• AdorA2B
• Lactobacillus murinus
• irritable bowel syndrome with diarrhea
• spermidine
• stress
• type I interferon
• xanthine

• Irritable Bowel Syndrome/metabolism
• Diarrhea/metabolism
• Spermidine/pharmacology
• Spermidine/metabolism
• Animals
• Humans
• Male
• Stress, Psychological/complications
• Stress, Psychological/metabolism
• Mice, Inbred C57BL
• Interferon Type I/metabolism
• Mice
• Dendritic Cells/metabolism

• angiogenesis
• atherosclerosis
• chronic obstructive pulmonary disease (COPD)
• gasotransmitter
• heart failure
• hydrogen sulfide
• hypertension
• pain
• reproduction
• therapeutic

• 82090014 National Natural Science Foundation of China

• Gastrointestinal tract
• H2S
• Microorganisms
• Treatment

Chronic visceral pain is one of the primary symptoms of patients with irritable bowel syndrome (IBS), which affects up to 15% of the population world-wide. The detailed mechanisms of visceral pain remain largely unclear. Our previous studies have shown that neonatal maternal deprivation (NMD) followed by adult multiple stress (AMS) advances the occurrence of visceral pain, likely due to enhanced norepinephrine (NE)-β₂ adrenergic signaling. This study was designed to explore the roles of P2X3 receptors (P2X3Rs) in the chronic visceral pain induced by combined stress. Here, we showed that P2X3Rs were co-expressed in β₂ adrenergic receptor (β₂-AR)-positive dorsal root ganglion neurons and that NE significantly enhanced ATP-induced Ca²⁺ signals. NMD and AMS not only significantly increased the protein expression of P2X3Rs, but also greatly enhanced the ATP-evoked current density, number of action potentials, and intracellular Ca²⁺ concentration of colon-related DRG neurons. Intrathecal injection of the P2X3R inhibitor A317491 greatly attenuated the visceral pain and the ATP-induced Ca²⁺ signals in NMD and AMS rats. Furthermore, the β₂-AR antagonist butoxamine significantly reversed the expression of P2X3Rs, the ATP-induced current density, and the number of action potentials of DRG neurons. Overall, our data demonstrate that NMD followed by AMS leads to P2X3R activation, which is most likely mediated by upregulation of β₂ adrenergic signaling in primary sensory neurons, thus contributing to visceral hypersensitivity.

• Dorsal root ganglion
• Irritable bowel syndrome
• P2X3 receptor
• Stress
• Visceral hypersensitivity
• β2 adrenergic receptor

Na_v1.7 is closely associated with neuropathic pain. Hydrogen sulfide (H₂S) has recently been reported to be involved in numerous biological functions, and it has been shown that H₂S can enhance the sodium current density, and inhibiting the endogenous production of H₂S mediated by cystathionine β-synthetase (CBS) using O-(carboxymethyl) hydroxylamine hemihydrochloride (AOAA) can significantly reduce the expression of Na_v1.7 and thus the sodium current density in rat dorsal root ganglion (DRG) neurons. In the present study, it was shown that the fluorescence intensity of H₂S was increased in a spared nerve injury (SNI) model and AOAA inhibited this increase. Na_v1.7 is expressed in DRG neurons, and the expression of CBS and Na_v1.7 were increased in DRG neurons 7, 14 and 21 days post-operation. AOAA inhibited the increase in the expression of CBS, phosphorylated (p)-MEK1/2, p-ERK1/2 and Na_v1.7 induced by SNI, and U0126 (a MEK blocker) was able to inhibit the increase in p-MEK1/2, p-ERK1/2 and Na_v1.7 expression. However, PF-04856264 did not inhibit the increase in CBS, p-MEK1/2, p-ERK1/2 or Na_v1.7 expression induced by SNI surgery. The current density of Na_v1.7 was significantly increased in the SNI model and administration of AOAA and U0126 both significantly decreased the density. In addition, AOAA, U0126 and PF-04856264 inhibited the decrease in rheobase, and the increase in action potential induced by SNI in DRG neurons. There was no significant difference in thermal withdrawal latency among each group. However, the time the animals spent with their paw lifted increased significantly following SNI, and the time the animals spent with their paw lifted decreased significantly following the administration of AOAA, U0126 and PF-04856264. In conclusion, these data show that Na_v1.7 expression in DRG neurons is upregulated by CBS-derived endogenous H₂S in an SNI model, contributing to the maintenance of neuropathic pain.

