Increased levels of SV2A botulinum neurotoxin receptor in clinical sensory disorders and functional effects of botulinum toxins A and E in cultured human sensory neurons
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Abstract:
There is increasing evidence that botulinum neurotoxin A may affect sensory nociceptor fibers, but the expression of its receptors in clinical pain states, and its effects in human sensory neurons, are largely unknown.We studied synaptic vesicle protein subtype SV2A, a receptor for botulinum neurotoxin A, by immunostaining in a range of clinical tissues, including human dorsal root ganglion sensory neurons, peripheral nerves, the urinary bladder, and the colon. We also determined the effects of botulinum neurotoxins A and E on localization of the capsaicin receptor, TRPV1, and functional sensitivity to capsaicin stimuli in cultured human dorsal root ganglion neurons.Image analysis showed that SV2A immunoreactive nerve fibers were increased in injured nerves proximal to the injury (P = 0.002), and in painful neuromas (P = 0.0027); the ratio of percentage area SV2A to neurofilaments (a structural marker) was increased proximal to injury (P = 0.0022) and in neuromas (P = 0.0001), indicating increased SV2A levels in injured nerve fibers. In the urinary bladder, SV2A nerve fibers were found in detrusor muscle and associated with blood vessels, with a significant increase in idiopathic detrusor over-activity (P = 0.002) and painful bladder syndrome (P = 0.0087). Colon biopsies showed numerous SV2A-positive nerve fibers, which were increased in quiescent inflammatory bowel disease with abdominal pain (P = 0.023), but not in inflammatory bowel disease without abdominal pain (P = 0.77) or in irritable bowel syndrome (P = 0.13). In vitro studies of botulinum neurotoxin A-treated and botulinum neurotoxin E-treated cultured human sensory neurons showed accumulation of cytoplasmic vesicles, neurite loss, and reduced immunofluorescence for the heat and capsaicin receptor, TRPV1. Functional effects included dose-related inhibition of capsaicin responses on calcium imaging after acute treatment with botulinum neurotoxins A and E.Differential levels of SV2A protein expression in clinical disorders may identify potential new targets for botulinum neurotoxin therapy. In vitro studies indicate that treatment with botulinum neurotoxins A and E may affect receptor expression and nociceptor function in sensory neurons.Keywords:
Neurotoxin
Dorsal root ganglion
Summary The sensory innervation of the rabbit urinary bladder was studied using local application of the specific sensory neurotoxin capsaicin (8‐methyl‐N‐vanillyl‐6‐nonenamide). This agent has its major effect by damaging small diameter unmyelinated sensory nerves. The drug produced a 51% reduction in the bladder content of the neuropeptide substance P. It therefore appears that a substantial proportion of the bladder's content of the peptide is to be found in capsaicin‐sensitive sensory nerves. Cystometrograms carried out before and after treatment with capsaicin were similar; this suggests that capsaicin‐sensitive sensory nerves may not be of importance in the afferent limb of the micturition reflex. In vitro muscle strip studies demonstrated a small reduction in the sensitivity of the detrusor muscle to electrical stimulation of its intramural nerves. It is possible that in vitro intramural nerve stimulation leads to release of neurotransmitters from sensory as well as motor nerves. It is proposed that small diameter sensory nerves in the bladder wall may have a role in the transmission of the sensation of pain and in the triggering of inflammatory reactions rather than forming the afferent limb of the micturition reflex.
Capsaicin
Rabbit (cipher)
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Dorsal root ganglion
Sensory nerve
Sensory neuron
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肠易激综合征是一种常见的消化系统功能性疾病,儿童发病率较高.主要表现以腹痛或腹部不适,伴有大便性状改变和排便习惯改变为特征,缺乏形态学改变和生化学异常.其发病原因和机制尚不完全明了,主要与脑-肠轴异常、感染、内脏高敏感、肠道运动异常、神经与免疫等因素有关,在此基础上提出了神经-免疫-内分泌网络调控机制.诊断主要依靠症状学评分,无特异性的辅助检查确诊,故需有一定的诊断标准.随着科学发展,诊断标准亦不断完善.治疗主要是综合治疗,无特异性治疗.该文主要就儿童肠易激综合征的研究现状作一综述。
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ABSTRACT The perception of noxious environmental stimuli by nociceptive sensory neurons is an essential mechanism for the prevention of tissue damage. Etv4 is a transcriptional factor expressed in most nociceptors in dorsal root ganglia (DRG) during the embryonic development. However, its physiological role remains unclear. Here, we show that Etv4 ablation results in defects in the development of the peripheral peptidergic projections in vivo, and in deficits in axonal elongation and growth cone morphology in cultured sensory neurons in response to NGF. From a mechanistic point of view, our findings reveal that NGF regulates Etv4-dependent gene expression of molecules involved in extracellular matrix (ECM) remodeling. Etv4-null mice were less sensitive to noxious heat stimuli and chemical pain, and this behavioral phenotype correlates with a significant reduction in the expression of the pain-transducing ion channel TRPV1 in mutant mice. Together, our data demonstrate that Etv4 is required for the correct innervation and function of peptidergic sensory neurons, regulating a transcriptional program that involves molecules associated with axonal growth and pain transduction.
