Mo2036 Remodeling of Colonic Sensory Afferents in a Rat Model of Post-Infectious Gut Dysfunction: Implication of Neurotrophic Factors

Abstract

Background: Inflammation-induced visceral hypersensitivity is associated, at least partially, to peripheral sensitization of sensory afferents by locally released neurotrophic factors. Aims: Here, we explore the potential role of neurotrophic factors in long-term changes in visceral afferents innervating non-primary areas of inflammation (colon) in a rat model of Trichinella spiralis (TS)-induced gut dysfunction. Methods: Inflammatory-like changes, mucosal mast cells (MMCs) dynamics, and expression of nerve growth factor (NGF) and glial cell linederived neurotrophic factors (GDNF, artemin and neurturin) were determined in the colon of control and TS-infected rats, up to day 30 post-infection (PI). Markers of sensory afferents (high affinity nerve growth factor receptor, TrkA; GDNF family receptor alpha 3, GFRα3; calcitonin gene-related peptide, CGRP; and transient receptor potential vanilloid channel1, TRPV1) were assessed in thoracolumbar (T12-L2, TL) and lumbosacral (L6-S2, LS) DRGs. Functionality of colonic afferents at 14 and 30 days PI was determined by assessing changes in TRPV1 levels in TL and LS DRGs following intracolonic capsaicin. Results: TS infection induced a primary jejunitis with concomitant inflammatory-like changes in the colon: an increase in histological scores, IL-13 up-regulation and MMC infiltration (Table 1). Inflammation was partly resolved at day 30 PI, except for a persistent MMC infiltrate (Table 1). Colonic expression of neurotrophic factors showed a transient reduction by day 14 PI (25%50%), with the exception of artemin that showed a biphasic response with an up-regulation (by 30%; P<0.05) at day 30 PI (Table 2). Overall, TS infection did not affect DRG expression of none of the genes assessed, except for a transient down-regulation of TPRV1 in TL DRGs at day 14 PI. Afferent stimulation with intracolonic capsaicin induced a down-regulation of TRPV1 expression in TL and LS DRGs, an effect significantly enhanced in LS DRGs of TSinfected rats, at either 14 or 30 days PI (Table 2). Intracolonic capsaicin also up-regulated peripheral artemin in non-infected rats, an effect absent in TS-infected animals at day 30 PI (Table 2). Capsaicin-induced changes in colonic expression of artemin correlated negatively with the down-regulation of TRPV1 in LS DRGs. Conclusions: During intestinal inflammation, changes in expression of neurotrophic factors and remodeling of visceral afferents are observed outside the primary region affected by the inflammatory insult. These observations suggest that extended remodelation of sensory afferents, probably related to local changes in neurotropins, might occur during inflammatory conditions of the gut. Similar mechanisms might be operating in states of widespread alterations of visceral sensitivity. Table 1 Colonic inflammation-related changes during T. spiralis infection