Post-amputation pain causes great suffering to amputees, but still no effective drugs are available due to its elusive mechanisms. Our previous clinical studies found that surgical removal or radiofrequency treatment of the neuroma at the axotomized nerve stump effectively relieves the phantom pain afflicting patients after amputation. This indicated an essential role of the residual nerve stump in the formation of chronic post-amputation pain (CPAP). However, the molecular mechanism by which the residual nerve stump or neuroma is involved and regulates CPAP is still a mystery. In this study, we found that nociceptors expressed the mechanosensitive ion channel TMEM63A and macrophages infiltrated into the dorsal root ganglion (DRG) neurons worked synergistically to promote CPAP. Histology and qRT-PCR showed that TMEM63A was mainly expressed in mechanical pain-producing non-peptidergic nociceptors in the DRG, and the expression of TMEM63A increased significantly both in the neuroma from amputated patients and the DRG in a mouse model of tibial nerve transfer (TNT). Behavioral tests showed that the mechanical, heat, and cold sensitivity were not affected in the Tmem63a^-/- mice in the naïve state, suggesting the basal pain was not affected. In the inflammatory and post-amputation state, the mechanical allodynia but not the heat hyperalgesia or cold allodynia was significantly decreased in Tmem63a^-/- mice. Further study showed that there was severe neuronal injury and macrophage infiltration in the DRG, tibial nerve, residual stump, and the neuroma-like structure of the TNT mouse model, Consistent with this, expression of the pro-inflammatory cytokines TNF-α, IL-6, and IL-1β all increased dramatically in the DRG. Interestingly, the deletion of Tmem63a significantly reduced the macrophage infiltration in the DRG but not in the tibial nerve stump. Furthermore, the ablation of macrophages significantly reduced both the expression of Tmem63a and the mechanical allodynia in the TNT mouse model, indicating an interaction between nociceptors and macrophages, and that these two factors gang up together to regulate the formation of CPAP. This provides a new insight into the mechanisms underlying CPAP and potential drug targets its treatment.
Animals ; Mice ; Amputation, Surgical ; Chronic Pain/pathology* ; Disease Models, Animal ; Ganglia, Spinal/pathology* ; Hyperalgesia/etiology* ; Ion Channels/metabolism* ; Macrophages ; Neuroma/pathology*

OBJECTIVE: To investigate the relationship between bone marrow edema and pathological changes, symptoms and signs of severe knee osteoarthritis. METHODS: From January 2020 to March 2021, 160 patients with severe knee osteoarthritis who underwrent MRI of the knee at the Department of Bone and Joint, Wangjing Hospital, China Academy of Chinese Medical Sciences were included. Eighty patients with bone marrow edema were selected as the case group, including 12 males and 68 females, aged from 51 to 80 years old with an average of (66.58±8.10) years old, the duration of disease 5 to 40 months with an average of (15.61±9.25) months. Eighty patients without bone marrow edema were selected as the control group, including 15 males and 65 females, aged from 50 to 80 years old with an average of (67.82±8.05) years old, the duration of disease 6 to 37 months with an average of (15.75±8.18) months, BMI was (28.26±3.13) kg·m^-2 ranged from 21.39 to 34.46 kg·m^-2. The degree of bone marrow edema was evaluated by knee whole oragan magnetic resonance imaging score (WORMS). The degree of knee osteoarthritis was evaluated by Kellgren- Lawrence(K-L) grade and Western Ontario and McMaster University Osteoarthritis Index (WOMAC). The degree of joint pain was evaluated by visual analogue scale(VAS) and WOMAC pain score, the joint signs were evaluated by tenderness, percussion pain, joint swelling and joint range of motion. To explore the relationship between bone marrow edema and knee osteoarthritis, the prevalence of bone marrow edema and K-L grade were compared between the two groups. Furthermore the WORMS score and WOMAC index, pain-related score, and sign-related score correlation coefficient were analyzed to further explore the relationship between bone marrow edema and knee osteoarthritis index, joint pain symptoms and signs. RESULTS: There was 68.75% (55/80) of the patients in the case group were in K-L grade Ⅳ, and 52.5% (42/80) in the control group, indicating a higher proportion of patients with grade Ⅳ in the case group than the control group (χ²=4.425, P<0.05). In the case group, there was a strong correlation between bone marrow edema WORMS score and knee osteoarthritis WOMAC index. (r=0.873>0.8, P<0.001), a moderate correlation between WORMS score and VAS score and WOMAC pain score(r=0.752, 0.650>0.5, P<0.001), a moderate correlation between WORMS score and percussion pain score (r=0.784>0.5, P<0.001), and a weak correlation between WORMS score and VAS and tenderness score, joint swelling score and joint range of motion score (r=0.194, 0.259, 0.296<0.3, P<0.001). CONCLUSION Our study suggests that severe knee osteoarthritis is associated with an increased risk of bone marrow edema. Bone marrow edema can also lead to knee osteoarthritis joint pain, with percussion pain being a positive sign, but tenderness, joint swelling and limitation of activity are not significantly related to bone marrow edema.
Male ; Female ; Humans ; Osteoarthritis, Knee/pathology* ; Bone Marrow/pathology* ; Knee Joint/diagnostic imaging* ; Bone Marrow Diseases/etiology* ; Pain/pathology* ; Arthralgia ; Edema/pathology*