• SEMA3F
• congenital
• pseudo-obstruction

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 β₂ adrenergic receptors at the protein and mRNA levels was markedly higher in NMD rats with AMSs than in rats with NMD alone. Inhibition of β₂ 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-β₂ adrenergic signaling in DRGs.

• Dorsal root ganglion
• Irritable bowel syndrome
• Norepinephrine
• Stress
• Visceral pain

• Adrenergic Agents/pharmacology
• Animals
• Ganglia, Spinal/drug effects
• Hyperalgesia/drug therapy
• Hyperalgesia/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
• Visceral Pain/metabolism

• bladder
• colon
• dorsal root ganglia
• inflammation
• nociceptors
• pain
• sensory afferents

• Animals
• Humans
• Nociception
• Nociceptive Pain/physiopathology
• Sensory Receptor Cells/pathology
• Viscera/pathology
• Voltage-Gated Sodium Channels/metabolism

• Interstitial cells of Cajal
• Neonatal maternal separation
• Neuronal nitric oxide synthase
• irritable bowel syndrome

• Animals
• Animals, Newborn
• Biomarkers/metabolism
• Diarrhea/enzymology
• Diarrhea/etiology
• Diarrhea/pathology
• Disease Models, Animal
• Female
• Gastrointestinal Motility
• Interstitial Cells of Cajal/pathology
• Irritable Bowel Syndrome/enzymology
• Irritable Bowel Syndrome/etiology
• Irritable Bowel Syndrome/pathology
• Male
• Maternal Deprivation
• Mice
• Mice, Inbred C57BL
• Nitric Oxide Synthase/metabolism
• Stress, Psychological/complications

• 13182KFDA660 KFDA
• 14182KFDA978 KFDA

The pathogenesis of pain in lumbar disc herniation (LDH) remains poorly understood. We have recently demonstrated that voltage-gated sodium channels (VGSCs) in dorsal root ganglion (DRG) neurons were sensitized in a rat model of LDH. However, the detailed molecular mechanism for sensitization of VGSCs remains largely unknown. This study was designed to examine roles of the endogenous hydrogen sulfide synthesizing enzyme cystathionine β-synthetase (CBS) in sensitization of VGSCs in a previously validated rat model of LDH. Here we showed that inhibition of CBS activity by O-(Carboxymethyl) hydroxylamine hemihydrochloride (AOAA) significantly attenuated pain hypersensitivity in LDH rats. Administration of AOAA also reduced neuronal hyperexcitability, suppressed the sodium current density, and right-shifted the V_1/2 of the inactivation curve, of hindpaw innervating DRG neurons, which is retrogradely labeled by DiI. In vitro incubation of AOAA did not alter the excitability of acutely isolated DRG neurons. Furthermore, CBS was colocalized with Na_V1.7 and Na_V1.8 in hindpaw-innervating DRG neurons. Treatment of AOAA markedly suppressed expression of Na_V1.7 and Na_V1.8 in DRGs of LDH rats. These data suggest that targeting the CBS-H₂S signaling at the DRG level might represent a novel therapeutic strategy for chronic pain relief in patients with LDH.