Nociceptor
Dorsal root ganglion
Sensory neuron
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Capsaicin is a neurotoxin that can deplete sensory nerves of their content of substance P and interfere with certain sensory functions, such as responses of animals to noxious heat stimuli. In adult guinea pigs, a species that is susceptible to the effects of capsaicin on both substance P content and sensory function, capsaicin induces selective depletion of substance P from dorsal root ganglia and the dorsal spinal cord, sites of the cell bodies and central terminals of primary afferent neurons, respectively. As the onset of thermal analgesia in guinea pigs precedes depletion of substance P, direct neural actions of capsaicin probably account for its effects on sensory function. Capsaicin interferes with the retrograde transport of nerve growth factor (NGF) to the cell bodies of sensory nerves. Decreased availability of NGF at the site of neural protein synthesis leads to decreased synthesis of substance P. After failure of synthesis of substance P, the content of the peptide in sensory nerves gradually decreases until depletion occurs.
Capsaicin
Neurotoxin
Dorsal root ganglion
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Dorsal root ganglion
Neurotoxin
Ankyrin
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Despite the absence of synaptic contacts, cross-excitation of neurons in sensory ganglia during signal transmission is considered to be chemically mediated and appears increased in chronic pain states. In this study, we modulated neurotransmitter release in sensory neurons by direct application of type A botulinum neurotoxin (BoNT/A) to sensory ganglia in an animal model of neuropathic pain and evaluated the effect of this treatment on nocifensive. Unilateral sciatic nerve entrapment (SNE) reduced the ipsilateral hindpaw withdrawal threshold to mechanical stimulation and reduced hindpaw withdrawal latency to thermal stimulation. Direct application of BoNT/A to the ipsilateral L4 dorsal root ganglion (DRG) was localized in the cell bodies of the DRG and reversed the SNE-induced decreases in withdrawal thresholds within 2 days of BoNT/A administration. Results from this study suggest that neurotransmitter release within sensory ganglia is involved in the regulation of pain-related signal transmission.
Dorsal root ganglion
Neurotoxin
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Sensory neurons expressing the GPCR Mrgprd mediate the effects of a bioactive lipid to cause abdominal pain.
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Background: Irritable bowel syndrome (IBS) is a functional gastrointestinal syndrome with an expanding worldwide incidence.Low FODMAP diet is a recently developed dietary strategy consists of limiting foods that are high fermentable, which might induce or aggravate IBS symptoms.Aerobic exercise is beneficial in reducing the risk of all types of gastrointestinal symptoms.Objective: Investigate the effect of low FODMAP diet and aerobic exercise on irritable bowel syndrome post abdominal surgeries.Patients and methods: Forty five female and male patients participated in this study.They were divided into three equal groups, group (A) received low FODMAP diet group (B) received aerobic exercise (walking on treadmill 25-40 minutes 3 times per week) group (C) received both low FODMAP diet and aerobic exercise.Evaluation was done preand post-12 weeks of treatment by IBS Severity Scoring System (IBS-SSS) and IBS Quality of Life (IBS-QOL).Results: There was significant reduction in post-treatment values of IBS-SSS and IBS-QOL in comparison to pretreatment values in the three groups, Post-treatment comparison between three groups showed significant difference in IBS-SSS and IBS-QOL, which revealed a significant reduction in IBS-SSS and IBS-QOL of group C compared to that of group A and group B. Conclusion: combining low FODMAP diet and aerobic exercise had a greater effect on irritable bowel syndrome through reducing IBS symptoms and improving quality of life.
Aerobic Exercise
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