Central sensitization is essential in maintaining chronic pain induced by chronic pancreatitis (CP), but cortical modulation of painful CP remains elusive. Here, we examined the role of the anterior cingulate cortex (ACC) in the pathogenesis of abdominal hyperalgesia in a rat model of CP induced by intraductal administration of trinitrobenzene sulfonic acid (TNBS). TNBS treatment resulted in long-term abdominal hyperalgesia and anxiety in rats. Morphological data indicated that painful CP induced a significant increase in FOS-expressing neurons in the nucleus tractus solitarii (NTS) and ACC, and some FOS-expressing neurons in the NTS projected to the ACC. In addition, a larger portion of ascending fibers from the NTS innervated pyramidal neurons, the neural subpopulation primarily expressing FOS under the condition of painful CP, rather than GABAergic neurons within the ACC. CP rats showed increased expression of vesicular glutamate transporter 1, and increased membrane trafficking and phosphorylation of the N-methyl-D-aspartate receptor (NMDAR) subunit NR2B and the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) subunit GluR1 within the ACC. Microinjection of NMDAR and AMPAR antagonists into the ACC to block excitatory synaptic transmission significantly attenuated abdominal hyperalgesia in CP rats, which was similar to the analgesic effect of endomorphins injected into the ACC. Specifically inhibiting the excitability of ACC pyramidal cells via chemogenetics reduced both hyperalgesia and comorbid anxiety, whereas activating these neurons via optogenetics failed to aggravate hyperalgesia and anxiety in CP rats. Taken together, these findings provide neurocircuit, biochemical, and behavioral evidence for involvement of the ACC in hyperalgesia and anxiety in CP rats, as well as novel insights into the cortical modulation of painful CP, and highlights the ACC as a potential target for neuromodulatory interventions in the treatment of painful CP.
Animals ; Anxiety/etiology* ; Chronic Pain/etiology* ; GABAergic Neurons ; Gyrus Cinguli/metabolism* ; Hyperalgesia/metabolism* ; Pancreatitis, Chronic/pathology* ; Rats ; Rats, Sprague-Dawley ; Receptors, N-Methyl-D-Aspartate/metabolism* ; Trinitrobenzenesulfonic Acid/toxicity*

