Objective: To investigate the clinical characteristics and related factors of corticosteroid induced adrenal crisis (AC) in children with primary nephrotic syndrome (NS). Methods: Case control study. The case group included 7 children aged 1 to 18 years with NS combined with AC hospitalized in Peking University First Hospital from January 2016 to May 2021 (AC group). According to the ratio of case group: control group 1: 4, 28 children aged 1 to 18 years who were diagnosed with NS without AC during the same period were matched as controls (non-AC group). Clinical data were collected. The clinical characteristics of AC were described. The clinical parameters were compared between the 2 groups by t test, Mann-Whitney U test or Fisher's test. Receiver operating characteristic (ROC) curve was used to analyze the cutoff values of clinical parameters for prediction of AC. Results: The AC group included 4 boys and 3 girls aged 6.9 (4.6, 10.8) years. The non-AC group included 20 boys and 8 girls aged 5.2 (3.3, 8.4) years. All AC events occurred during the relapse of NS with infection. Seven children had gastrointestinal symptoms such as nausea, vomiting and abdominal pain. Six children had poor mental state or impaired consciousness. No significant differences in NS course, corticosteroid treatment course, corticosteroid type, steroid dosage, steroid medication interval, the proportion of gastroenteritis and fever existed between the two groups (all P>0.05). Compared with the non-AC group, the duration from the onset of the relapse of NS until hospitalization in the AC group was significantly shorter (0.2 (0.1, 0.6) vs. 1.0 (0.4, 5.0) month,U=25.50, P=0.005). The 24 h urinary total protein (UTP) level was significantly higher in the AC group (193 (135, 429) vs. 81 (17, 200) mg/kg, U=27.00,P=0.036) than the non-AC group. The serum albumin level in the AC group was significantly lower((13.1±2.1) vs. (24.5±8.7) g/L,t=-6.22,P<0.001) than the non-AC group. There were significantly higher total white blood cell counts ((26±9)×10⁹ vs. (11±5)×10⁹/L,t=4.26,P=0.004), percentage of neutrophils (0.71±0.08 vs. 0.60±0.19,t=2.56,P=0.017) and the proportion of children with C reactive protein level≥8 mg/L (3/7 vs. 0,P=0.005) in the AC group than in the non-AC group. ROC curve analysis showed that the cutoff value of 24 h UTP was 122 mg/(kg·d) with a sensitivity of 100.0% and specificity of 70.4%. The cutoff value of serum albumin was 17.0 g/L with a sensitivity of 100.0% and specificity of 82.1%. Conclusions: Gastrointestinal symptoms and poor mental state were prominent manifestations of AC in children with NS. High 24 h UTP level, low serum albumin level, high peripheral white blood cell counts, high neutrophils percentage, and high C-reactive protein level during the early stage of NS relapse may be related to the occurrence of AC in children with NS.
Nephrotic Syndrome/drug therapy* ; Humans ; Child ; Adolescent ; Male ; Female ; Gastrointestinal Diseases/diagnosis* ; Adrenal Cortex Hormones/therapeutic use* ; Nausea/chemically induced* ; Vomiting/chemically induced* ; Abdominal Pain/chemically induced* ; Mental Processes/drug effects* ; China

