNFR1 Signaling is Required for the Full Expression of Acute and Chronic Itch in Mice via Peripheral and Central Mechanisms

Increasing evidence suggests that cytokines and chemokines play crucial roles in chronic itch. In the present study, we evaluated the roles of tumor necrosis factor-alpha （TNF-c0 and its receptors TNF receptor subtype-I （TNFR1） and TNFR2 in acute and chronic itch in mice. Compared to wild-type （WT） mice, TNFRl-knockout （TNFR1-KO） and TNFR1/R2 double-KO （DKO）, but not TNFR2-KO mice, exhibited reduced acute itch induced by compound 48/80 and chloroquine （CQ）. Application of the TNF-synthesis inhibitor thalidomide and the TNF-at antagonist etanercept dose-dependently suppressed acute itch. Intradermal injection of TNF-α was not sufficient to evoke scratching, but potentiated itch induced by compound 48/80, but not CQ. In addition, compound 48/80 induced TNF-α mRNA expression in the skin, while CQ induced its expression in the dorsal root ganglia （DRG） and spinal cord. Furthermore, chronic itch induced by dry skin was reduced by administration of thalidomide and etaner- cept and in TNFR1/R2 DKO mice. Dry skin induced TNF- expression in the skin, DRG, and spinal cord and TNFR1 expression only in the spinal cord. Thus, our findings suggest that TNF-c^-fNFR1 signaling is required for the full expression of acute and chronic itch via peripheral and central mechanisms, and targeting TNFR1 may be benefi- cial for chronic itch treatment.

Recent advances in the understanding and management of chronic pancreatitis pain

Abdominal pain is the most common symptom of chronic pancreatitis(CP)and is often debilitating for patients and very difficult to treat.To date,there exists no cure for the disease.Treatment strategies focus on symptom management and on mitigation of disease progression by reducing toxin exposure and avoiding recurrent inflammatory events.Traditional treatment protocols start with medical management followed by consideration of procedural or surgical intervention on selected patients with severe and persistent pain.The incorporation of adjuvant therapies to treat comorbidities including psychiatric disorders,exocrine pancreatic insufficiency,mineral bone disease,frailty,and malnutrition,are in its early stages.Recent clinical studies and animal models have been designed to improve investigation into the pathophysiology of CP pain,as well as to improve pain management.Despite the array of tools available,many therapeutic options for the management of CP pain provide incomplete relief.There still remains much to discover about the neural regulation of pancreas-related pain.In this review,we will discuss research from the last 5 years that has provided new insights into novel methods of pain phenotyping and the pathophysiology of CP pain.These discoveries have led to improvements in patient selection for optimization of outcomes for both medical and procedural management,and identification of potential future therapies.

Regulatory effect of mild moxibustion on P2X3 receptors in spinal cord,anterior cingulate cortex and thalamic ventral posterolateral nucleus of rats with IBS visceral hyperalgesia

Objective To observe the therapeutic effect of mild moxibustion on irritable bowel syndrome(IBS)visceral hyperalgesia model rats and its regulatory effect on P2X3 receptors in the spinal cord,anterior cingutate cortex(ACC)and thalamic ventral posterolateral nucleus(VPL).Methods Thirty 8-day-old newborn rats were randomly divided into a normal group(n=6)and a modeling group(n=24)according to the completely random number table method.Rats in the normal group were bred routinely,and those in the modeling group were subjected to preparing IBS chronic visceral hyperalgesia model using colorectal distention(CRD)in stimulation method.Rats successfully modelled were re-divided into a model group,a mild moxibustion group,a P2X3 receptor antagonist group,and a normal saline group according to the completely random number table method with 6 rats in each group.Rats in each group received corresponding interventions from the 37-day old,once a day for 7 consecutive days.Immunohistochemistry and Western blot assays were used to detect P2X3 protein expressions in the spinal cord,ACC and VPL of rats.Results Under different intensities of CRD stimulation,the abdominal withdrawal reflex(AWR)scores of the model group were significantly increased versus the normal group(all P<0.05);the AWR scores of the mild moxibustion group and the P2X3 receptor antagonist group were significantly reduced versus the model group(all P<0.01).The P2X3 protein expressions in rat spinal cord,ACC and VPL tissues of the model group were significantly increased versus the normal group(all P<0.01);the P2X3 protein expressions in rat spinal cord,ACC and VPL tissues of the mild moxibustion group and the P2X3 receptor antagonist group were significantly reduced versus the model group(all P<0.01).Conclusion Mild moxibustion can inhibit the P2X3 receptor expressions in the spinal cord,ACC,and VPL tissues of IBS visceral hyperalgesia model rats,which may be the mechanism of mild moxibustion in relieving the central sensitization of rats with IBS visceral hyperalgesia.