The study aimed to analyze the clinicopathological features, treatment, and prognosis factors of primary esophageal small-cell carcinoma (PESC). The clinical records and follow-up data of 100 patients with PESC were collected, and the clinicopathological features and treatments were examined. Log-rank test and Cox regression model were performed to identify the independent prognostic factors. Progressive dysphagia, weight loss, and abdominal pain were the most common initial symptoms in the 100 patients with PESC. The primary tumor site mainly occurred in the middle of the chest (51%, 51/100), and the ulcer type was the most common under gastroscope (31%, 31/100). One or more positive markers of epithelial origin were present in all of the enrolled patients. At the time of diagnosis, 80 cases had limited disease (LD) and 20 cases had extensive disease (ED). The 1-, 3-, and 5-year survival rates of PESC patients were 57.0%, 18.0%, and 11.0%, respectively, with a median survival time (MST) of 13.8 months. In all PESC patients, multivariate Cox regression analysis indicated that the significant prognostic factors included the lesion length (=2.661, <0.001), TNM staging (=1.464, =0.016), and treatment methods (=0.333, <0.001). Besides, in patients with LD, the lesion length (=2.638, =0.001) and treatment methods (=0.285, <0.001) were independent prognostic factors. The MST of patients in surgery + chemotherapy group (21.6 months) was longer than that of the surgery only group (8.3 months, =0.021), while patients in surgery+ chemotherapy+ radiotherapy group were also associated with a longer MST than the chemotherapy + radiotherapy group (31.0 months, 9.8 months, respectively; <0.001). PESC is a rare esophageal malignant tumor with poor prognosis. Our findings reveal that the lesion length, TNM staging, and treatment method are independent prognostic factors for PESC patients. Moreover, surgery-based comprehensive treatments may prolong the survival of patients with LD.
Abdominal Pain ; etiology ; Carcinoma, Small Cell ; mortality ; pathology ; surgery ; Deglutition Disorders ; etiology ; Esophageal Neoplasms ; mortality ; pathology ; surgery ; Esophagectomy ; Humans ; Neoplasm Staging ; Prognosis ; Retrospective Studies ; Survival Rate ; Weight Loss

ObjectiveTo evaluate the analgesic effect of intrarectal local anesthesia (IRLA) versus that of periprostatic nerve block anesthesia (PPNB) in initial transrectal ultrasound-guided prostate biopsy (TRUS-PB) for patients with different prostate volumes (PV).

METHODSA total of 253 patients undergoing initial TRUS-PB in our hospital from January 2014 to November 2017 were divided into three PV groups (<50 ml, 50－100 ml, and >100 ml), each again randomized into three subgroups (control, IRLA, and PPNB) with the random number table method. The pain during the procedure was assessed based on the Visual Analogue Scale (VAS) scores and the blind method was used by the biopsy operator, VAS valuator and data analyst.

RESULTSAmong the patients with PV <50 ml, the VAS scores in the blank control, IRLA, and PPNB subgroups were 4.39±0.87, 3.51±0.84 and 3.43±1.07, respectively, remarkably higher in the control than in the IRLA and PPNB groups (P<0.05), but with no statistically significant differences between the latter two (P>0.05). Among those with PV of 50－100 ml, the VAS scores in the three subgroups were 4.50±1.05, 4.38±1.13 and 3.38±1.44, respectively, markedly higher in the control and IRLA than in the PPNB group (P<0.05), but with no statistically significant differences between the former two groups (P>0.05). Among those with PV >100 ml, the VAS scores in the three subgroups were 5.19±1.05, 5.00±1.25 and 4.19±0.91, respectively, remarkably higher in the former two groups than in the latter (P<0.05), but with no statistically significant differences between the former two groups (P>0.05).

CONCLUSIONSEither IRLA or PPNB can be recommended for initial TRUS-PB in patients with PV <50 ml, PPNB for those with PV of 50－100 ml, and PPNB with other painkillers for those with PV >100 ml.

Administration, Rectal ; Aged ; Anesthesia, Local ; methods ; Anesthetics, Local ; administration & dosage ; Biopsy ; Humans ; Male ; Nerve Block ; methods ; Pain Measurement ; Pain, Procedural ; etiology ; prevention & control ; Prospective Studies ; Prostate ; pathology

