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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:

Generating appropriate reflex response to the gut lumen contents

Participates in reflexes between organs

Convey signals from digestive organs to the CNS –

Trigger reflex

Co-ordination with other body system

Relate to sensation including discomfort, nausea, pain and satiety

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intrinsic and extrinsic内源性和外源性

Primary afferent neurons ：Extrinsic 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 ganglia

Intestinofugal neuron 肠离心神经元

Parts of the afferent limbs of entero-enteric reflex pathways

Have cell bodies in ENS

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Intrinsic 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).

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I Intrinsic Primary Afferent Neurons and

Nerve Circuits within the Intestine

Reference:

Furness JB, Jones C., Nurgali K., Clerc N. Intrinsic primary neurons and nerve circuits within the intestine. Progress in Neurobiology 2004, 72: 143 - 164

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1. Types of neurons that form enteric nerve circuits

According to the

functions,

key transmitters

projections to targets

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LM: 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 (<1%)

(4) Excitatory longitudinal muscle motor neurons (25%)

(5) Inhibitory longitudinal muscle motor neurons (2%)

(6) Excitatory circular muscle motor neurons (12%)

(7) Inhibitory circular muscle motor neurons (16%)

(8) Descending interneurons local reflex (5%)

(9) Descending interneurons (2%): secretomotor reflex

(10) Descending MMC interneurons (4%)

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LM: longitudinal muscle; MP: myenteric plexus; CM: circular muscle; SM: submucosal plexus; Muc: mucosa

Submucosal Neurons

(11) Submucosal intrinsic primary afferent neurons (11%)

(12) Non-cholinergic secretomotor/vasodilator neurons (45%)

(13) Cholinergic secretomotor/vasodilator neurons (15%)

(14) Cholinergic secretomotor (non-vasodilator) neurons (29%)

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2. Characteristics of intrinsic primary afferent neurons (IPANs) Shape: round or oval

Processes: multi-axonal or pseudounipolar( 假单极 )Signal Conduction:

traverse the cell bodies (transcellular conduction)can be conducted to output synapses via an axon reflex (axon reflex conduction). transcellular conduction can be modified by the synaptic inputs that it receives.

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2. Characteristics of IPANs- Conti

Communication:

with other neurons in the myenteric and submucosal ganglia.

2 Myenteric intrinsic primary afferent neurons (26%)

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2. Characteristics of intrinsic afferent neurons- Conti

Electrophysiology

Broad action potential carried by both sodium and calcium current

Followed by early and late (slow) afterhyperpolarizing potential (AHP)

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2. Characteristics of IPANs- Conti

Sensitivity- Chemosensitivity ( 化学敏感性 ) and Mechanosensitivity ( 机械敏感性 )

Chemosensitive IPANs

IPANS respond to chemicals, such as inorganic acid and short chain

May be indirect, via 5-HT or ATP

SAC, stretch open channel;

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Mucosal mechanoreceptors:

Puffs of nitrogen gas on the mucosal induce C-Fos expression in IPAN

Blocked by TTX

Unaffected by hexamethonium ( 六甲铵 ), the nicotinic receptor antagonist

Mostly indirect, through the release of 5-HT from enterochromaffin cells ( 肠嗜铬细胞 ) in the mucous membrane ( 粘膜 )

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3. Enteric nerve circuits

Intrinsic reflexes that affect motility, water and electrolyte secretion and blood flow all occur in the intestine

Circuits for motility control

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Secretomotor and vasomotor reflexes

LM: longitudinal muscle; MP: myenteric plexus; CM: circular muscle; SM: submucosal plexus; Muc: mucosa

2. Myenteric intrinsic primary afferent neurons

9. Descending interneurons: secretomotor reflex

11. Submucosal intrinsic primary afferent neurons

12. Non-cholinergic secretomotor/vasodilator neurons

13. Cholinergic secretomotor/vasodilator neurons

14. Cholinergic secretomotor (non-vasodilator) neurons

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II Extrinsic Primary Afferent NeuronsThe rich sensory innervation ( 神经支配 ) of the gastrointestinal tract comprise:

Intrinsic sensory neurons contained entirely within the gastrointestinal wall

Intestinofugal fibres 肠离心神经纤维 that project to prevertebral ganglia ( 椎前神经节 )

Vagal and spinal afferent that projects to the central nervous system.

