Primary afferent neurons of the gut

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Transcript Primary afferent neurons of the gut

Primary afferent neurons of the gut
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
Extrinsic primary afferent
Primary afferent neurons:
neurons, including:
intrinsic and extrinsic
Vagal primary afferent neuron
have cell bodies in (nodose and
jugular) ganglia 神经节
Spinal primary afferent
 have cell bodies in dorsal root
Intestinofugal neuron 肠离心神
Parts of the afferent limbs of
entero-enteric reflex pathways
Have cell bodies in ENS
Intrinsic primary afferent neurons, IPANs, within
Myenteric 肌间 IPANs: respond
Distortion of their processes in the
external muscle layers
changes in luminal chemistry, via
processes in the mucosa,
submucosal 粘膜下 IPANs
Mechanical distortion of the
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).
I Intrinsic Primary Afferent Neurons and
Nerve Circuits within the Intestine
Furness JB, Jones C., Nurgali K., Clerc N. Intrinsic primary neurons and nerve circuits
within the intestine. Progress in Neurobiology 2004, 72: 143 - 164
1. Types of neurons that form enteric nerve circuits
According to the
 functions,
 key transmitters
 projections to targets
Myenteric Neurons
(1) Ascending interneurons( 5%)
(2) Myenteric intrinsic primary
afferent neurons (26%)
(3) Intestinofugal neurons (<1%)
LM: longitudinal muscle; MP: myenteric
plexus; CM: circular muscle; SM:
submucosal plexus; Muc: mucosa.
(8) Descending interneurons local
reflex (5%)
(9) Descending interneurons (2%):
secretomotor reflex
(10) Descending MMC
interneurons (4%)
(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%)
Submucosal Neurons
(11) Submucosal intrinsic primary
afferent neurons (11%)
(12) Non-cholinergic
secretomotor/vasodilator neurons
LM: longitudinal muscle; MP:
myenteric plexus; CM: circular muscle;
SM: submucosal plexus; Muc: mucosa
(13) Cholinergic
secretomotor/vasodilator neurons
(14) Cholinergic secretomotor
(non-vasodilator) neurons (29%)
2. Characteristics of intrinsic primary afferent neurons (IPANs)
Shape: round or oval
Processes: multi-axonal or
Signal Conduction:
traverse the cell bodies
(transcellular conduction)
can be conducted to
output synapses via an
axon reflex (axon reflex
 transcellular conduction
can be modified by the
synaptic inputs that it
2. Characteristics of IPANs- Conti
with other neurons in the
myenteric and submucosal
2 Myenteric intrinsic primary afferent neurons (26%)
2. Characteristics of intrinsic afferent neurons- Conti
Broad action potential carried by both sodium and calcium current
Followed by early and late (slow) afterhyperpolarizing potential
2. Characteristics of IPANs- Conti
Sensitivity- Chemosensitivity (化学敏感性) and Mechanosensitivity
Chemosensitive IPANs
IPANS respond to chemicals, such as inorganic acid and short chain
May be indirect, via 5-HT or ATP
SAC, stretch open
Mucosal mechanoreceptors:
Puffs of nitrogen gas on the mucosal induce C-Fos expression
Blocked by TTX
Unaffected by hexamethonium (六甲铵), the nicotinic receptor
Mostly indirect, through the release of 5-HT from
enterochromaffin cells (肠嗜铬细胞) in the mucous membrane
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
Secretomotor and vasomotor
LM: longitudinal muscle; MP:
myenteric plexus; CM: circular
muscle; SM: submucosal plexus;
Muc: mucosa
2. Myenteric intrinsic primary afferent
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
II Extrinsic Primary Afferent Neurons
The rich sensory innervation (神经支配) of the gastrointestinal tract
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.
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
the area postrema (最
Peripheral trigger
for vomiting
Projection from nTS
Reflex connection with other brain stem nuclei: vago-vagal reflex
To preganglinoic neurons
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.
Limbic system
(2) Spinal Afferent
Cell Body: dorsal root
Input: to the cord
through the dorsal roots
Visceral convergence
and referred pain (牵涉
Projection to the brain:
Via spinothalamic tract,
spinoreticular tract and
dorsal columns.
Generally nociceptive
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
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.
(1)Mucosal Receptors
Reference: 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
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
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
Amino acid receptors
Vagal afferent C-fibers
Slowly adapting
Some units respond to many individual amino acids, others appear quite
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
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
(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
Tension and stretch receptors in gastrointestinal muscle
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.
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
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
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
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.
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
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.
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
Topographic maps and plots illustrating
the density and distribution of IGLEs and
IMAs in stomach.
Function of IGLEs and IMAs
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.
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
Physiological importance of muscle receptors
reflex regulation of gastrointestinal function.
Receptors in the esophagus are responsible for initiating secondary
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
Reflex excitation of antral motility
Gastric secretion
Pancreatic enzyme secretion
Receptive relaxation of the stomach
(3) Serosal 浆膜 and mesenteric 肠系膜
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
Response characteristics
In small intestine, “movement receptor”.
Some receptors response to the stimulation within physiologial
level, while other only sensitive to pathological stimulation
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
39 高阈值
A. low threshold 低阈值 B. high threshold 高阈值 C. wide dynamic 宽阈值
III Intestinofugal afferent neurons (IFANs)
Szurszewski J.H., Ermilov L.G., Miller S.M. Prevertebral ganglia and intestinofugal
afferent neurons. Gut 2002, 51(suppl. 1): i6 – i10
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
They detect
changes in volume.
When activated by colonic 结肠 distension,
IFANs release acetylcholine at the PVG,
and evoke nicotinic fast excitatory postsynaptic potentials (FEPSPs)
This reflex arc
formed by IFANs and sympathetic PVG neurones
provides a protective buffer 缓冲 against large increases in tone
and intraluminal pressure.
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
arranged in series with both longitudinal and circular muscle layers.
Tension receptor
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.
Release of SP and
CGRP modulated by
central preganglionic
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
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
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
IV Inflammatory and non-inflammatory
Bueno L., Fioramonti J. Visceral perception: inflammatory and noninflammatory 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 –
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.
The endogenous compounds that mediate inflammation (autacoids) and
related exogenous compounds including the synthetic prostaglandins.
1. Introduction
 An enormous range of chemical mediators have been implicated in
sensory 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
Alteration of the phenotype 表现型 of the afferent nerve, for example
through alterations in the expression of mediators, channels, and
or modulating the activity of these by changing the ligand-binding
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.
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.
 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
 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.
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.
 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.
 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
 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.
4. Some Mediators
(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
 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.
 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.
(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
 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
 PGE2 acts through multiple EP receptors.
 In the gastrointestinal tract, EP1 receptors appear to play a
major role in direct activation of mucosal mesenteric
 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.
 Two isoforms 异构体 of the COX enzyme have been
 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 in
this syndrome.
 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
 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.
(3) Tachykinins 速激肽
 The tachykinins (TKs) are a family of small peptides
 Share the common C-terminal sequence Phe苯丙氨酸-XGly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)
 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.
 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.
(4) Calcitonin gene-related peptide 降钙素基因相关
肽 (CGRP)
 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.
 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.
 The intravenous administration of the CGRP1 receptor
antagonist 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
 CGRP is also involved in the mediation of pain produced
by lower gut distension.