• cholinergic neurons
• early life adversity
• enteric nervous system development
• irritable bowel syndrome
• porcine model

• Dorsal root ganglion
• Excitability
• Lumbar disc herniation
• Neuropathic pain
• Voltage-gated sodium channels

• Action Potentials/physiology
• Animals
• Ganglia, Spinal/physiopathology
• Intervertebral Disc Displacement/physiopathology
• Lumbar Vertebrae/physiopathology
• Male
• Neurons/physiology
• Rats
• Rats, Sprague-Dawley
• Voltage-Gated Sodium Channels/physiology

• IBS
• gastrointestinal
• models
• pain
• rodent

• chronic pancreatitis
• dorsal root ganglion
• norepinephrine
• protein kinase A
• purinergic receptors

The hippocampal long-term potentiation (LTP) was implicated in the formation of visceral hypersensitivity in rats with irritable bowel syndrome in our previous study. Recent studies have shown that protein kinase M ζ (PKMζ) may be responsible for the maintenance of LTP in memory formation. However, it remains unclear whether PKMζ is involved in the visceral hypersensitivity. In this study, a rat model of visceral hypersensitivity was generated by neonatal maternal separation (NMS). The visceral hypersensitivity was assessed by recording responses of the external oblique abdominal muscle to colorectal distension. Our results demonstrated that hippocampal LTP and visceral hypersensitivity were enhanced significantly in rats of NMS. ζ-Pseudosubstrate inhibitory peptide (ZIP) could dose dependently inhibit the maintenance of Cornu Ammonis area 1 LTP in rats of NMS. Furthermore, Western blot data showed that the expression of hippocampal phosphorylated PKMζ (p-PKMζ) significantly increased in rats of NMS. In addition, bilateral intrahippocampal injections of ZIP attenuated the visceral hypersensitivity dose dependently in rats of NMS. The maximal inhibition was observed at 30 min, and significant inhibition lasted for 1.5–2 h after ZIP application. Besides, data from the open-field test and Morris water maze showed that ZIP did not influence the movement and spatial procedural memory in rats of NMS. In conclusion, p-PKMζ might be a critical protein in the maintenance of hippocampal LTP, which could result in visceral hypersensitivity.

• chronic visceral pain
• hippocampus
• long-term potentiation
• neonatal maternal separation
• protein kinase M ζ

Psychological stress is an important factor for the development of irritable bowel syndrome (IBS). More and more clinical and experimental evidence showed that IBS is a combination of irritable bowel and irritable brain. In the present review we discuss the potential role of psychological stress in the pathogenesis of IBS and provide comprehensive approaches in clinical treatment. Evidence from clinical and experimental studies showed that psychological stresses have marked impact on intestinal sensitivity, motility, secretion and permeability, and the underlying mechanism has a close correlation with mucosal immune activation, alterations in central nervous system, peripheral neurons and gastrointestinal microbiota. Stress-induced alterations in neuro-endocrine-immune pathways acts on the gut-brain axis and microbiota-gut-brain axis, and cause symptom flare-ups or exaggeration in IBS. IBS is a stress-sensitive disorder, therefore, the treatment of IBS should focus on managing stress and stress-induced responses. Now, non-pharmacological approaches and pharmacological strategies that target on stress-related alterations, such as antidepressants, antipsychotics, miscellaneous agents, 5-HT synthesis inhibitors, selective 5-HT reuptake inhibitors, and specific 5-HT receptor antagonists or agonists have shown a critical role in IBS management. A integrative approach for IBS management is a necessary.

• Psychological stress
• Irritable bowel syndrome
• Microbiota-gut-brain axis
• Immune activation

• Animals
• Brain/physiopathology
• Humans
• Intestines/innervation
• Irritable Bowel Syndrome/etiology
• Irritable Bowel Syndrome/physiopathology
• Irritable Bowel Syndrome/psychology
• Irritable Bowel Syndrome/therapy
• Prognosis
• Risk Factors
• Stress, Psychological/complications
• Stress, Psychological/physiopathology
• Stress, Psychological/psychology
• Stress, Psychological/therapy

• Ca(v)3.2
• Cystathionine-γ-lyase
• HEK293 cells
• Hydrogen sulfide
• T-type calcium channel