between the duodenum and stomach, in this case to regulate gastric emptying. ... CNS mediate co-ordination with other bo
Progress in Neurobiology 72 (2004) 143–164
Intrinsic primary afferent neurons and nerve circuits within the intestine John B. Furness a,∗ , Clare Jones b , Kulmira Nurgali a , Nadine Clerc b a
Department of Anatomy & Cell Biology and Centre for Neuroscience, University of Melbourne, Parkville, Vic. 3010, Australia b Lab ITIS, UMR CNRS-Univ Méditerranée, Marseille, France Received 30 August 2003; accepted 3 December 2003
Abstract Intrinsic primary afferent neurons (IPANs) of the enteric nervous system are quite different from all other peripheral neurons. The IPANs are transducers of physiological stimuli, including movement of the villi or distortion of the mucosa, contraction of intestinal muscle and changes in the chemistry of the contents of the gut lumen. They are the first neurons in intrinsic reflexes that influence the patterns of motility, secretion of fluid across the mucosal epithelium and local blood flow in the small and large intestines. In the guinea pig small intestine, where they have been characterized in detail, IPANs have Dogiel type II morphology, that is they are large round or oval neurons with multiple processes, some of which end close to the luminal surface of the intestine, and some of which form synapses with enteric interneurons, motor neurons and with other IPANs. The IPANs have well-defined ionic currents through which their excitability, and their functions in enteric nerve circuits, is determined. These include voltage-gated Na+ and Ca2+ currents, a long lasting calcium-activated K+ current, and a hyperpolarization-activated cationic current. The IPANs exhibit long-term changes in their states of excitation that can be induced by extended periods of low frequency activity in synaptic inputs and by inflammatory mediators, either applied directly or released during an inflammatory challenge. The IPANs may be involved in pathological changes in enteric function following inflammation. © 2003 Elsevier Ltd. All rights reserved.
Contents 1. 2.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Neural control of intestinal function: types of neurons that form enteric nerve circuits . . Intrinsic primary afferent neurons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Why use this terminology? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. What properties are expected of primary afferent neurons? . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Primary afferent neurons: intrinsic and extrinsic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Characteristics of intrinsic primary afferent neurons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4.1. Chemosensitive IPANs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4.2. IPANs sensitive to stretch or distortion at the level of the myenteric plexus . . . 2.4.3. Mucosal mechanoreceptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5. Polymodal nature of IPANs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
144 144 144 144 146 146 147 150 150 151 151
Abbreviations: A1 , adenosine 1 receptor; AC, adenylyl cyclase; ACh, acetylcholine; AHP, afterhyperpolarizing potential; BK, large-conductance potassium channel; BB, bombesin; CCK, cholecystokinin; CGRP, calcitonin gene related peptide; ChAT, choline acetyltransferase; CNS, central nervous system; COX-2, cyclooxygenase-2; DAG, diacyl glycerol; ENK, enkephalin; EPSP, excitatory post-synaptic potential; GABA, ␥-aminobutyric acid; GAL, galanin; CaV , voltage-dependent Ca2+ conductance; gKCa , Ca2+ -dependent K+ conductance; gNaV , voltage-dependent Na+ conductance; GRP, gastrin releasing peptide (the mammalian form of bombesin); H2 , histamine 2 receptor; HVA, high voltage-activated Ca2+ channel; 5-HT, 5-hydroxytryptamine; IA , A-type K+ current; IAHP , AHP current; IBS, irritable bowel syndrome; ICaV , voltage-dependent Ca2+ current; Ih, hyperpolarization-activated cation current; IK, intermediate-conductance potassium channel; IL, interleukin; IP3, inositol triphosphate; IPAN, intrinsic primary afferent neuron; IR, immunoreactivity; M2 , muscarinic 2 receptor; NFP, neurofilament protein; NK, neurokinin; NOS, nitric oxide synthase; NPY, neuropeptide Y; PACAP, pituitary adenylyl cyclase-activating peptide; PDBu, phorbol dibutyrate; PG, prostaglandin; PKA, protein kinase A; PKC, protein kinase C; PLC, phospholipase C; Rin, input resistance; SK, small-conductance potassium channel; SOM, somatostatin; SSPE, sustained slow post-synaptic potential; TEA, tetraethylammonium; TK, tachykinin; TNBS, trinitrobenzene sulfonic acid; TNF, tumor necrosis factor; TTX, tetrodotoxin; TTX-R INaV , TTX-resistant sodium current; VIP, vasoactive intestinal peptide ∗ Corresponding author. Tel.: +61-3-83448859; fax: +61-3-93475219. E-mail address:
[email protected] (J.B. Furness). 0301-0082/$ – see front matter © 2003 Elsevier Ltd. All rights reserved. doi:10.1016/j.pneurobio.2003.12.004
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Synaptically-mediated changes in IPAN excitability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6.1. Slow excitatory post-synaptic potentials (slow EPSPs) . . . . . . . . . . . . . . . . . . . . . . . 2.6.2. Sustained slow post-synaptic excitation (SSPE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.7. Synaptic interactions between IPANs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.8. IPANS are activated in groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.9. Changes in IPAN excitability caused by inflammatory mediators . . . . . . . . . . . . . . . . . . . . . 2.10. Are IPANs involved in neuropathologies? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Enteric nerve circuits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Involvement of IPANs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Inter-species differences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Circuits for motility control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.1. Different patterns of motility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Secretomotor and vasomotor reflexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6.
