Effects of PGE₂ in guinea pig colonic myenteric ganglia

Abstract

is a proinflammatory mediator that can influence many cell types. This study was conducted to determine whether PGE2 alters the electrical activity of distal colonic myenteric neurons, because colitis is typically associated with altered motility and changes in neural signaling may be involved. The electrical properties of intact myenteric neurons were evaluated with intracellular microelectrodes. Acute application of PGE 2 elicited a prolonged depolarization in both AH and S neurons with little effect on input resistance or electrical excitability. PGE 2 effects were suppressed by tetrodotoxin (TTX) or neurokinin (NK) receptor antagonists, indicating that PGE 2 acts directly and indirectly to depolarize colonic neurons. PGE 2-evoked depolarization was concentration dependent (ϳ3 M EC 50) and was attenuated by the E prostanoid (EP)1/2 receptor antagonist, AH-6809. When preparations were maintained for 48 h in the presence of the stable PGE 2 analog PGE2-ethanolamide (10 M), neurons exhibited a significant membrane depolarization and enhanced excitability. These results suggest that PGE 2 can play a role in altered motility in colitis by evoking changes in the electrical properties of myenteric neurons. motility; inflammation; colitis; innervation; enteric nervous system THE NERVOUS SYSTEM OF THE bowel, which is known as the enteric nervous system (ENS) regulates visceromotor, secretomotor, and vasomotor activities in the wall of the intestines. Given that much of the morbidity associated with inflammatory bowel disease is caused by disordered gastrointestinal motor function and that colonic smooth muscle function is regulated by the ENS, it is quite possible that alterations in the excitability of the enteric neurons contribute to intestinal dysmotility. A variety of immune-mediated inflammatory disorders exist, including Crohn's disease and ulcerative colitis, and dysmotility, hypersecretion, and enhanced perception of pain are common features (17,22,23,46). It is now clear that cutaneous and visceral inflammations lead to enhanced excitability of extrinsic primary afferent neurons and altered reflex activity (5,8,14,48). Changes may also occur in the afferent components of intrinsic enteric neural circuitry, and such changes could contribute to altered motor reflex activity in the inflamed bowel.In guinea pig bowel, it is possible to identify the functional role of a given neuron on the basis of consensus knowledge regarding the electrical, morphological, chemical coding, and axonal projection patterns of these cells. For example, a class of cells known as AH neurons, on the basis of electrical properties, functions as the afferent limb of the peristaltic reflex circuit (19) and is considered to have roles as intrinsic primary afferent neurons and interneurons (for review, see Ref. 30). These cells have a Dogiel type II morphology (multiple processes) and extend projections to other ganglia and to the lamina propria (7,34,40,42), where they could respond to stimuli originating at the mucosal surface. Therefor...

Immunohistochemical analysis of substance P-containing neurons in rat small intestine

“…To distinguish intrinsic and extrinsic SP-positive fibres from each other by conventional immunohistochemistry, CGRP cannot be used as a specific marker for either of them. PGE 2 is released, for instance, in response to the distention of the gut wall (Roza and Reeh 2001) or to pathogen-derived substances such as cholera toxin (Peterson and Whipp 1995) and depolarizes enteric neurons, including type II neurons (Dekkers et al 1997;Manning et al 2002).…”

Differential Role of Cyclooxygenase 1 and 2 Isoforms in the Modulation of Colonic Neuromuscular Function in Experimental Inflammation

“…Moreover, experimental colitis induced by trinitrobenzenesulfonic acid in guinea pigs is characterized by increased COX-2 expression in the colonic wall, and the products of this enzyme seem to be responsible for an enhanced excitability of myenteric AH neurons. In this model, the inhibition of COX-2, but not COX-1, restored the normal electrical properties of AH neurons, whereas the application of prostaglandin E 2 to inflamed colonic preparations decreased the afterhyperpolarization of AH neurons and slowed their accommodation rate (Manning et al, 2002;Linden et al, 2004). However, there is still uncertainty on the role of COX isoforms in motor alterations associated with chronic intestinal inflammation and on the hypothesis that COX-derived mediators may regulate differently gut motility under physiological or pathological conditions (Costa, 2004).…”

Colitis-induced neuroplasticity disrupts motility in the inflamed and post-inflamed colon

“…In TNBS colitis, a major contributor to the hyperexcitability in AH neurons is an increase in a hyperpolarizationactivated cation conductance (8). In this model, the AH neuron hyperexcitability involves activation of COX-2 because chronic exposure to prostaglandin E2 results in AH neuron hyperexcitability in normal preparations (15) and because inhibition of COX-2, but not COX-1, prevents AH neuron hyperexcitability in animals with TNBS colitis (16).…”