Primary afferent neurons of the gut

1

• Primary afferent neurons of the gut
• (??????????)
• 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

2
Primary afferent neurons

• Extrinsic primary afferent neurons, including
• Vagal primary afferent neuron
• have cell bodies in (nodose and jugular) ganglia
  ???
• Spinal primary afferent neuron
• have cell bodies in dorsal root ganglia
• Intestinofugal neuron ??????
• Parts of the afferent limbs of entero-enteric
  reflex pathways
• Have cell bodies in ENS

intrinsic and extrinsic ???????
3

• Intrinsic primary afferent neurons, IPANs, within
  ENS

• Myenteric ?? IPANs respond to
• Distortion of their processes in the external
  muscle layers
• changes in luminal chemistry, via processes in
  the mucosa,
• submucosal ??? 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).
4
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
5

• Types of neurons that form enteric nerve circuits
• According to the
• functions,
• key transmitters
• projections to targets

6

• Myenteric Neurons
• Ascending interneurons( 5)
• Myenteric intrinsic primary afferent neurons
  (26)
• Intestinofugal neurons (lt1)
• Excitatory longitudinal muscle motor neurons
  (25)
• Inhibitory longitudinal muscle motor neurons (2)
• Excitatory circular muscle motor neurons (12)
• Inhibitory circular muscle motor neurons (16)

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)
7
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)
LM longitudinal muscle MP myenteric plexus
CM circular muscle SM submucosal plexus Muc
mucosa
8
2. Characteristics of intrinsic primary afferent
neurons (IPANs)

• Shape round or oval
• Processes multi-axonal or pseudounipolar(???)
• 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 (?????) 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 channel
12

• Mucosal mechanoreceptors
• Puffs of nitrogen gas on the mucosal induce C-Fos
  expression in IPAN
• Blocked by TTX
• Unaffected by hexamethonium (???), the nicotinic
  receptor antagonist
• Mostly indirect, through the release of 5-HT from
  enterochromaffin cells (?????) in the mucous
  membrane (??)

13

• 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

14

• 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/vasodil
ator neurons 13. Cholinergic secretomotor/vasodi
lator neurons 14. Cholinergic secretomotor
(non-vasodilator) neurons
15

• II Extrinsic Primary Afferent Neurons
• The rich sensory innervation (????) of the
  gastrointestinal tract comprise
• Intrinsic sensory neurons contained entirely
  within the gastrointestinal wall
• Intestinofugal fibres ??????? that project to
  prevertebral ganglia (?????)
• Vagal and spinal afferent that projects to the
  central nervous system.

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• Pathway to the central nervous system
• (1) Vagus Afferent (????????)

• Cell body superior and inferior (jugular and
  nodose) vagal ganglia
• Direct input
• nucleus tracuts solitarius (nTS) (???)
• dorsal motor nucleus of the vagus (DMV) (??????)
• the area postrema (???)
• 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 (?????)of the spinal
  cord
• Motorneurons supply the face and salivary glands
• Through the midbrain ?? and reticular nuclei ????
  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 through the dorsal roots
• Visceral convergence and referred pain (???)
• 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 (????)
• Lie in or immediately below the mucosal
  epithelium
• Detect the physical and chemical nature of
  luminal contents
• Muscle Receptors (????)
• Deep in the muscularis externae area
• Influenced by changes in muscle tension
• Serosal and Mesenteric Receptors (????????)
• Lie beneath the serosa or in the mesenteric
  attachments
• Sensitive to movements and distortion of the
  viscera

21

• 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 (??) pathway
• mainly conduct visual pain.

22

• 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 (??) 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 (??) and
  levulose (??) with slow adaptation
• Not sensitive to osmotic stimuli, acid or gross
  mechanical stimuli
• Only actively transported sugars are effective
• Blocked by phlorhizin(???), which prevent the
  transfer of glucose transportation
• Slowly absorptive mannose (???) or nonabsorbable
  mannitol (???)were ineffective

25

• 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 ?????
• 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 ?
• Regulation of insulin secretion
• Peripheral trigger for emesis

27

• (2) Muscle receptors
• Project pathway
• Afferent pathway for muscle receptors is mainly
  vagal
• Muscle receptors in the distal colon ??, rectum
  ?? and anal canal ?? 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 (?????) and stretch receptor
  (?????)
• 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

29

• Two kind of muscle receptors, IGLEs and IMAs
• Intraganglionic laminar endings ??????, IGLEs
• Location in myenteric ganglia
• Characteristic appearance laminae (??) of puncta
  (??) distributed on either or both muscle poles
  of ganglia

30
Each case shows a single axon entering a
myenteric ganglion and terminating as highly
arborizing ?? 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.
31

• Intramuscular array (IMA) ?????
• Location within the muscle
• Forms Consisting of an array of terminals
  running parallels to the muscle fiber

32

• 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 (BD).
• In panel (E), processes from the ending pass
  adjacently to a cluster of myenteric neurons.
• This afferents parent axon divided into five
  second-order branches which in turn divided into
  39 higher order terminal telodendra (???),
  forming a presumptive receptive field 4.93 mm
  long by 0.32 mm wide.