Fluoxetine, an anti-depressant drug, has recently been shown to provide neuroprotection in central nervous system injury, but its roles in subarachnoid hemorrhage (SAH) remain unclear. In this study, we aimed to evaluate whether fluoxetine attenuates early brain injury (EBI) after SAH. We demonstrated that intraperitoneal injection of fluoxetine (10 mg/kg per day) significantly attenuated brain edema and blood-brain barrier (BBB) disruption, microglial activation, and neuronal apoptosis in EBI after experimental SAH, as evidenced by the reduction of brain water content and Evans blue dye extravasation, prevention of disruption of the tight junction proteins zonula occludens-1, claudin-5, and occludin, a decrease of cells staining positive for Iba-1, ED-1, and TUNEL and a decline in IL-1β, IL-6, TNF-α, MDA, 3-nitrotyrosine, and 8-OHDG levels. Moreover, fluoxetine significantly improved the neurological deficits of EBI and long-term sensorimotor behavioral deficits following SAH in a rat model. These results indicated that fluoxetine has a neuroprotective effect after experimental SAH.
Animals ; Apoptosis ; drug effects ; Blood-Brain Barrier ; drug effects ; Brain Edema ; drug therapy ; etiology ; Cytokines ; genetics ; metabolism ; Disease Models, Animal ; Fluoxetine ; pharmacology ; therapeutic use ; In Situ Nick-End Labeling ; Male ; Neuroprotective Agents ; pharmacology ; therapeutic use ; Pain Measurement ; Psychomotor Performance ; drug effects ; RNA, Messenger ; metabolism ; Rats ; Rats, Sprague-Dawley ; Subarachnoid Hemorrhage ; complications ; drug therapy ; pathology ; Time Factors ; Vasospasm, Intracranial ; drug therapy ; etiology

Injury to peripheral nerves can lead to neuropathic pain, along with well-studied effects on sensory neurons, including hyperexcitability, abnormal spontaneous activity, and neuroinflammation in the sensory ganglia. Neuropathic pain can be enhanced by sympathetic activity. Peripheral nerve injury may also damage sympathetic axons or expose them to an inflammatory environment. In this study, we examined the lumbar sympathetic ganglion responses to two rat pain models: ligation of the L5 spinal nerve, and local inflammation of the L5 dorsal root ganglion (DRG), which does not involve axotomy. Both models resulted in neuroinflammatory changes in the sympathetic ganglia, as indicated by macrophage responses, satellite glia activation, and increased numbers of T cells, along with very modest increases in sympathetic neuron excitability (but not spontaneous activity) measured in ex vivo recordings. The spinal nerve ligation model generally caused larger responses than DRG inflammation. Plasticity of the sympathetic system should be recognized in studies of sympathetic effects on pain.
Action Potentials ; physiology ; Animals ; Disease Models, Animal ; Female ; Ganglia, Sympathetic ; pathology ; Glial Fibrillary Acidic Protein ; metabolism ; Hyperalgesia ; etiology ; Ligation ; adverse effects ; Macrophages ; pathology ; Male ; Neurogenic Inflammation ; etiology ; Pain ; etiology ; pathology ; Patch-Clamp Techniques ; Peripheral Nerve Injuries ; complications ; Rats ; Rats, Sprague-Dawley ; Receptors, Antigen, T-Cell, alpha-beta ; metabolism

To investigate the behavioral and biomolecular similarity between neuralgia and depression, a trigeminal neuralgia (TN) mouse model was established by constriction of the infraorbital nerve (CION) to mimic clinical trigeminal neuropathic pain. A mouse learned helplessness (LH) model was developed to investigate inescapable foot-shock-induced psychiatric disorders like depression in humans. Mass spectrometry was used to assess changes in the biomolecules and signaling pathways in the hippocampus from TN or LH mice. TN mice developed not only significant mechanical allodynia but also depressive-like behaviors (mainly behavioral despair) at 2 weeks after CION, similar to LH mice. MS analysis demonstrated common and distinctive protein changes in the hippocampus between groups. Many protein function families (such as cell-to-cell signaling and interaction, and cell assembly and organization,) and signaling pathways (e.g., the Huntington's disease pathway) were involved in chronic neuralgia and depression. Together, these results demonstrated that the LH and TN models both develop depressive-like behaviors, and revealed the involvement of many psychiatric disorder-related biomolecules/pathways in the pathogenesis of TN and LH.
Animals ; Avoidance Learning ; physiology ; Brain-Derived Neurotrophic Factor ; metabolism ; Depression ; etiology ; pathology ; Disease Models, Animal ; Electroshock ; adverse effects ; Functional Laterality ; Helplessness, Learned ; Hindlimb Suspension ; psychology ; Hippocampus ; metabolism ; Male ; Mass Spectrometry ; Mice ; Mice, Inbred C57BL ; Orbit ; innervation ; Pain Measurement ; Proteomics ; methods ; Reaction Time ; physiology ; Signal Transduction ; physiology ; Trigeminal Neuralgia ; etiology ; pathology

