Functional Neuroplasticity in Acute Diverticulitis: Differential Regulation of Colonic Excitatory Nerve Pathways By Cyclooxygenase Isoforms

Introduction. Prostanoids generated by cyclooxygenase isoforms (COX-1, COX-2) contribute to regulate intestinal motor functions. However, the role played by these pathways in human intestinal motility during inflammation is unknown. Objectives. This study examines the effects of COX inhibitors on excitatory neuromuscular activity of colonic tissues dissected from patients with acute diverticulitis (AD). Methods. Longitudinal muscle preparations were obtained from distal colon of patients undergoing surgery for AD (7 M, 6 F; age range: 38-69) or uncomplicated cancer (sex-age matched controls). Colonic strips were set up in organ baths and connected to isotonic transducers to determine the effects of indomethacin (IND, COX-1/COX-2 inhibitor, 1 µM), SC-560 (COX-1 inhibitor, 0.1 µM) or DFU (COX-2 inhibitor, 1 µM) on contractions evoked by electrical field stimulation (EFS: 0.5 ms, 30 mA, 10 Hz, 100 pulses) in the presence of guanethidine (10 µM) and Nω-nitro-L-arginine methylester (100 µM). Atropine (1 µM) or L-732,138 (NK1 receptor antagonist, 10 µM) were used to facilitate the recording of contractions driven by tachykinins or acetylcholine, respectively. Colonic preparations were also stimulated by substace P (SP, 1 µM) in the presence of tetrodotoxin (1 µM). Results. In the presence of L-732,138, EFS of normal preparations evoked atropine-sensitive contractions. IND enhanced EFS-induced cholinergic responses (+103.9%). SC-560 or DFU mimicked the effect of IND, but were less effective (+67.1% and +53.9%, respectively). In the presence of atropine, EFS elicited L-732,138-sensitive contractions. In this setting, IND, DFU and SC-560 blunted EFS-induced tachykininergic responses (-56.4%, -44.9% and -23.2%, respectively). In colonic tissues from AD patients, none of tested COX inhibitors affected the cholinergic contractions evoked by EFS. When AD preparations were maintained in the presence of atropine, both IND and DFU decreased tachykininergic contractions elicited by EFS (-67.3% and -71.1%, respectively), while SC-560 was without effects. In the presence of tetrodotoxin, the application of SP to normal colonic preparations evoked contractile responses which were reduced by IND, SC-560 and DFU (-58.3%, -35.5% and -30.5%, respectively). In the presence of AD, the effect of SC-560 no longer occurred, whereas IND and DFU blunted SP-induced contractions (-71.3% and -66.1%, respectively). Conclusions. In normal colon, both COX-1 and COX-2 down-regulate the contractile responses driven by cholinergic nerves, while they enhance tachykininergic pathways. In the presence of AD, these regulatory patterns are subjected to remodelling: there is a loss of modulation by both COX isoforms on cholinergic system, while COX-2 ensures a facilitatory control on tachykininergic motor activity. These functional changes may contribute to an enhanced colonic contractility and thereby painful stimuli in patients with AD.