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1. Pathway to the central nervous system

(1) Vagus Afferent （迷走神经传入纤维）

Cell body: superior and inferior (jugular and nodose) vagal ganglia

Direct input:

nucleus tracuts solitarius (nTS); （孤束核）dorsal motor nucleus of the vagus (DMV); （迷走神经背核）the area postrema （最后区）

Peripheral trigger for vomiting

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Projection from nTS

Reflex connection with other brain stem nuclei: vago-vagal reflex

To preganglinoic neurons

DMV

Nuclues ambiguus

Intermediolateral column （中间外侧柱） of the spinal cord

Motorneurons supply the face and salivary glands

Through the midbrain 中脑 and reticular nuclei 网状核团 to higher centers: processing of afferent information, mechanism unknown.

Hypothalamus

Limbic system

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(2) Spinal Afferent

Cell Body: dorsal root ganglia

Input: to the cord thro

ugh the dorsal roots

Visceral convergence and referred pain （牵涉痛）

Projection to the brain:

Via spinothalamic tract, spinoreticular tract and dorsal columns.

Generally nociceptive

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2. Gastrointestinal Receptors:

free naked endings situated at different levels within and outside the wall of the viscera

Mucosal Receptors （粘膜受体）Lie in or immediately below the mucosal epithelium

Detect the physical and chemical nature of luminal contents

Muscle Receptors （肌肉受体）Deep in the muscularis externae area

Influenced by changes in muscle tension

Serosal and Mesenteric Receptors （浆膜和肠系膜受体）Lie beneath the serosa or in the mesenteric attachments

Sensitive to movements and distortion of the viscera

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The muscle and mucosal receptors have afferent pathways mainly in the vagus nerve

mainly transit physiological stimulation

The serosal and mesenteric endings have a predominately splanchnic （内脏） pathway

mainly conduct visual pain.

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(1)Mucosal ReceptorsReference: Grundy D., Scratcherd T. Sensory afferent from the gastrointestinal tract. In: Johnson

L.R., Alpers D.M., Jacobson E.D., Christensen H.D., Wlash J.H. eds. Handbook of physiology: the gastrointestinal system. New York, NY: Trven 593-620. (1989)

Project pathway

Relay information mainly to the brain stem via unmyelinated （无髓） vagal afferent fibers.

Sensitivity

Sensitive to light stroking of the mucosa

Generating a brief burst of impulses each time the stimulus passes over the receptive field

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Relatively insensitive to distension, contraction, or compression except the distortion of the mucosa occurs 、

Multimodal Receptors – response to both mechanical and chemical stimuli

Not very specific

Sensitive to acid, alkali, hyper- or hypo- osmotic solution.

Mechanism unknown

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Glucoreceptors or carbohydrate receptor

In proximal regions has afferent pathways in vagus

From more distal regions followed a splanchnic pathway

Respond to intraluminal glucose, lactose （乳糖） and levulose （果糖） with slow adaptation

Not sensitive to osmotic stimuli, acid or gross mechanical stimuli

Only actively transported sugars are effective

•Blocked by phlorhizin （根皮苷） , which prevent the transfer of glucose transportation

•Slowly absorptive mannose （甘露糖） or nonabsorbable mannitol （甘露醇） were ineffective

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Amino acid receptors

Vagal afferent C-fibers

Slowly adapting

Some units respond to many individual amino acids, others appear quite specific

Do not response to osmotic stimulation or mechanical stimulation

Importance: inform CNS about the quantity and quality of amino acid?

Thermoreceptors 温度感受器Follow vagus pathway

Three types

•Warm receptor (39 – 50 oC)

•Cold receptor (10 – 36 oC)

•Mixed receptor (10 – 36 or 45 – 50 oC)

Do not respond to chemical (glucose or acid) and mechanical stimuli

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Importance:

Detect the texture and passage of solid or semisolid material through mechanical sensitivity

Involved in numerous reflex responses to luminal chemicals through chemical sensitive receptors

Signaling satiety 饱Regulation of insulin secretion

Peripheral trigger for emesis

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(2) Muscle receptors

Project pathway

Afferent pathway for muscle receptors is mainly vagal

Muscle receptors in the distal colon 结肠 , rectum 直肠 and anal canal 肛管 have an afferent pathway in the pelvic nerves to the sacral cord

Tension and stretch receptors in gastrointestinal muscle

Reference:

Phillips R.J., Powley T.L. Tension and stretch receptors in gastrointestinal smooth muscle: re-evaluating vagal mechanoreceptor electrophysiology. Brain Research Review 2000, 34: 1-26.