The pathophysiology of visceral pain in patients with irritable bowel syndrome remains largely unknown. Our previous study showed that neonatal maternal deprivation (NMD) does not induce visceral hypersensitivity at the age of 6 weeks in rats. The aim of this study was to determine whether NMD followed by adult stress at the age of 6 weeks induces visceral pain in rats and to investigate the roles of adrenergic signaling in visceral pain. Here we showed that NMD rats exhibited visceral hypersensitivity 6 h and 24 h after the termination of adult multiple stressors (AMSs). The plasma level of norepinephrine was significantly increased in NMD rats after AMSs. Whole-cell patch-clamp recording showed that the excitability of dorsal root ganglion (DRG) neurons from NMD rats with AMSs was remarkably increased. The expression of β adrenergic receptors at the protein and mRNA levels was markedly higher in NMD rats with AMSs than in rats with NMD alone. Inhibition of β adrenergic receptors with propranolol or butoxamine enhanced the colorectal distention threshold and application of butoxamine also reversed the enhanced hypersensitivity of DRG neurons. Overall, our data demonstrate that AMS induces visceral hypersensitivity in NMD rats, in part due to enhanced NE-β adrenergic signaling in DRGs.
Adrenergic Agents ; pharmacology ; Animals ; Ganglia, Spinal ; drug effects ; Hyperalgesia ; drug therapy ; physiopathology ; Hypersensitivity ; drug therapy ; Male ; Maternal Deprivation ; Neurons ; drug effects ; Patch-Clamp Techniques ; methods ; Rats, Sprague-Dawley ; Signal Transduction ; drug effects ; Stress, Physiological ; physiology ; Visceral Pain ; chemically induced ; metabolism

Investigation of pain requires measurements of nociceptive sensitivity and other pain-related behaviors. Recent studies have indicated the superiority of gait analysis over traditional evaluations (e.g., skin sensitivity and sciatic function index [SFI]) in detecting subtle improvements and deteriorations in animal models. Here, pain-related gait parameters, whose criteria include (1) alteration in pain models, (2) correlation with nociceptive threshold, and (3) normalization by analgesics, were identified in representative models of neuropathic pain (spared nerve injury: coordination data) and inflammatory pain (intraplantar complete Freund's adjuvant: both coordination and intensity data) in the DigiGait™ and CatWalk™ systems. DigiGait™ had advantages in fixed speed (controlled by treadmill) and dynamic SFI, while CatWalk™ excelled in intrinsic velocity, intensity data, and high-quality 3D images. Insights into the applicability of each system may provide guidance for selecting the appropriate gait imaging system for different animal models and optimization for future pain research.
Analgesics ; administration & dosage ; Animals ; Freund's Adjuvant ; administration & dosage ; Gait ; drug effects ; Gait Analysis ; methods ; Image Processing, Computer-Assisted ; Inflammation ; chemically induced ; Male ; Neuralgia ; physiopathology ; prevention & control ; Pain ; etiology ; physiopathology ; prevention & control ; Rats, Sprague-Dawley

Animals ; Cells, Cultured ; NAV1.8 Voltage-Gated Sodium Channel ; metabolism ; Pain ; chemically induced ; metabolism ; Proto-Oncogene Proteins c-akt ; metabolism ; Rats ; Scorpion Venoms ; pharmacology ; Up-Regulation

Accumulating evidence suggests that obesity is associated with chronic pain. However, whether obesity is associated with acute inflammatory pain is unknown. Using a well-established obese mouse model induced by a high-fat diet, we found that: (1) the acute thermal pain sensory threshold did not change in obese mice; (2) the model obese mice had fewer nociceptive responses in formalin-induced inflammatory pain tests; restoring the obese mice to a chow diet for three weeks partly recovered their pain sensation; (3) leptin injection induced significant phosphorylation of STAT3 in control mice but not in obese mice, indicating the dysmodulation of topical leptin-leptin receptor signaling in these mice; and (4) leptin-leptin receptor signaling-deficient mice (ob/ob and db/db) or leptin-leptin receptor pathway blockade with a leptin receptor antagonist and the JAK2 inhibitor AG 490 in wild-type mice reduced their nociceptive responses in formalin tests. These results indicate that leptin plays a role in nociception induced by acute inflammation and that interference in the leptin-leptin receptor pathway could be a peripheral target against acute inflammatory pain.
Animals ; Diet, High-Fat ; adverse effects ; Inflammation ; chemically induced ; metabolism ; Leptin ; metabolism ; pharmacology ; Male ; Mice ; Mice, Inbred C57BL ; Nociception ; drug effects ; physiology ; Nociceptive Pain ; etiology ; metabolism ; Obesity ; complications ; metabolism ; Pain Measurement ; Pain Threshold ; drug effects ; physiology ; Receptors, Leptin ; metabolism ; Signal Transduction ; drug effects ; physiology