33

• 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 ?????

34
Topographic maps and plots illustrating the
density and distribution of IGLEs and IMAs in
stomach.
35

• 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.

36

• Physiological importance of muscle receptors
• reflex regulation of
  gastrointestinal function.
• Receptors in the esophagus are responsible for
  initiating secondary peristalsis
• Afferent fibers from corpus ?? 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 ?? and mesenteric ??? receptors
• Mechanoreceptor
• Anatomy
• Endings are associated with the peritoneum ??,
  either under the serosa or the viscus ?? near the
  mesenteric attachment or in the mesentery and
  omentum ??.
• Are found along the entire length of the
  gastrointestinal tract and accessory organs
• Have their cell bodies in the thoracic ?, lumbar
  ?, and sacral ? spinal ganglia, run mainly in the
  pelvic ?(??) and splanchnic nerve ???? to the
  spinal cord

38

• Response characteristics
• In small intestine, movement receptor.
• Some receptors response to the stimulation within
  physiologial level, while other only sensitive to
  pathological stimulation

39
Low threshold, high threshold and wide dynamic
nerves
Unit 1 low threshold ??? Unit 2 wide dynamic ???
Unit 3 high threshold ???
40
A. low threshold ??? B. high threshold ??? C.
wide dynamic ???
41
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
42

• 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 ?? 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 ?? against large
  increases in tone and intraluminal pressure.

45

• Visceral spinal afferent neurons have axon
  collaterals ??
• form en passant synapses with PVG neurons.
• has a higher (gt15 cm H2O) threshold for
  activation compared with IFANs.
• arranged in series with both longitudinal and
  circular muscle layers.
• Tension receptor

46

• release substance P (SP) P?? and calcitonin gene
  related peptide (CGRP) ???????? in prevertebral
  ganglia,
• evoke slow excitatory postsynaptic potentials
  (S-EPSPs) in sympathetic neurons.

47

• Release of SP and CGRP modulated by central
  preganglionic nerves.

• Central preganglionic nerves release neurotensin
  ????? which facilitates release of SP.
• preganglionic nerves release enkephalins ???
  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

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• Importance of IFANs
• Provide a protective buffer ?? 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 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 ???
• occur in the absence of a direct stimulation
• results in afferent hyperexcitability to both
  chemical and mechanical stimuli

52

• Alteration of the phenotype ??? 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 ???, e.g., cholera toxin ????.
• These toxins trigger release of 5-HT from EC
  cells to bring about an orchestrated response to
  dilute and subsequently eliminate the pathogenic
  ??? material from the body and preclude further
  consumption of the potentially harmful material.

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• 3. Visceral Hypersensitivity (??????)
• 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.

59

• A number of proinflammatory mediators (??????? )
  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
61

• (1) Bradykinin ??? (BK).
• Nonapeptide ?? 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).

62

• 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 ?? whole animal
  studies showing that
• B2 receptor antagonists ??? 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.

63

• 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 ???? to treat visceral
  hypersensitivity in inflammatory conditions.

64

• (2) Prostaglandins and leukotrienes ?????.
• Products of arachidonic acid ????? oxygenation
  are a major contributor to hyperalgesia ???? in
  the somatic ?? 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 (????) (COX) and lipoxygenase
  ???? enzyme

65

• 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 ?????? and elevation of
  intracellular cAMP,
• the membrane-permeable cAMP analog dibutyryl ????
  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.

66

• Two isoforms ??? 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 in this syndrome.

67

• 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 ?????? cells,
• may be important in the maintenance of the
  inflammatory state.

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(3) Tachykinins ???

• The tachykinins (TKs) are a family of small
  peptides
• Share the common C-terminal sequence
  Phe????-X-Gly???-Leu???-Met???NH2.
• Three peptides of this family, substance P,
  neurokinin ???? 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)

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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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(4) Calcitonin gene-related peptide ????????
(CGRP)

• CGRP is present in most splanchnic ??? afferents
• CGRP immunoreactivity ?????? almost disappears
  from the gut after either splanchnic nerve
  section or treatment with the sensory neurotoxin
  capsaicin ???.

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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 ???.

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• The intravenous administration of the CGRP1
  receptor antagonist human (h)-CGRP-(8-37)
• suppresses the abdominal cramps ?? observed after
  the intraperitoneal ??? administration of acetic
  acid ?? in awake rats and
• blocks the inhibition of gastric emptying induced
  by peritonitis ???.
• CGRP is also involved in the mediation of pain
  produced by lower gut distension.