1. Introduction The enteric nervous system is involved in many physiological and pathophysiological processes in the gastrointestinal tract. It is essential to normal life, as indicated by the high morbidity or mortality associated with congenital or acquired abnormalities of the enteric nervous system (De Giorgio et al., 2000; Sharkey and Lomax, 2001). Pathological conditions involving enteric neuronal abnormalities include achalasia and chronic intestinal pseudo-obstruction, that cause dysmotilities, and conditions such as infantile hypertrophic pyloric stenosis and Hirschsprung’s disease that are potentially fatal. By contrast, animals and humans have low morbidity after comprehensive interference with the sympathetic or parasympathetic divisions of the autonomic nervous system, such as removal of the sympathetic chains (Cannon et al., 1929), or total infracardiac vagotomy (Kuntz, 1945). For a long time after their discovery in the mid-19th century, the internal structures of the intrinsic ganglia of the gastrointestinal tract and the circuits that they form remained a mystery. However, with the advent of new technologies in the last 20 years, the organization of enteric circuits has been substantially unraveled, and in very recent years many important advances in understanding the roles of individual neurons in the circuits have been made. Each of the major neuron types, intrinsic primary afferent neurons, interneurons and motor neurons, has been characterized. Of these, the identification of the intrinsic primary afferent neurons has been the most recent, and a significant portion of this review relates to these neurons and their properties. 1.1. Neural control of intestinal function: types of neurons that form enteric nerve circuits Substantial agreement exists between laboratories concerning the classification of neurons in the small and large intestines of the guinea pig (Costa et al., 1996; Furness et al.,
152 152 153 154 154 154 155 156 156 156 156 157 158 159 159 159
2000; Brookes, 2001). There are 14 types of neuron in the small intestine (Fig. 1, Table 1), although some of these types can be subdivided. For example, the inhibitory neurons to the circular muscle can be divided into subgroups with short and with long axons, which have slightly different chemical coding.
2. Intrinsic primary afferent neurons 2.1. Why use this terminology? Cervero (1994) has provided a valuable summary of the conceptual differences between the afferent innervation of tissues and organs and their sensory innervation. As he points
Fig. 1. The types of neurons in the small intestine of the guinea pig, all of which have been defined by their functions, cell body morphologies, chemistries, key transmitters and projections to targets. The numbers adjacent to the neurons correspond to the numbers in Table 1, which lists each of the neuron types by their functions and provides data on the their chemistries and the percentages of their cell bodies in the myenteric or submucosal ganglia. LM: longitudinal muscle; MP: myenteric plexus; CM: circular muscle; SM: submucosal plexus; Muc: mucosa.
Table 1 Types of neurons in the enteric nervous system Chemical coding
Function/comments
Myenteric neurons Excitatory circular muscle motor neurons (6)
12%
Short: ChAT/TK/ENK/GABA; long: ChAT/TK/ENK/NFP
Inhibitory circular muscle motor neurons (7)
16%
Excitatory longitudinal muscle motor neurons (4) Inhibitory longitudinal muscle motor neurons (5)
25% About 2%
Short: NOS/VIP/PACAP/ENK/NPY/GABA; long: NOS/VIP/PACAP/dynorphin/BB/NFP ChAT/calretinin/TK NOS/VIP/GABA
Ascending interneurons (1) Descending interneurons local reflex (8)
5% 5%
ChAT/calretinin/TK ChAT/NOS/VIP ± BB ± NPY
Descending interneurons (secretomotor reflex) (9)
2%
ChAT/5-HT
Descending interneurons (migrating myoelectric complex) (10) Myenteric intrinsic primary afferent neurons (2) Intestinofugal neurons (3) Excitatory motor neurons to the muscularis mucosae* Inhibitory motor neurons to the muscularis mucosae*
4% 26%
