Background: Faecal urgency and incontinence with rectal hypersensitivity is a distressing, unexplained disorder that is inadequately treated. We aimed to determine whether expression of the heat and capsaicin receptor vanilloid receptor 1 (TRPV1 or VR1) was changed in rectal sensory fibres, and to correlate nerve fibre density with sensory abnormalities. Methods: We compared full-thickness rectal biopsy samples from nine patients with physiologically characterised rectal hypersensitivity with tissue samples from 12 controls. Sensory thresholds to rectal balloon distension and heating the rectal mucosa were measured before biopsy. We assessed specimens with immunohistochemistry and image analysis using specific antibodies to TRPV1; nerve growth factor (NGF) receptor tyrosine kinase A; glial cell line-derived neurotrophic factor (GDNF); neuropeptides calcitonin gene-related peptide (CGRP) and substance P; the related vanilloid receptor-like protein (VRL) 2; glial markers S-100 and glial fibrillary acid protein (GFAP); and the nerve structural marker peripherin. Findings: In rectal hypersensitivity, nerve fibres immunoreactive to TRPV1 were increased in muscle, submucosal, and mucosal layers: in the mucosal layer, the median% area positive was 0·44 (range 0·30-0·59) in patients who were hypersensitive and 0·11 (0·00-0·21) in controls (p=0·0005). The numbers of peripherin-positive fibres also increased in the mucosal layer (hypersensitive 3·00 [1·80-6·50], controls 1·20 [0·39-2·10]: (p=0·0002). The increase in TRVP1 correlated significantly with the decrease in rectal heat (p=0·03) and the distension (p=0·02) sensory thresholds. The thresholds for heat and distension were also significantly correlated (p=0·0028). Expression of nerve fibres positive for GDNF (p=0·001) and tyrosine kinase A (p=0·002) was also increased, as were cell bodies of the submucosal ganglia immunoreactive to CGRP (p=0·0009). Interpretation: Faecal urgency and rectal hypersensitivity could result from increased numbers of polymodal sensory nerve fibres expressing TRPV1. The triggering factor or factors remain uncertain, but drugs that target nerve terminals that express this receptor, such as topical resiniferatoxin, deserve consideration.
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