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Tension receptor ( 张力感受器 ) and stretch receptor ( 牵张感受器 )

Active tension : force develop during a contraction of the muscle

Passive tension: force develop when a noncontracting muscle is extended.

Tension receptor

sensitive to active tension

as Golgi tension organ

in series with the muscle

Stretch receptor

responses to passive tension

as the muscle spindle

parallel to the muscle

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Two kind of muscle receptors, IGLEs and IMAs

Intraganglionic laminar endings 节内片状末梢 , IGLEs

Location: in myenteric ganglia

Characteristic appearance: laminae ( 片状 ) of puncta ( 色斑 ) distributed on either or both muscle poles of ganglia

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Each case shows a single axon entering a myenteric ganglion and terminating as highly arborizing 分叉 laminar endings upon neurons within the ganglion.

As illustrated in (B), in which the ganglion cells are more darkly stained, the laminae of IGLEs were plates of puncta superficial (or deep) to subsets of myenteric neurons.

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Intramuscular array (IMA) 肌肉内末梢Location: within the muscle

Forms: Consisting of an array of terminals running parallels to the muscle fiber

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Tracing of a single axon ending as several overlapping intramuscular arrays (IMAs) in the ventral forestomach of the rat.

The parent axon branches several times (A) before terminating within the circular muscle layers.

Upon entering the muscle, the individual terminals run for several millimeters, creating a distinct pattern of parallel elements (B–D).

In panel (E), processes from the ending pass adjacently to a cluster of myenteric neurons.

This afferent’s parent axon divided into five second-order branches which in turn divided into 39 higher order terminal telodendra ( 终树突 ), forming a presumptive receptive field 4.93 mm long by 0.32 mm wide.

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Distribution of IGLEs and IMAs.

IGLEs: the esophagus and small intestine

IGLEs and IMAs: mixed innervation of the stomach

IMAs: the lower esophageal sphincter and pyloric sphincter 幽门括约肌

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Topographic maps and plots illustrating the density and distribution of IGLEs and IMAs in stomach.

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Function of IGLEs and IMAs

IGLES,

with their global distribution throughout the GI tract,

may be a general type of tension receptor in the gut,

detecting and then coordinating complex rhythmic motor movements.

IMAs,

with a more focal innervation pattern in regions

which exhibit frequent, sustained non-rhythmic adjustments,

may be a special type of mechanoreceptor which detects muscle stretch and/or length.

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Physiological importance of muscle receptors

reflex regulation of gastrointestinal function.

Receptors in the esophagus are responsible for initiating secondary peristalsis

Afferent fibers from corpus 胃体 could play a role in signaling the initial phase of postprandial satiety, and may also give rise to the feeling of fullness experienced after a large meal.

Serve as the afferent pathway for a number of vagovagal reflex, such as:

Reflex excitation of antral motility

Gastric secretion

Pancreatic enzyme secretion

Receptive relaxation of the stomach

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(3) Serosal 浆膜 and mesenteric 肠系膜 receptorsMechanoreceptor

Anatomy

Endings are associated with the peritoneum 腹膜 , either under the serosa or the viscus 内脏 near the mesenteric attachment or in the mesentery and omentum 网膜 .

Are found along the entire length of the gastrointestinal tract and accessory organs

Have their cell bodies in the thoracic 胸 , lumbar 腰 , and sacral 骶 spinal ganglia, run mainly in the pelvic 盆 ( 神经 ) and splanchnic nerve 内脏神经 to the spinal cord

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Response characteristics

In small intestine, “movement receptor”.

Some receptors response to the stimulation within physiologial level, while other only sensitive to pathological stimulation

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Low threshold, high threshold and wide dynamic nerves

Unit 1 low threshold 低阈值 Unit 2 wide dynamic 宽阈值 Unit 3 high threshold 高阈值

40A. low threshold 低阈值 B. high threshold 高阈值 C. wide dynamic 宽阈值

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III Intestinofugal afferent neurons (IFANs)

Reference:

Szurszewski J.H., Ermilov L.G., Miller S.M. Prevertebral ganglia and intestinofugal afferent neurons. Gut 2002, 51(suppl. 1): i6 – i10

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Intestinofugal afferent neurones (IFANs) - unique subset of myenteric ganglion neurones

Relay mechanosensory information to sympathetic prevertebral ganglion (PVG) neurones.

IFANs are arranged in parallel to the circular muscle fibres and respond to circular muscle stretch rather than tension.

