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1) Describe the anatomical components/pathways that are involved
in carrying sensory information from the organs (cervical,
thoracic, abdominal, pelvic) to the brain.
2) Describe the functional differences between the sensory and
the autonomic nervous system.
3) Describe how visceral 10 afferent anatomy and responses are
or are not different from somatic 10 afferents.
4) Describe the functional and anatomical differences between
vagal and spinal visceral afferents.
5) Describe the anatomical basis for referred pain.
6) Discuss what roles visceral afferents may be playing when
they are not producing the conscious sensation of pain.
Lecture Objectives:
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Viscera and their pathology
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5
6
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10
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Visceral Pain:
1) Visceral pain is pain that results from activation of
nociceptors (or afferents capable of transmitting noxious stimuli)
innervating, cervical, thoracic, abdominal or pelvic organs.
2) Visceral pain usually arises in response to distension,
ischemia or inflammation. Not so much from burning or cutting
stimuli.
3) Is very often accompanied by other symptoms including nausea,
vomiting and emotional manifestations (e.g., fear, depression).
These are referred to as the affective aspects of visceral
pain.
4) Pain is described as sickening, deep, squeezing, dull,
cramping. It often only become “sharp” or “stabbing” when it
spreads to the body wall (next slide).
5) Visceral pain is often associated with overt pathology –
cancer, obstruction, inflammation (all –itises, gastritis,
pancreatitis, esophagitis, colitis). It can also have a neuropathic
component when organs change shape.
6) Is also found in patients with no clear pathology but with
functional symptoms (e.g., irritable bowel syndrome (IBS),
characterized by pain plus constipation or diarrhea). These
syndromes are called Functional Gastrointestinal Disorders
(FGID).
7) The most common types of GI disease include Inflammatory
Bowel Diseases (Crohn’s and Ulcerative Colitis) and Celiac Disease.
Pain is variable in these conditions.
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The relation of the organ to the mesothelium determines, in
part, how pain is perceived
1) All organs are held in position to varying degrees by layers
of connective tissue derived from the mesothelium. Nerves
innervating the organ run in and through these tissues.
2) Called plura on the lungs, pericardium on the heart and
peritoneum for the abdominal and pelvic organs.
3) These tissues start out on the thoracic, abdominal or pelvic
wall and wrap over the organ. When this tissue is on the wall it is
call parietal, when it on the organ it is call visceral, e.g.,
parietal and visceral peritoneum. Visceral afferents run in and
through the visceral peritoneum, plura or pericadium.
4) Many organs (esp. abdominal) are suspended by two enveloping
layers of connective tissue (plura, pericardium or peritoneum),
forming suspensory ligaments with specific names, e.g., mesentery
of the intestines. Large nerve bundles are contained in these
mesenteries, running with blood vessels.
5) Other organs are pinned against the body wall under this
tissue, e.g., kidneys, pancreas, as well as the ascending and
descending colon. In the abdomen these organs are called
“retroperitoneal”. Disease from these organs can spread to the body
wall and engage somatic nociceptors.
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Note location up against the body wall
Note proximity to bone
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Unlike somatic structures, most organs get input for 10
afferents from two sources
lumbar
Pelvic splan.
1211
1
1
1
2
2
3
3
4
CG
cervical
thoracic
vagus nerve
nodose ganglionNTS
SMG
IMG
45
5
5
1098
8
7
7
6
6
5
4
4
3
3
2
21
Spinal or “Sympathetic”
greater splanchnic nerve
prevertebral ganglia
least
lumbar s.n.
Pelvic nerve
Craniosacral or “Parasympathetic”
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Visceral primary afferents
•Anatomically much less complex than cutaneous afferents. The
fanciest belong to vagal afferents.
•Visceral nociceptors (1st neuron in pain pathway) are usually
unmyelinated (aka C-fiber) or lightly myelinated (A∂ fiber) – no
known Ab fibers.
•They respond to noxious mechanical stimulation (aka high
threshold mechanical stimulation) and/or noxious heat (fire),
noxious cold, or chemical (pH) stimuli. But not to cutting. They
can detect temperature and TRP channel agonists but may not produce
equivalent sensations.
