Visceral Pain—Peripheral Sensitisation Gut: First Published As 10.1136/Gut.47.Suppl 4.Iv54 on 1 December 2000

iv54 Gut 2000;(Suppl IV)47:iv54–iv55

Visceral pain—peripheral sensitisation Gut: first published as 10.1136/gut.47.suppl_4.iv54 on 1 December 2000. Downloaded from

G F Gebhart

The viscera receive dual sensory innervation. LT and HT pelvic nerve colonic The majority of visceral sensory ﬁbres termi- afferents encode in the noxious range nate in the spinal cord but sensory ﬁbres contained in the vagus and pelvic nerves, which 40 Low terminate in the brain stem and lumbosacral threshold fibres spinal cord, respectively, also innervate the 30 same visceral organs. Figure 1 illustrates this unique pattern of innervation for the gastro- 20 intestinal tract, classically referred to as sympa- (imp/20 s) thetic and parasympathetic, but more appro- 10 priately designated by nerve name (for High

Response to distension Response threshold fibres example, hypogastric nerve, pelvic nerve). 0 Visceral sensory axons are almost exclusively 0 20406080 100 thinly myelinated Aä fibres and unmyelinated Distending pressure (mm Hg) C fibres. Activity in most visceral sensory neu- Figure 2 Mechanosensitive pelvic nerve sensory fibres rones, whether in vagal aVerent fibres or spinal that innervate the urinary bladder or distal colon have low a erent fibres, does not reach consciousness. (<5 mm Hg) or high (>30 mm Hg) thresholds for response V to distension. Both low (LT) and high (HT) threshold For example, there is regular input into the sensory fibres encode the distending pressure well into the central nervous system from gastric and noxious range (>40 mm Hg). (Modified from Sengupta 3 hepatic chemoreceptors, aortic baroreceptors, and Gebhart. ) etc., that is not perceived. ganglia (where they can give oV collateral axons Sensory innervation of the gastrointestinal to influence autonomic ganglion cell bodies tract involves all layers of a viscus (mucosa, and, accordingly, secretory and motor func- muscle, and serosa) and visceral receptors tions) and paravertebral ganglia (see fig 1). exhibit chemosensitivity, thermosensitivity, In contrast with aVerent fibres arising from and mechanosensitivity. Visceral receptors, in somatic structures, the number of spinal visceral Department of fact, are generally polymodal in character (that aVerent fibres is estimated to be less than 10% of Pharmacology, College is, respond to multiple modalities of stimula- the total spinal aVerent input from all sources. of Medicine, tion). The cell bodies of visceral aVerent Some compensation for this relative paucity of University of Iowa, neurones, in common with the cell bodies of visceral input is provided by the significantly http://gut.bmj.com/ 2-454 Bowen Science Building, Iowa City, somatic aVerent neurones, are located in dorsal greater rostrocaudal intraspinal spread of vis- Iowa 52242-1109, USA root ganglia (except for the nodose ganglia ceral aVerent fibre terminals. Visceral C fibres G F Gebhart which contain the cell bodies of vagal sensory have been found to have many more terminal neurones). However, the route visceral aVerent swellings (suggestive of synapses) and terminal Correspondence to: areas, and to exhibit rostrocaudal distribution Professor G F Gebhart. neurones take to the spinal cord typically [email protected] involves passage through or near prevertebral over several spinal cord segments.

Experimentally, balloon distension is the on September 26, 2021 by guest. Protected copyright. NTS most reliable stimulus for hollow visceral organs and is the most widely used stimulus in Paravertebral both human and non-human animal experi- 2 ganglia Vagus nerve ments. Accordingly, we know most about the response properties of mechanosensitive vis- Greater ceral aVerent fibres, usually those innervating splanchnic nerve the muscle layer. Hollow viscera are innervated by two populations of mechanosensitive aVer- ent fibres: a larger group (70–80%) of fibres

Lumbar CG have low thresholds for response and a smaller colonic n. group (20–30%) of aVerent fibres have high SMG thresholds for response (for example, >30 mm Hg distending pressure) (fig 2). Visceral mechanoreceptors that have low IMG Hypogastric thresholds for response (for example, <5 mm nerve Hg) respond within the physiological range. Pelvic Interestingly, as illustrated in fig 2, these aVer- nerve ent fibres also respond to distending pressures in the noxious range (>30 mm Hg) and encode Figure 1 Representation of visceral sensory innervation of the gastrointestinal tract. The sensory innervation that anatomically exists in association with the sympathetic nervous stimulus intensity fairly well. Note also that system is shown on the left. These spinal visceral sensory fibres traverse both prevertebral response magnitude in the noxious range is (CG, coeliac ganglion, IMG, inferior mesenteric ganglion, SMG, superior mesenteric ganglion) and paravertebral ganglia en route to the spinal cord. Pelvic and vagus nerve innervation to the sacral spinal cord and brain stem, respectively, is shown on the right. Abbreviations used in this paper: IBS, irritable (Modified from Sengupta and Gebhart.1) bowel syndrome; CRD, colorectal distension.