Increasing evidence suggests that spinal microglia regulate pathological pain in males. In this study, we investigated the effects of several microglial and astroglial modulators on inflammatory and neuropathic pain following intrathecal injection in male and female mice. These modulators were the microglial inhibitors minocycline and ZVEID (a caspase-6 inhibitor) and the astroglial inhibitors L-α-aminoadipate (L-AA, an astroglial toxin) and carbenoxolone (a connexin 43 inhibitor), as well as U0126 (an ERK kinase inhibitor) and D-JNKI-1 (a c-Jun N-terminal kinase inhibitor). We found that spinal administration of minocycline or ZVEID, or Caspase6 deletion, reduced formalin-induced inflammatory and nerve injury-induced neuropathic pain primarily in male mice. In contrast, intrathecal L-AA reduced neuropathic pain but not inflammatory pain in both sexes. Intrathecal U0126 and D-JNKI-1 reduced neuropathic pain in both sexes. Nerve injury caused spinal upregulation of the astroglial markers GFAP and Connexin 43 in both sexes. Collectively, our data confirmed male-dominant microglial signaling but also revealed sex-independent astroglial signaling in the spinal cord in inflammatory and neuropathic pain.
2-Aminoadipic Acid ; toxicity ; Animals ; Anti-Inflammatory Agents ; therapeutic use ; Astrocytes ; pathology ; Carbenoxolone ; pharmacology ; Caspase 6 ; deficiency ; metabolism ; Connexin 43 ; metabolism ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Enzyme Inhibitors ; pharmacology ; Female ; Glial Fibrillary Acidic Protein ; metabolism ; Male ; Mice ; Mice, Transgenic ; Microglia ; pathology ; Minocycline ; therapeutic use ; Neuralgia ; chemically induced ; drug therapy ; pathology ; Pain Measurement ; Phenylurea Compounds ; pharmacology ; Sex Characteristics ; Spinal Cord ; pathology ; Time Factors

Recent studies have shown that the chemokine receptor CXCR3 and its ligand CXCL10 in the dorsal root ganglion mediate itch in experimental allergic contact dermatitis (ACD). CXCR3 in the spinal cord also contributes to the maintenance of neuropathic pain. However, whether spinal CXCR3 is involved in acute or chronic itch remains unclear. Here, we report that Cxcr3 mice showed normal scratching in acute itch models but reduced scratching in chronic itch models of dry skin and ACD. In contrast, both formalin-induced acute pain and complete Freund's adjuvant-induced chronic inflammatory pain were reduced in Cxcr3 mice. In addition, the expression of CXCR3 and CXCL10 was increased in the spinal cord in the dry skin model induced by acetone and diethyl ether followed by water (AEW). Intrathecal injection of a CXCR3 antagonist alleviated AEW-induced itch. Furthermore, touch-elicited itch (alloknesis) after compound 48/80 or AEW treatment was suppressed in Cxcr3 mice. Finally, AEW-induced astrocyte activation was inhibited in Cxcr3 mice. Taken together, these data suggest that spinal CXCR3 mediates chronic itch and alloknesis, and targeting CXCR3 may provide effective treatment for chronic pruritus.
Acetamides ; therapeutic use ; Animals ; Chemokine CXCL10 ; metabolism ; Chloroquine ; toxicity ; Chronic Disease ; Cyclopropanes ; adverse effects ; Dehydration ; complications ; Dinitrofluorobenzene ; adverse effects ; Disease Models, Animal ; Formaldehyde ; toxicity ; Freund's Adjuvant ; toxicity ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Motor Activity ; drug effects ; Pain ; chemically induced ; Pruritus ; chemically induced ; pathology ; Pyrimidines ; therapeutic use ; Receptors, CXCR3 ; antagonists & inhibitors ; genetics ; metabolism ; Skin ; pathology ; Spinal Cord ; drug effects ; metabolism ; pathology ; Time Factors ; p-Methoxy-N-methylphenethylamine ; toxicity