•Many visceral afferents (perhaps the majority) can detect both
noxious and non-noxious stimuli (Rick’s broad dynamic range
neurons); e.g., the GI tract is heavily innervated by sensory
neurons that can do more than one job. But, the GI tract also has
professional nociceptors; those neurons that fire in response to
noxious stimuli (intense distension, low pH).
•Vagal afferents are thought to convey different aspects of pain
from afferents arising from spinal afferents. However, with respect
to neurochemistry and physiology, they have things in common (e.g.
firing properties, peptides and TRP channels) and things that are
unique (below).
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The majority of vagal afferents code over a wide range of
mechanical stimuli and yet, are not considered to contribute to
pain sensations.
Colon afferents can code intensity well, but these are in a
minority
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Reconstruction of Central Projection of Single Visceral
Afferent.Take home message? Single visceral (in this case spinal)
afferent projects to a large number of spinal neurons making it
very likely that synaptic activity generated by this fiber will
overlap with somatic sensation.
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Referred Pain – makes it even more sloppy
Referred pain is due to somatic and visceral afferents sharing
the same second order sensory neurons in the dorsal horn.
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1) Right lower quadrant:a. Acute appendicitis
b. Mesenteric lymphadenitis
c. Infective distal ileitis
d. Crohn’s disease
e. In women:
i. Ectopic pregnancy
ii. Ruptured ovarian cyst
iii. Acute salpingitis
f. Renal disorders
i. Right ureteric calculus
ii. Acute pyelonephritis
g. Acute cholecystitis
h. Acute rheumatic fever
i. Pyogenic sacroiliitus
2) Right upper quadrant:a. Acute cholecystitis
b. Biliary colic
c. Acute hepatic distension or inflammation
d. Perforated duodenal ulcer
3) Central abdominal pain
a. Gastroenteritis
b. Small intestinal colic
c. Acute pancreatitis
4) Left upper quadrant
a. Perisplenitis
b. Splenic infarct
5) Left lower quadrant
a. Acute diverticulitis
b. Pyogenic sacroiliitis
Examples of Referred Pain for the GI tract
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•How could nonprofessional (dedicated) visceral nociceptors
transmitted noxious stimuli?
•Frequency Coding – low frequency firing pattern is interpreted
by the CNS as normal function. At high frequency, stimulation is
perceived as pain.
•Silent afferents – In the bladder and colon there are sensory
fibers that do not normally fire even at potentially noxious levels
of stimulation. Following inflammation, these fibers become active
and may be active even during normal micturition producing painful
sensation. These fibers would be a special class of sensory neurons
that would be classified as nociceptors.
•Note - the two choice above do not begin to consider changes
that could (and probably do) occur in the spinal cord and brain.
Changes in primary afferents may be the first step in changes that
occur throughout the pain pathway.
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% R
epor
ting
Pai
n
Pressure
NPP
IBSpatient
Normal patient
Allodynia in the GI tract can be a real problem
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Visceral innervation is sloppy – dually projecting afferents in
the periphery and convergence centrally
From Kannampalli and Sengupta , JNM, 2015, 21:147
DRG DRG
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The Vagal System
Components of the Vagus nerve include:• Visceral motor output
from the dorsal motor nucleus (DMN) of the vagus.• Somatic motor
output from the nucleus ambiguus.• Somatic sensory neurons located
in superior vagal ganglion (jugular in the rodents and other
mammals) that project to trigeminal nucleus (not shown in diagram
below). In rodents some of these project to organs in thoracic and
abdomen and project centrally to the paratrigeminal nucleus. •
Visceral sensory neurons located in the inferior vagal ganglion
(aka nodose) that project to the nucleus tactus solitarius
(nTS).
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First stop of nodose afferents is the NTS
DMN
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More vagal tidbits (but important)
• Vagus mean “wanderer”.
• It is 80-85% sensory.
