Voltage-gated ion channel Nav1.7 innervation in patients with idiopathic rectal hypersensitivity and paroxysmal extreme pain disorder (familial rectal pain)

Faecal urgency and incontinence with rectal hypersensitivity is a chronic, unexplained condition that is difficult to treat. The aim of this study was to determine if there was an altered level of the voltage gated tetrodotoxin-sensitive (TTX-s) sodium channel Nav1.7 in rectal sensory fibres, since this channel has been implicated in clinical nociceptive disorders. Full thickness rectal biopsies from patients with physiologically characterised rectal hypersensitivity (n = 7) were compared with control tissues (n = 10). Formalin fixed specimens were studied by immunohistochemistry using affinity purified antibodies to Nav1.7 and the pan-neuronal structural marker PGP9.5, and the immunoreactive nerve fibres quantified by computerised image analysis. In rectal hypersensitivity, Nav1.7 immunoreactive nerve fibres were significantly increased in mucosal (P = 0.0004), sub-mucosal (P = 0.019), and muscle layers (P = 0.0076), while PGP9.5 immunoreactive nerve fibres were increased significantly only in the mucosa (P = 0.04); ratios of Nav1.7:PGP9.5 showed a significant increase in all layers, suggesting increased expression of Nav1.7, and nerve sprouting in the mucosa. The cause of this increase remains uncertain, but may be due to increase of nerve growth factor (NGF), which regulates the expression of both Nav1.7 and TRPV1, which we have previously reported to be increased in this condition. In paroxysmal extreme pain disorder (familial rectal pain), where the gene that encodes Nav1.7 is mutated, Nav1.7 protein was undetectable in the rectum (n = 2), which suggests reduced Nav1.7 immunoreactivity or expression. Drugs that target Nav1.7-expressing nerve terminals may be useful for treating rectal hypersensitivity, and combining these with TRPV1 antagonists may enhance efficacy.