They detect changes in volume.

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When activated by colonic 结肠 distension,

IFANs release acetylcholine at the PVG,

and evoke nicotinic fast excitatory postsynaptic potentials (F-EPSPs)

This reflex arc

formed by IFANs and sympathetic PVG neurones

provides a protective buffer 缓冲 against large increases in tone and intraluminal pressure.

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Visceral spinal afferent neurons have axon collaterals 侧枝 form en passant synapses with PVG neurons.

has a higher (>15 cm H2O) threshold for activation compared with IFANs.

arranged in series with both longitudinal and circular muscle layers.

Tension receptor

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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.

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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 SP

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Importance 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 tract

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IV Inflammatory and non-inflammatory mediators

Reference:

Bueno L., Fioramonti J. Visceral perception: inflammatory and non-inflammatory mediators.Gut 2002; 51(Suppl):i9 – 23

Kirkup 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.

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The endogenous compounds that mediate inflammation (autacoids) and related exogenous compounds including the synthetic prostaglandins.

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1. Introduction An enormous range of chemical mediators have been implicated in s

ensory signal transduction in the visceral

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 stimuli

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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.\

Any given mediator may recruit one or more of these pathways to produce its effect on visceral sensation

interference with any of these mechanisms is likely to modulate the “gain” in visceral sensory pathway in the short and/or long term.

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2. Sensory Signal Transduction via Mediators

Before activation of extrinsic afferent nerves, specific stimuli arising within the lumen of the gastrointestinal tract may activate specialized cells present in the mucosa.

5-HT, released from enterochromaffin (EC) cells in the intestinal mucosa, act as principal sensory transducers.

EC cells “taste” luminal contents and release their mediators across the basolateral membrane to generate action potentials in the afferent nerve endings.

Stimulus intensity is encoded in the amount of mediator release and represents the balance between the mechanisms causing releasing and the uptake mechanisms that limit the site and duration of activation.

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5-HT act directly on vagal extrinsic afferent nerves in the mucosa through activation of ionotropic 5-HT3 receptors

The physiological stimuli for the release of 5-HT from EC cells, suggesting a role for this process in mechanotransduction.

However, a large body of data implicate this mechanism in the detection of bacterial enterotoxins 肠毒素 , e.g., cholera toxin 霍乱毒素 .

These toxins trigger release of 5-HT from EC cells to bring about an orchestrated response to dilute and subsequently eliminate the pathogenic 致病性 material from the body and preclude further consumption of the potentially harmful material.

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3. Visceral Hypersensitivity ( 内脏高敏感性 )

Vagal and spinal afferent fibers each respond to mechanical stimulation such as distension and contraction.

Vagal afferent encode events within the physiological range.

Some spinal afferents respond over a wide dynamic range extending from physiological to pathophysiological levels of distension.

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These spinal endings can contribute to signaling visceral pain through some intensity code that recognize extreme levels of distension or contraction.

Other spinal afferents, however, response only to noxious levels of distension,

the high-threshold mechanoreceptos that fail to respond under normal circumstances.

called “sleeping” or silent nociceptos that can be awakened under conditions of injury or inflammation.

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mechanosensitivity is not fixed either in terms of threshold for activation

or gain in the stimulus-response relationship,

the threshold can be reduced and the gain increased under certain stimulations.

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A number of proinflammatory mediators ( 前炎性细胞因子 ) have been implicated in the sensitization process,

examples of some of the key agents in this phenomenon are detailed below.

Proinflammatory: Capable of promoting inflammation. For example, air pollution may have proinflammatory effects.

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4. Some Mediators

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(1) Bradykinin 缓激肽 (BK).

Nonapeptide 九肽 generated from plasma during tissue damage and inflammation.

Mediates its effects via two G protein-coupled receptors, B1 and B2

the latter being constitutive

the former induced by some cytokines and nerve growth factor (NGF).

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In vitro studies in uninflamed preparations have shown that BK powerfully activates mesenteric spinal afferents with serosal terminals

through an action on B2 receptors and

though BK induced release of prostaglandins contributes to the overall magnitude of the response.

These findings corroborate 证明 whole animal studies showing that

B2 receptor antagonists 阻断剂 attenuate visceral pain in acute inflammation model

In chronic inflammation models, the role of the inducible B1 receptor in visceral nociception mechanisms becomes more dominant.

