Jejunal afferent nerve sensitivity in wild‐type and TRPV1 knockout mice

Abstract

The aim of this study was to investigate the contribution of the TRPV1 receptor to jejunal afferent sensitivity in the murine intestine. Multiunit activity was recorded in vitro from mesenteric afferents supplying segments of mouse jejunum taken from wild-type (WT) and TRPV1 knockout (TRPV1 −/− ) animals. In WT preparations, ramp distension of the gut (up to 60 mmHg) produced biphasic changes in afferent activity so the pressure-response curve had an initial rapid increase in afferent discharge followed by a second phase of slower increase in activity. Afferent response to distension was significantly lower in TRPV1 −/− than in WT mice. Single-unit analysis revealed three functional types of afferent fibres: (1) low-threshold fibres (2) wide dynamic range fibres and (3) high-threshold fibres. There was a marked downward shift of the pressure-response curve for wide dynamic range fibres in the TRPV1 −/− mice as compared to the WT controls. The afferent response to intraluminal hydrochloric acid (20 mM) was also attenuated in the TRPV1 −/− mice. In contrast, the response to bath application of bradykinin (1 µM, 3 ml) was not significantly different between the two groups. The TRPV1 antagonist capsazepine (10 µM) significantly attenuated the nerve responses to distension, intraluminal acid and bradykinin, as well as the spontaneous discharge in WT mice. The WT jejunal afferents responded to capsaicin with rapid increases in afferent activity, whereas TRPV1 −/− afferents were not at all sensitive to capsaicin. Previous evidence indicates that TRPV1 is not mechanosensitive, so the results of the present study suggest that activation of TRPV1 may sensitize small intestinal afferent neurones.

The Mechanosensitivity of Mouse Colon Afferent Fibers and Their Sensitization by Inflammatory Mediators Require Transient Receptor Potential Vanilloid 1 and Acid-Sensing Ion Channel 3

“…TRPV1, known for its thermosensing abilities (Caterina et al, 1997), has previously been implicated in visceral mechanosensation. Deletion of TRPV1 impairs afferent fiber detection of mechanical stimuli in the jejunum (Rong et al, 2004) and bladder (Birder et al, 2002). The diminished stretch-evoked responses of colon afferent fibers in TRPV1 knock-out mice lend additional support to the hypothesis that TRPV1 is an important mediator or modulator of mechanosensitivity in the viscera.…”

“…Application of capsazepine, a TRPV1 antagonist, to pelvic nerve afferent fiber receptive fields in control mice also attenuated stretch-evoked responses. This finding should be interpreted with caution, however, because the concentration necessary for an effect in our preparation was higher than used by other groups in different in vitro preparations (Rong et al, 2004).…”

“…Protein expression levels of both TRPV1 and ASIC3 are increased in biopsy specimens from patients with inflammatory bowel disease, a condition in which visceral pain is a prominent symptom (Yiangou et al, 2001a,b). In animals, TRPV1 is present in neurons throughout the viscera (Birder et al, 2001;Ward et al, 2003), in which it has been shown to participate in mechanosensation in the small intestine (Rong et al, 2004) and bladder (Birder et al, 2002). ASIC3 is also expressed in sensory neurons (Alvarez de la Rosa et al, 2002) and has been implicated in mechanosensation in the skin (Price et al, 2001).…”

TRP channels in neurogastroenterology: opportunities for therapeutic intervention

“…(Reviews by Di Marzo et al, 2002;Geppetti and Trevisani, 2004;Holzer, 2008b;Blackshaw et al, 2010). Animal experiments have demonstrated an important role for TRPV1 both in gastro-esophageal (Bielefeldt and Davis, 2008), small intestinal (Rong et al, 2004) and colonic visceral mechanosensitivity as well as in hypersensitivity induced by intracolonic administration of zymosan or neonatal irritation of the colon (Winston et al, 2007). In addition, TRPV1 was shown to be up-regulated in nociceptive visceral afferents of rodents with experimental trinitrobenzene sulfonic acid (TNBS)-induced colitis (Miranda et al, 2007;De Schepper et al, 2008a).…”

Transient receptor potential vanilloid channels functioning in transduction of osmotic stimuli

“…Intravesical instillation of TRPV1 activators is used to treat hyperactive bladder in spinal cord disease (Dinis et al 2004, Lazzeri et al 2004, Stein et al 2004, Apostolidis et al 2005. Another instance of an altered response to mechanical stimuli in trpv1 K/K mice relates to the response of the jejunum to stretch (Rong et al 2004). Afferent jejunal nerve fibers were found to respond with decreased frequency of discharge in trpv1 K/K mice when compared with wild type.…”