www.gutjnl.com Visceral pain iv55

100 IBS Control Gut: first published as 10.1136/gut.47.suppl_4.iv54 on 1 December 2000. Downloaded from

80 Inflamed 60 Normal subjects 40 100 0

20 mm Hg 8006004002000 1000 1200 1400 18001600 2000 Time (s)

0 Figure 4 Visceral sensory fibres sensitise to experimental Proportion reporting pain (%) reporting Proportion organ inflammation. In this example, responses of a high 0 100 200 300 threshold pelvic nerve sensory fibre are shown before (control) Balloon volume (ml air) and 30 minutes after intracolonic instillation of 2.5% acetic acid (inflamed). Note that response magnitude to distension Figure 3 Illustration of the presence of visceral (bottom) increases after inflammation and that response hyperalgesia in patients with irritable bowel syndrome threshold decreases from about 30 to 10 mm Hg. (IBS). (Modified from Ritchie.5) Intracolonic typically greater than response magnitude of mustard oil 10 Hz high threshold fibres at the same distending (2 ml, 5%) pressure. Visceral mechanoreceptors that have 100 s high thresholds for response do not begin to respond until the distending pressure is at or exceeds pressures that are likely noxious. How do responses of visceral sensory fibres change in response to visceral inflammation? As they typically do, clinical observations led the way to changes in the way in which visceral pain is considered. In 1973, Ritchie4 docu- mented that irritable bowel syndrome (IBS) CRD CRD patients reported pain at lower volumes of balloon distension of the colon than normal Figure 5 Example of a mechanically insensitive (silent) pelvic nerve sensory fibre. Before intracolonic instillation of subjects (fig 3). the C fibre excitant mustard oil, this fibre did not respond to As illustrated, less than 10% of normal 100 mm Hg colonic distension (CRD) (not shown). After subjects reported pain at a distending volume of mustard oil treatment, the fibre began to discharge and acquired sensitivity to CRD. (Modified from Sengupta and about 60 ml whereas greater than 50% of IBS Gebhart.1) patients reported pain at the same distending volume. This leftward shift in the psychophysical activity and inflammation did not provoke any function of IBS patients suggests the presence of change in resting activity. Another conse- hyperalgesia in IBS. Qualitatively similar out- quence of visceral inflammation is the awaken- http://gut.bmj.com/ comes have been confirmed subsequently by ing of what have been termed “silent nocicep- others and also extended to other hollow viscera tors,” which are really mechanically insensitive in patients with other of the so called functional aVerent fibres that acquire mechanosensitivity bowel disorders (non-cardiac chest pain, non- after visceral inflammation. Such silent or ulcer dyspepsia, and IBS). Accordingly, it is sleeping aVerents are present in all tissues considered that the altered sensations (bloating, studied (including human skin), are normally

discomfort, and abdominal pain) associated unresponsive to acute noxious stimulation, and on September 26, 2021 by guest. Protected copyright. with these functional disorders represent vis- are believed to add to the aVerent barrage ceral hyperalgesia.6 If this hypothesis is correct, received by the central nervous system when then visceral aVerent fibres should exhibit sensi- tissue is injured. An example of a silent aVerent tisation and the spinal neurones on which they fibre innervating the colon of the rat is terminate should undergo a change in excitabil- illustrated above. This fibre did not respond to ity, mechanisms of primary and secondary either high intensity colorectal distension hyperalgesia, respectively (see discussion in (CRD) or urinary bladder distension, the prin- Mayer and Gebhart6). cipal organs innervated by the pelvic nerve. Experimental inflammation of hollow organs After intracolonic instillation of mustard oil, a has been shown to sensitise responses of mech- C fibre excitant, the fibre became active and anosensitive visceral sensory fibres and to mechanosensitive (fig 5). awaken so called silent aVerent fibres. By sensitisation is meant an increase in response mag- 1 Sengupta JN, Gebhart GF. Gastrointestinal aVerent fibers nitude to distending stimuli, sometimes associ- and sensation. In: Johnson, LR, ed. Physiology of the gastrointestinal tract. New York: Raven Press, 1994:483–519. ated with a reduction in response threshold 2 Ness TJ, Gebhart GF. Visceral pain: a review of experimen- and/or an increase in spontaneous activity. tal studies. Pain 1990;41:167–234. 3 Sengupta JN, Gebhart GF. Mechanosensitive aVerent fibers That is, the excitability of the sensory neurone in the gastrointestinal and lower urinary tracts. In: Gebhart is increased, as illustrated (fig 4) for a high GF, ed. Visceral pain. Progress in Pain Research and Manage- ment, vol. 5. Seattle: IASP Press, 1995:75–98. threshold mechanosensitive pelvic nerve fibre 4 Ritchie J. Pain from distension of the pelvic colon by inflat- innervating the colon of the rat. ing a balloon in the irritable colon syndrome. Gut 1973;14: 125–32. In this example, response threshold de- 5 Ritchie J. Mechanisms of pain in the irritable bowel creases from 30 to 10 mm Hg and response syndrome. In: Read N, ed. Irritable bowel syndrome.New York: Grune and Stratton, 1985:163–71. magnitude is increased for all distending pres- 6 Mayer EA, Gebhart GF. Basic and clinical aspects of sures. This sensory fibre had no spontaneous visceral hyperalgesia. Gastroenterology 1994;107:271–93.