• Dogma says that vagal visceral sensory fibers do not carry
“pain”information for the gut (it may transmit pain for organs of
the thoracic cavity). Moreover, most visceral sensory information
carried in the vagus does NOT reach consciousness. It may be
associated with general feelings like hunger, satiety, nausea, as
well as emotional components of visceral pain. How do we know this?
(Hint: what patient population could provide insight into this
issue?)
• Visceral afferents encode physical and chemical events
(distension, contraction, pH) and relay this information back to
the CNS to modulate function.
• The vagus provides sensory fibers to organs from the pharynx
to the colon splenic flexure (at least).
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Spinal Visceral Sensory - Conscious Pain
Spinal ganglion
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Spinal Visceral Pathways• Sensory fibers originate in the spinal
or dorsal root ganglia.
• Only 1-2% of all spinal sensory neurons innervate viscera.
• Sensory fibers must “hitch a ride’ with components of the
sympathetic nervous system and the sacral portion of the
parasympathetic system. They do not belong to either system!
• For the sympathetic system innervating the abdominal organs,
sensory fibers run with the greater (T5 to T 8) splanchnic nerve,
the lesser (T10 to T11) splanchnic nerve, the least (T12 )
splanchnic nerve , the lumbar splanchnics (there are usually 4 in
humans), and sacral splanchnics.
• For the afferents innervating pelvic organs, sensory fibers
run with pelvic splanchnic nerves that also contain preganglionic
parasympathetic fibers.
• Visceral afferents arising from DRG will project to second
order neurons in the dorsal horn that then ascend in the
spinothalamic tract or if they enter the postsynaptic dorsal column
pathway (below) they end up in the nucleus gracilis and cuneatus
(normally associated with proprioception) .
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When we normally think of ascending pain pathways…..
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… But spinal visceral afferents can synapse on postsynaptic DC
neurons that project to medulla – into regions typically associated
with proprioception
William D. Willis et al. PNAS 1999;96:7675-7679
©1999 by National Academy of Sciences
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Visceral Pain Comorbidities – Pain is only the beginning
1) Depression – persistent visceral pain can lead to depression,
depression can cause pain and each condition can exacerbate the
other.
2) Nausea – Primarily the domain of vagal afferents (see below).
#1 reason that chemotherapies are aborted. Even more so than
vomiting.
3) Cachexia – Weakness, fatigue and muscle loss. Can accompany
pain, is negative symptom for any GI disorder, especially GI
cancers.
Vagal afferents have implicated in the “affective” aspects of
visceral pain.
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What are visceral afferents doing when they aren’t transmitting
nociceptive stimuli (for those that can)
• Vagal afferents may be modulating somatic pain:
– Somatic reflexes can be facilitated or inhibited depending on
intensity of stimulation.
– Vagal reflexes important for homeostasis of GI tract and
vascular system via connections to both sympathetic and
parasympathetic systems.
– Modulation of the immune system
– GI tract has more immune cells that the rest of the immune
system. Vagal and spinal afferent express both cytokines and
receptors for immune regulators
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Nodose vs DRG (all) neurons for regulators of immune
function
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Take home message1) Most organs get innervation from 2 different
afferent populations (vagal
and spinal), that run with, but do not belong to the sympathetic
and parasympathetic nervous system.
2) Spinal visceral afferents project widely to the dorsal horn
and can use ascending pathways that include small fibers ascending
in the dorsal column.
3) Vagal pathways are responsible for many of the
non-nociceptive features of that accompany visceral pain (affective
pain aspects).
4) Referred pain is due to convergence of primary visceral
afferents on 2nd
order neurons that receive somatic input.
5) When not transmitting noxious sensations visceral afferents
are very busy regulating somatic sensations and homeostasis
including the maintenance of target tissues (not discussed) and
regulation of immune and vascular systems.
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Physiology and immunology of the vagal cholinergic
antiinflammatory pathway
J Clin Invest DOI: 10.1172/JCI30555
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Majority of spinal visceral afferents are peptidergic and
release CGRP – important for vascular and immune regulation
Visceral afferent ending
Sympathetic ending
norepinephrine