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Home , Organ (biology), Thoracic cavity, Visceral pain

Lecture Objectives:

1) Describe the anatomical components/pathways that are involved in carrying sensory information from the organs (cervical, thoracic, abdominal, pelvic) to the . 2) Describe the functional differences between the sensory and the autonomic . 3) Describe how visceral 10 afferent 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 . 6) Discuss what roles visceral afferents may be playing when they are not producing the conscious sensation of pain. Viscera and their

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8 4 : 1) Visceral pain is pain that results from activation of (or afferents capable of transmitting noxious stimuli) innervating, cervical, thoracic, abdominal or pelvic organs. 2) Visceral pain usually arises in response to distension, or . Not so much from burning or cutting stimuli. 3) Is very often accompanied by other symptoms including , 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 – , obstruction, inflammation (all –itises, gastritis, , 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., (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. The relation of the to the determines, in part, how pain is perceived 1) All organs are held in position to varying degrees by layers of connective derived from the mesothelium. innervating the organ run in and through these tissues. 2) Called plura on the , on the 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 (plura, pericardium or peritoneum), forming suspensory with specific names, e.g., of the intestines. Large bundles are contained in these , running with vessels. 5) Other organs are pinned against the body wall under this tissue, e.g., kidneys, , as well as the ascending and descending colon. In the these organs are called “retroperitoneal”. Disease from these organs can spread to the body wall and engage somatic nociceptors. Note location up against the body wall

Note proximity to Unlike somatic , most organs get input for 10 afferents from two sources Spinal or “Sympathetic” Craniosacral or “Parasympathetic” NTS nodose ganglion

1 2 cervical 3 4 5 greater 6 7 splanchnic 8 1 nerve 2 thoracic 3 4 5 6 7 CG 8 9 10 SMG 11 12 1 2 lumbar 3 IMG 4 least 5 1 2 lumbar s.n. 3 4 Pelvic 5 Pelvic prevertebral splan. ganglia nerve 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 , they have things in common (e.g. firing properties, peptides and TRP channels) and things that are unique (below). 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 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. – 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. Examples of Referred Pain for the GI tract

1) Right lower quadrant: 2) Right upper quadrant: a. Acute appendicitis a. Acute cholecystitis b. Mesenteric lymphadenitis b. Biliary colic c. Infective distal ileitis c. Acute hepatic distension or inflammation d. Crohn’s disease d. Perforated duodenal ulcer e. In women: 3) Central i. Ectopic pregnancy a. Gastroenteritis ii. Ruptured ovarian cyst b. Small intestinal colic iii. Acute salpingitis c. Acute pancreatitis f. Renal disorders 4) Left upper quadrant i. Right ureteric calculus a. Perisplenitis ii. Acute pyelonephritis b. Splenic infarct g. Acute cholecystitis 5) Left lower quadrant h. Acute rheumatic fever a. Acute diverticulitis i. Pyogenic sacroiliitus b. Pyogenic sacroiliitis •How could nonprofessional (dedicated) visceral nociceptors transmitted noxious stimuli? •Frequency Coding – low frequency firing pattern is interpreted by the CNS as normal . 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 and brain. Changes in primary afferents may be the first step in changes that occur throughout the pain pathway. Allodynia in the GI tract can be a real problem

Normal patient IBS patient % % ReportingPain

NPP

Pressure Visceral innervation is sloppy – dually projecting afferents in the periphery and convergence centrally

DRG DRG

From Kannampalli and Sengupta , JNM, 2015, 21:147 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 ) 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). First stop of nodose afferents is the NTS

DMN 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 ). 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 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 to the colon splenic flexure (at least). Spinal Visceral Sensory - Conscious Pain

Spinal ganglion Spinal Visceral Pathways • Sensory fibers originate in the spinal or dorsal 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 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) . When we normally think of ascending pain pathways….. … 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 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 .

Vagal afferents have implicated in the “affective” aspects of visceral pain. 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 of GI tract and vascular system via connections to both sympathetic and parasympathetic systems. – Modulation of the – 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 Nodose vs DRG (all) neurons for regulators of immune function Take home message

1) Most organs get innervation from 2 different afferent (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. Physiology and of the vagal cholinergic antiinflammatory pathway

J Clin Invest DOI: 10.1172/JCI30555 Majority of spinal visceral afferents are peptidergic and release CGRP – important for vascular and immune regulation

Visceral afferent ending

norepinephrine

Sympathetic ending