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 Ca 2+ 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. Introduction ............................................................................ 144 1.1. Neural control of intestinal function: types of neurons that form enteric nerve circuits .. 144 2. Intrinsic primary afferent neurons ........................................................ 144 2.1. Why use this terminology? ........................................................ 144 2.2. What properties are expected of primary afferent neurons? ........................... 146 2.3. Primary afferent neurons: intrinsic and extrinsic ..................................... 146 2.4. Characteristics of intrinsic primary afferent neurons ................................. 147 2.4.1. Chemosensitive IPANs .................................................... 150 2.4.2. IPANs sensitive to stretch or distortion at the level of the myenteric plexus ... 150 2.4.3. Mucosal mechanoreceptors ................................................ 151 2.5. Polymodal nature of IPANs ....................................................... 151 Abbreviations: A 1 , 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; Ca V , voltage-dependent Ca 2+ conductance; gK Ca , Ca 2+ -dependent K + conductance; gNa V , voltage-dependent Na + conductance; GRP, gastrin releasing peptide (the mammalian form of bombesin); H 2 , histamine 2 receptor; HVA, high voltage-activated Ca 2+ channel; 5-HT, 5-hydroxytryptamine; I A , A-type K + current; I AHP , AHP current; IBS, irritable bowel syndrome; I CaV , voltage-dependent Ca 2+ current; Ih, hyperpolarization-activated cation current; IK, intermediate-conductance potassium channel; IL, interleukin; IP3, inositol triphosphate; IPAN, intrinsic primary afferent neuron; IR, immunoreactivity; M 2 , 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 INa V , TTX-resistant sodium current; VIP, vasoactive intestinal peptide ∗ Corresponding author. Tel.: +61-3-83448859; fax: +61-3-93475219. E-mail address: j.furness@unimelb.edu.au (J.B. Furness). 0301-0082/$ – see front matter © 2003 Elsevier Ltd. All rights reserved. doi:10.1016/j.pneurobio.2003.12.004