Mounting evidence supports an important role of chemokines, produced by spinal cord astrocytes, in promoting central sensitization and chronic pain. In particular, CCL2 (C-C motif chemokine ligand 2) has been shown to enhance N-methyl-D-aspartate (NMDA)-induced currents in spinal outer lamina II (IIo) neurons. However, the exact molecular, synaptic, and cellular mechanisms by which CCL2 modulates central sensitization are still unclear. We found that spinal injection of the CCR2 antagonist RS504393 attenuated CCL2- and inflammation-induced hyperalgesia. Single-cell RT-PCR revealed CCR2 expression in excitatory vesicular glutamate transporter subtype 2-positive (VGLUT2) neurons. CCL2 increased NMDA-induced currents in CCR2/VGLUT2 neurons in lamina IIo; it also enhanced the synaptic NMDA currents evoked by dorsal root stimulation; and furthermore, it increased the total and synaptic NMDA currents in somatostatin-expressing excitatory neurons. Finally, intrathecal RS504393 reversed the long-term potentiation evoked in the spinal cord by C-fiber stimulation. Our findings suggest that CCL2 directly modulates synaptic plasticity in CCR2-expressing excitatory neurons in spinal lamina IIo, and this underlies the generation of central sensitization in pathological pain.
Animals ; Benzoxazines ; pharmacology ; therapeutic use ; Chemokine CCL2 ; antagonists & inhibitors ; genetics ; metabolism ; pharmacology ; Excitatory Amino Acid Agents ; pharmacology ; Excitatory Amino Acid Agonists ; pharmacology ; Female ; Freund's Adjuvant ; toxicity ; Hyperalgesia ; chemically induced ; metabolism ; prevention & control ; Long-Term Potentiation ; drug effects ; physiology ; Luminescent Proteins ; genetics ; metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Myelitis ; chemically induced ; drug therapy ; metabolism ; Neurons ; drug effects ; Pain Management ; Somatostatin ; genetics ; metabolism ; Spinal Cord ; cytology ; Spiro Compounds ; pharmacology ; therapeutic use ; Vesicular Glutamate Transport Protein 2 ; genetics ; metabolism ; Vesicular Inhibitory Amino Acid Transport Proteins ; genetics ; metabolism