Pain and itch are unpleasant sensations that often accompany infections caused by viral, bacterial, parasitic, and fungal pathogens. Recent studies show that sensory neurons are able to directly detect pathogens to mediate pain and itch. Nociceptor and pruriceptor neurons respond to pathogen-associated molecular patterns, including Toll-like receptor ligands, N-formyl peptides, and bacterial toxins. Other pathogens are able to silence neuronal activity to produce analgesia during infection. Pain and itch could lead to neuronal modulation of the immune system or behavioral avoidance of future pathogen exposure. Conversely, pathogens could modulate neuronal signaling to potentiate their pathogenesis and facilitate their spread to other hosts. Defining how pathogens modulate pain and itch has critical implications for sensory neurobiology and our understanding of host-microbe interactions.
Animals ; Humans ; Infection ; complications ; etiology ; pathology ; Neurons ; pathology ; Pain ; etiology ; pathology ; Pruritus ; etiology ; pathology

Postoperative internal hernia is a rare clinical complication which often occurs after digestive tract reconstruction. Roux-en-Y anastomosis is a common type of digestive tract reconstruction. Internal hernia after Roux-en-Y reconstruction, which occurs mainly in the mesenteric defect caused by incomplete closure of mesenteric gaps in the process of digestive tract reconstruction, is systematically called, in our research, as mesenteric internal hernia after Roux-en-Y reconstruction. Such internal hernia can be divided, according to the different structures of mesentric defect, into 3 types: the type of mesenteric defect at the jejunojejunostomy (J type), the type of Petersen's defect (P type), and the type of mesenteric defect in the transverse mesocolon (M type). Because of huge differences in the number of cases and follow-up time among existing research reports, the morbidity of internal hernia after LRYGB fluctuates wildly between 0.2% and 9.0%. Delayed diagnosis and treatment of mesenteric internal hernia after Roux- en-Y reconstruction may result in disastrous consequences such as intestinal necrosis. Clinical manifestations of internal hernia vary from person to person: some, in mild cases, may have no symptoms at all while others in severe cases may experience acute intestinal obstruction. Despite the difference, one common manifestation of internal hernia is abdominal pain. Surgical treatment should be recommended for those diagnosed as internal hernia. A safer and more feasible way to conduct the manual reduction of the incarcerated hernia is to start from the distal normal empty bowel and trace back to the hernia ring mouth, enabling a faster identification of hernia ring and its track. The prevention of mesenteric internal hernia after Roux-en-Y reconstruction is related to the initial surgical approach and the technique of mesenteric closure. Significant controversy remains on whether or not the mesenteric defect should be closed in laparoscopic Roux-en-Y anastomosis. This article is to review the reports and researches on internal hernia resulting from the mesenteric defect after Roux-en-Y digestive tract reconstruction in recent years, so as to promote understanding and attention on this disease. And more active preventive measures are strongly suggested to be taken in operations where digestive tract reconstruction is involved.
Abdominal Pain ; diagnosis ; Anastomosis, Roux-en-Y ; adverse effects ; methods ; Gastric Bypass ; adverse effects ; methods ; Hernia, Abdominal ; diagnosis ; etiology ; prevention & control ; surgery ; Humans ; Intestinal Obstruction ; etiology ; Intestine, Small ; pathology ; surgery ; Laparoscopy ; adverse effects ; methods ; Mesentery ; pathology ; surgery ; Mesocolon ; pathology ; surgery ; Postoperative Complications ; prevention & control ; surgery ; Reconstructive Surgical Procedures ; adverse effects ; methods ; Retrospective Studies