Primary afferent neurons of the gut
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 –
Co-ordination with other body system
Relate to sensation including discomfort, nausea, pain and satiety
Extrinsic primary afferent
Primary afferent neurons：
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
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
projections to targets
(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
(9) Descending interneurons (2%):
(10) Descending MMC
(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%)
(11) Submucosal intrinsic primary
afferent neurons (11%)
LM: longitudinal muscle; MP:
myenteric plexus; CM: circular muscle;
SM: submucosal plexus; Muc: mucosa
(14) Cholinergic secretomotor
(non-vasodilator) neurons (29%)
2. Characteristics of intrinsic primary afferent neurons (IPANs)
Shape: round or oval
Processes: multi-axonal or
traverse the cell bodies
can be conducted to
output synapses via an
axon reflex (axon reflex
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
IPANS respond to chemicals, such as inorganic acid and short chain
May be indirect, via 5-HT or ATP
SAC, stretch open
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;
2. Myenteric intrinsic primary afferent
9. Descending interneurons:
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
Intestinofugal fibres 肠离心神经纤维 that project to prevertebral
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
nucleus tracuts solitarius
dorsal motor nucleus of
the vagus (DMV); （迷走
the area postrema （最
Projection from nTS
Reflex connection with other brain stem nuclei: vago-vagal reflex
To preganglinoic neurons
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.
(2) Spinal Afferent
Cell Body: dorsal root
Input: to the cord
through the dorsal roots
and referred pain （牵涉
Projection to the brain:
Via spinothalamic tract,
spinoreticular tract and
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.
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)
Relay information mainly to the brain stem via unmyelinated
（无髓） vagal afferent fibers.
Sensitive to light stroking of the mucosa
Generating a brief burst of impulses each time the stimulus passes over the
Relatively insensitive to distension, contraction, or compression except the
distortion of the mucosa occurs、
Multimodal Receptors – response to both mechanical and
Not very specific
Sensitive to acid, alkali, hyper- or hypo- osmotic solution.
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
•Slowly absorptive mannose （甘露糖） or nonabsorbable mannitol
Amino acid receptors
Vagal afferent C-fibers
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?
Follow vagus pathway
•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
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
sensitive to active tension
as Golgi tension organ
in series with the muscle
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
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
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
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
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
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.
parallel to the
fibres and respond
to circular muscle
stretch rather than
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.
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
Release of SP and
CGRP modulated by
which facilitates release
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
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.
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:
opening of ion channels present on the nerve terminals
occur in the absence of a direct stimulation
results in afferent hyperexcitability to both chemical and
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
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
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
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
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
Proinflammatory: Capable of promoting
inflammation. For example, air pollution may have
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
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
B2 receptor antagonists 阻断剂 attenuate visceral pain in acute
In chronic inflammation models, the role of the inducible
B1 receptor in visceral nociception mechanisms becomes
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
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
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
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
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
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
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.