Primary afferent neurons of the gut （消化道初级感觉神经元）Function:Monitoring and control of the digestive system, including:v Generating appropriate reflex response to the gut lumen contentsv Participates in reflexes between organsv Convey signals from digestive organs to the CNS Trigger reflex Co-ordination with other body system Relate to sensation including discomfort, nausea, pain and satiety1intrinsic and extrinsic 内源性和外源性Primary afferent neurons：vExtrinsic primary afferent neurons, including: Vagal primary afferent neuron have cell bodies in (nodose and jugular) ganglia 神经节 Spinal primary afferent neuron have cell bodies in dorsal root gangliavIntestinofugal neuron 肠离心神 经元 Parts of the afferent limbs of entero-enteric reflex pathways Have cell bodies in ENS2vIntrinsic primary afferent neurons, IPANs, within ENS Myenteric 肌间 IPANs: respond to Distortion of their processes in the external muscle layers changes in luminal chemistry, via processes in the mucosa, submucosal 粘膜下 IPANs detect: Mechanical distortion of the mucosa Luminal chemistry.LM, longitudinal muscle; CM, circular muscle; MP, myenteric plexus; SM, submucosa; Muc, mucosa. Nerve endings in the mucosa can be activated by hormones released from entero-endocrine cells (arrows).3I Intrinsic Primary Afferent Neurons andNerve Circuits within the IntestineReference:Furness JB, Jones C., Nurgali K., Clerc N. Intrinsic primary neurons and nerve circuits within the intestine. Progress in Neurobiology 2004, 72: 143 - 16441. Types of neurons that form enteric nerve circuitsAccording to the v functions, v key transmittersv projections to targets 5LM: longitudinal muscle; MP: myenteric plexus; CM: circular muscle; SM: submucosal plexus; Muc: mucosa. Myenteric Neurons(1) Ascending interneurons( 5%)(2) Myenteric intrinsic primary afferent neurons (26%)(3) Intestinofugal neurons (15 cm H2O) threshold for activation compared with IFANs. arranged in series with both longitudinal and circular muscle layers. Tension receptor45 release substance P (SP) P物质 and calcitonin gene related peptide (CGRP) 降钙素基因相关肽 in prevertebral ganglia, evoke slow excitatory postsynaptic potentials (S-EPSPs) in sympathetic neurons. 46 so mechanosensory information arriving in the PVG via axon collaterals of mechanosensory spinal afferent nerves can be modulated separately in the PVG without alteration of the signal referred centrally via the central extension of the same mechanosensory spinal afferent nerve Release of SP and CGRP modulated by central preganglionic nerves. Central preganglionic nerves release neurotensin 神经降压素 which facilitates release of SP. preganglionic nerves release enkephalins 脑啡 肽 inhibit release of SP47vImportance of IFANs Provide a protective buffer 缓冲 against large increase in tone and intraluminal pressure PVG forms an extended neural network which connects the lower intestinal tract to the upper gastrointestinal tract48IV Inflammatory and non-inflammatory mediatorsReference: Bueno L., Fioramonti J. Visceral perception: inflammatory and non- inflammatory mediators.Gut 2002; 51(Suppl):i9 23Kirkup A.J., Brunsden A.M., Grundy D. Receptors and transmission in the brain-gut axis: potential for novel therapies I. Receptors on visceral afferents. Am. J. Physiol. Gastrointest. Liver. Physiol. 2001, 280: G797 G794.Gebhart G.F. Pathobiology of visceral pain: molecular mechanisms and therapeutic implications. IV. Visceral afferent contributions to the pathobiology of visceral pain. Am. J. Physiol. Gastrointest. Liver. Physiol. 2000, 278: G834 838.49The endogenous compounds that mediate inflammation (autacoids) and related exogenous compounds including the synthetic prostaglandins. 501. Introductionv An enormous range of chemical mediators have been implicated in sensory signal transduction in the visceral v These substances are thought to produce their effects on visceral afferent nerves by three distinct processes: Direct activation opening of ion channels present on the nerve terminals Sensitization 敏感化 occur in the absence of a direct stimulation results in afferent hyperexcitability to both chemical and mechanical stimuli51 Alteration of the phenotype 表现型 of the afferent nerve, for example through alterations in the expression of mediators, channels, and receptors or modulating the activity of these by changing the ligand-binding characteristics or coupling efficiency of other receptors.vAny given mediator may recruit one or more of these pathways to produce its effect on visceral sensationvinterference with any of these mechanisms is likely to modulate the “gain” in visceral sensory pathway in the short and/or long term.522. Sensory Signal Transduction via Mediatorsv Before activation of extrinsic afferent nerves, specific stimuli arising within the lumen of the gastrointestinal tract may activate specialized cells present in the mucosa. v 5-HT, released from entero