Experimental colitis alters expression of 5-HT receptors and transient receptor potential vanilloid 1 leading to visceral hypersensitivity in mice

Abstract

Abnormalities of primary afferent nerve fibers are strongly associated with the visceral hypersensitivity state in inflammatory bowel disease. Hypersensitivity of afferent fibers occurs during inflammation. Therefore, to gain an insight into the alterations to receptors and channels expressed in primary afferent neurons, the current study aimed to investigate the time-dependent dynamic changes in levels of 5-hydroxytryptamine (5-HT)(3) receptors, 5-HT(4) receptors, transient receptor potential vanilloid type 1 (TRPV1) channels, and 5-HT regulatory factors in dextran sulfate sodium (DSS)-induced colitis model mice. 5-HT signaling molecules were detected by indirect staining with specific antibodies. TRPV1-immunoreactivity was detected by staining with fluorescein-conjugated tyramide amplification. To assess nociception, visceromotor responses (VMRs) to colorectal distension were measured by electromyography of abdominal muscles. Immunohistochemical analysis and VMRs to colorectal distention were measured during induction of DSS colitis (days 4 and 7). Inflammation led to downregulation of serotonin transporter immunoreactivities with concomitant increases in 5-HT and tryptophan hydroxylase-1-positive cell numbers. TRPV1-expressing nerve fibers gradually increased during DSS treatment. Abundant nonneuronal TRPV1-immunopositive cell-like structures were observed on day 7 of DSS treatment but not on day 4. The number of 5-HT(3) receptor-expressing nerve fibers in the mucosa was increased on day 7. On the other hand, the number of 5-HT(4) receptor-expressing nerve fibers in the mucosa decreased on day 7. We made the novel observation of increased expression of neuronal/nonneuronal TRPV1 channels and 5-HT(3) receptors, and decreased expression of 5-HT(4) receptors in the mucosa in a DSS-induced colitis model. Visceral hyperalgesia was observed on day 7 but not on day 4. A TRPV1 antagonist and a 5-HT(3) receptor antagonist attenuated the visceral hyperalgesia to the control level. The alterations of 5-HT signaling via 5-HT(3) receptors and of TRPV1 channels in mucosa may contribute to the visceral hypersensitivity in colitis model mice.

Serotonin signalling in the gut—functions, dysfunctions and therapeutic targets

“…Furthermore, the sensitivity of spinal afferents to 5-HT is enhanced during inflammation, both in terms of the proportion of afferent fibers responding to 5-HT and the intensity of the response 126 . This is consistent with the recent finding that the number of nerve fibers expressing 5-HT 3 receptors is increased in the mucosal layer of the DSS-inflamed colon 127 . Interestingly, the hypersensitivity to 5-HT persists following recovery from inflammation 126 , suggesting that the analgesic effect of 5-HT 3 agonists in IBS could involve attenuation of 5-HT’s ability to stimulate of spinal afferent terminals in the gut.…”

Upregulation of the Transient Receptor Potential Ankyrin 1 Ion Channel in the Inflamed Human and Mouse Colon and Its Protective Roles

“…Opposite direction of TRPV1 gene expression alterations compared to TRPA1 may reflect disparate functions in the various cell types they are expressed in the inflamed colon. Extrinsic sensory TRPV1 receptors mediated pro- and antiinflammatory functions and were upregulated in IBD [11]–[18], [55], [85]–[87]. Its protein is translocated intraaxonally to the periphery [88], albeit there is a report on TRPV1 mRNA in peripheral axons [89].…”

TRPV1 sensitization mediates postinflammatory visceral pain following acute colitis

“…Notably, upregulation of TRPV1 expression has been observed in both rodent models of colitis and colonic biopsies from patients with IBD (15,16,35,55). Increased TRPV1 expression has also been shown to correlate with the severity of abdominal pain in patients with IBD in clinical remission, thus identifying TRPV1 as an important predictor of visceral hypersensitivity (2).…”