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The wealth of evidence clearly indicates

a role of BK in the generation of visceral pain in the acute and chronic phases of inflammation,

antagonists of BK receptors could be useful therapeutically 治疗方面 to treat visceral hypersensitivity in inflammatory conditions.

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(2) Prostaglandins and leukotrienes 白细胞三烯 .

Products of arachidonic acid 花生四烯酸 oxygenation are a major contributor to hyperalgesia 痛觉过敏 in the somatic 躯体 realm,

they may play a similar role in visceral sensory transmission.

This groups of mediators comprises the prostaglandins (PGs) and leukotrienes (LKs), which are

synthesized from the precursor arachidonic acid

by cyclooxygenase ( 环氧合酶 ) (COX) and lipoxygenase 脂氧化酶 enzyme

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PGE2 acts through multiple EP receptors.

In the gastrointestinal tract, EP1 receptors appear to play a major role in direct activation of mucosal mesenteric afferent,

EP2 receptors may play a sensitizing role.

Critical to this function may be the activation of adenylate cyclase 腺苷酸环化酶 and elevation of intracellular cAMP,

the membrane-permeable cAMP analog dibutyryl 联丁酰基 cAMP mimics the sensitization process.

Such mechanisms may

underlie the enhanced responsiveness of visceral afferent neurons to chemical and mechanical stimuli in inflammatory conditions

and may be involved in the wakening the so-called “silent nociceptors” after an inflammatory insult.

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Two isoforms 异构体 of the COX enzyme have been characterized,

COX-1 and COX-2.

CON-1: constitutive and involved in controlling baseline visceral afferent sensitivity

in native tissue, naproxen significantly reduced the magnitude of the response to BK.

during inflammatory conditions such as colitis, upregulation of the inducible COX-2 occurs,

leading to augmented PG synthesis,

this enzyme may therefore be important in the genesis of persistent pain i

n this syndrome.

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Interleukin (IL)-1b and tumor necrosis factor (TNF)-a may underlie this increased expression of COX-2,

PGs contribute to the illness behavior and somatic and visceral hyperalgesia associated with elevated levels of these cytokines.

PGs are derived from virtually every type of tissue,

Especially in sympathetic nerve terminals and immunocompetent 有免疫活性的 cells,

may be important in the maintenance of the inflammatory state.

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The tachykinins (TKs) are a family of small peptides

Share the common C-terminal sequence Phe 苯丙氨酸 -X-Gly 甘氨酸 -Leu 亮氨酸 -Met 蛋氨酸 NH2.

Three peptides of this family, substance P, neurokinin 神经激肽 A and neurokinin B,

Neurotransmitters in mammals.

Three receptors for TKs G-protein coupled receptors

NK1 (substance P-preferring),

NK2 (neurokinin A-preferring)

NK3 (neurokinin B-preferring)

(3) Tachykinins 速激肽

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Tachykinins have an important role in the transmission of nociceptive messages from the gut.

Many C-afferent fibers have "silent receptors" for neurokinins that can be sensitized by inflammatory processes in peripheral tissues.

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data on visceral pain in animal models

NK1 receptor blockade

prevents visceral hyperalgesia related to inflammation through an anti-inflammatory action

inactive against an established hypersensitivity,

both NK2 and NK3 receptor blockade reduce visceral pain by

acting both centrally and peripherally for NK2 receptors and

only at the periphery for NK3 receptors.

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CGRP is present in most splanchnic 内脏的 afferents

CGRP immunoreactivity 免疫活性物质 almost disappears from the gut after either splanchnic nerve section or treatment with the sensory neurotoxin capsaicin 辣椒素 .

(4) Calcitonin gene-related peptide 降钙素基因相关肽 (CGRP)

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About 50% of CGRP immunoreactive afferent neurons also contain SP/NKA immunoreactivity.

Moreover, CGRP released at the spinal cord from central endings of primary afferents is important in the development of visceral hyperalgesia.

Alternatively, peripherally released CGRP may modify sensory inputs, causing changes in blood flow, smooth muscle contractions, immune reaction, and/or mast cell degranulation 脱颗粒 .

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The intravenous administration of the CGRP1 receptor anta

gonist human (h)-CGRP-(8-37)

suppresses the abdominal cramps 抽筋 observed after the intraperitoneal 腹膜内 administration of acetic acid 醋酸 in awake rats and

blocks the inhibition of gastric emptying induced by peritonitis 腹膜炎 .

CGRP is also involved in the mediation of pain produced by lower gut distension.