Bi-yuan-ling granule (BLG) is a traditional Chinese medicine compound composed mainly of baicalin and chlorogenic acid. It has been demonstrated to be clinically effective for various inflammatory diseases such as acute rhinitis, chronic rhinitis, atrophic rhinitis and allergic rhinitis. However, the underlying mechanisms of BLG against these diseases are not fully understood. This study aimed to explore the anti-inflammatory and analgesic activities of BLG, and examine its protective effects on mouse acute lung injury (ALI). The hot plate test and acetic acid-induced writhing assay in Kunming mice were adopted to evaluate the pain-relieving effects of BLG. The anti-inflammatory activities of BLG were determined by examining the effects of BLG on xylene-caused ear swelling in Kunming mice, the cotton pellet-induced granuloma in rats, carrageenan-induced hind paw edema and lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. The results showed that BLG at 15.5 mg/g could significantly relieve the pain by 82.5% (P<0.01) at 1 h after thermal stimulation and 91.2% (P<0.01) at 2 h after thermal stimulation. BLG at doses of 7.75 and 15.5 mg/g reduced the writhing count up to 33.3% (P<0.05) and 53.4% (P<0.01), respectively. Additionally, the xylene-induced edema in mice was markedly restrained by BLG at 7.75 mg/g (P<0.05) and 15.5 mg/g (P<0.01). BLG at 5.35 and 10.7 mg/g significantly reduced paw edema by 34.8% (P<0.05) and 37.9% (P<0.05) at 5 h after carrageenan injection. The granulomatous formation of the cotton pellet was profoundly suppressed by BLG at 2.68, 5.35 and 10.7 mg/g by 15.4%, 38.2% (P<0.01) and 58.9% (P<0.001), respectively. BLG also inhibited lung W/D ratio and the release of prostaglandin E2 (PGE2) in ALI mice. In addition, the median lethal dose (LD50), median effective dose (ED50) and half maximal inhibitory concentration (IC50) of BLG were found to be 42.7, 3.2 and 12.33 mg/g, respectively. All the findings suggest that BLG has significantly anti-inflammatory and analgesic effects and it may help reduce the damage of ALI.
Acetic Acid ; Acute Lung Injury ; chemically induced ; drug therapy ; pathology ; Analgesics ; pharmacology ; Animals ; Anti-Inflammatory Agents ; pharmacology ; Carrageenan ; administration & dosage ; Chlorogenic Acid ; pharmacology ; Dinoprostone ; antagonists & inhibitors ; biosynthesis ; Disease Models, Animal ; Dosage Forms ; Dose-Response Relationship, Drug ; Drugs, Chinese Herbal ; pharmacology ; Ear ; pathology ; Edema ; chemically induced ; drug therapy ; pathology ; Flavonoids ; pharmacology ; Lipopolysaccharides ; administration & dosage ; Male ; Mice ; Mice, Inbred Strains ; Pain ; chemically induced ; drug therapy ; physiopathology ; Rats ; Rats, Sprague-Dawley ; Xylenes ; administration & dosage

OBJECTIVETo investigate the therapeutic effect of acupoint injection of bee venom on collagen-induced arthritis (CIA) in rats and explore the mechanism of bee venom therapy in the treatment of rheumatoid arthritis.

METHODSFifteen male Wistar rats were randomly divided into bee venom treatment group (BV group), CIA model group, and control group. In the former two groups, CIA was induced by injections of collagen II+IFA (0.2 mL) via the tail vein, and in the control group, normal saline was injected instead. The rats in BV group received daily injection of 0.1 mL (3 mg/mL) bee venom for 7 consecutive days. All the rats were assessed for paw thickness and arthritis index from days 14 to 21, and the pain threshold was determined on day 21. The expressions of TRPV1 and TrkA in the dorsal root ganglion at the level of L4-6 were detected using immunohistochemistry and Western blotting, respectively.

RESULTSThe rats in CIA model group started to show paw swelling on day 10, and by day 14, all the rats in this group showed typical signs of CIA. In BV group, the rats receiving been venom therapy for 7 days showed a significantly smaller paw thickness and a low arthritis index than those in the model group. The pain threshold was the highest in the control group and the lowest in the model group. TRPV1-positive cells and TrkA expression in the dorsal root ganglion was significantly reduced in BV group as compared with that in the model group.

CONCLUSIONs Injection of bee venom can decrease expression of TRPV1 and TrkA in the dorsal root ganglion to produce anti-inflammatory and analgesic effects, suggesting the potential value of bee venom in the treatment of rheumatoid arthritis.

Analgesics ; pharmacology ; Animals ; Anti-Inflammatory Agents ; pharmacology ; Arthritis, Experimental ; chemically induced ; drug therapy ; Arthritis, Rheumatoid ; drug therapy ; Bee Venoms ; pharmacology ; Collagen ; Edema ; Ganglia, Spinal ; drug effects ; metabolism ; Injections ; Male ; Pain Threshold ; Random Allocation ; Rats ; Rats, Wistar ; Receptor, trkA ; metabolism ; TRPV Cation Channels ; metabolism