Altered prejunctional modulation of intestinal cholinergic and noradrenergic pathways by α₂‐adrenoceptors in the presence of experimental colitis

Abstract

1 This study investigates the influence of intestinal inflammation on: (1) the control of intestinal neurotransmission and motility by prejunctional a 2 -adrenoceptors and (2) the expression of intestinal a 2 -adrenoceptors. Experimental colitis was induced by intrarectal administration of 2,4-dinitrobenzenesulphonic acid (DNBS) to rats. 2 UK-14,304 inhibited atropine-sensitive electrically evoked contractions of ileal and colonic longitudinal muscle preparations. UK-14,304 acted with similar potency, but higher efficacy, on tissues from DNBS-treated animals; its effects were antagonized with greater potency by phentolamine than rauwolscine. 3 Electrically induced [3 H]noradrenaline release from ileal preparations was reduced in the presence of colitis. Tritium outflow was decreased by UK-14,304 and stimulated by rauwolscine or phentolamine: these effects were enhanced in preparations from animals with colitis. 4 Reverse transcription -polymerase chain reaction and Western blot assay demonstrated the protein expression of a 2A -adrenoceptors in mucosal and muscular tissues isolated from ileum and colon. The induction of colitis increased a 2A -adrenoceptor expression in both ileal and colonic muscular layers, without concomitant changes in mucosal tissues. 5 Induction of colitis reduced gastrointestinal propulsion of a charcoal suspension in vivo. In this setting, the gastrointestinal transit was inhibited by intraperitoneal (i.p.) UK-14,304 and stimulated by i.p. rauwolscine. After pretreatment with guanethidine, the stimulant action of rauwolscine no longer occurred, and UK-14,304 exerted a more prominent inhibitory effect that was antagonized by rauwolscine. 6 The present results indicate that, in the presence of intestinal inflammation, prejunctional a 2 -adrenoceptors contribute to an enhanced inhibitory control of cholinergic and noradrenergic transmission both at inflamed and noninflamed distant sites. Evidence was obtained that such modulatory actions depend on an increased expression of a 2A -adrenoceptors within the enteric nervous system.

Enteric Glia Are Targets of the Sympathetic Innervation of the Myenteric Plexus in the Guinea Pig Distal Colon

“…Therefore, the enteric nervous system may have evolved this mechanism to sustain neurons during sympathetic stimulation. In support of this hypothesis, myenteric neurons are rapidly lost when sympathetic neurotransmitter release is reduced during gut inflammation (Jacobson et al, 1997;Blandizzi et al, 2003;Linden et al, 2005;Motagally et al, 2009). …”

Altered adrenal chromaffin cell function during experimental colitis

“…Enteric, DRG, and postganglionic sympathetic neurons provide extensive innervation of the gastrointestinal tract and may therefore come into contact with both sources of inflammatory mediators. Local and systemic cytokines may contribute to the aberrant postganglionic sympathetic neuron function that occurs during colitis, since altered norepinephrine secretion has been observed in both inflamed and uninflamed regions of the gastrointestinal tract (10,31,32,50). In addition, overnight incubation of postganglionic sympathetic neurons in TNF-␣, an important proinflammatory cytokine in IBD pathogenesis, causes a similar inhibition of N-type I Ca as DSS-induced acute colitis (49).…”

“…An upregulation of ␣ 2 -adrenoceptors has also been described in rats during DNBS colitis and may increase presynaptic inhibition of norepinephrine secretion from sympathetic varicosities (10). Importantly, norepinephrine secretion from sympathetic neurons was found to be decreased in both inflamed and uninflamed regions of the gastrointestinal tract, suggesting that localized inflammation can modulate the function of distant sympathetic tissues (10,31,32,50). Although it is clear that sympathetic neurophysiology is altered during experimental colitis, it is currently unknown whether adrenal chromaffin cells (ACCs), which secrete catecholamines in the systemic circulation, are also modulated by gastrointestinal inflammation.…”

“…Hyperexcitability has been observed in tonically firing neurons of the guinea pig celiac ganglion during 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced ileitis (17). However, reduced norepinephrine secretion from sympathetic varicosities has been described in the acute dextran sulfate sodium (DSS), 2,4-dinitrobenzene sulfonic acid (DNBS), TNBS, and Trichinella spiralis models of gastrointestinal inflammation (10,31,32,50,59). During DSS-induced acute colitis in mice, inhibition of N-type voltage-gated Ca 2ϩ current (I Ca ) was observed in neurons of the superior mesenteric ganglion and may underlie the reduced norepinephrine secretion (50).…”

“…During DSS-induced acute colitis in mice, inhibition of N-type voltage-gated Ca 2ϩ current (I Ca ) was observed in neurons of the superior mesenteric ganglion and may underlie the reduced norepinephrine secretion (50). An upregulation of ␣ 2 -adrenoceptors has also been described in rats during DNBS colitis and may increase presynaptic inhibition of norepinephrine secretion from sympathetic varicosities (10). Importantly, norepinephrine secretion from sympathetic neurons was found to be decreased in both inflamed and uninflamed regions of the gastrointestinal tract, suggesting that localized inflammation can modulate the function of distant sympathetic tissues (10,31,32,50).…”