Deficiency of purinergic P2Y receptors in aganglionic intestine in Hirschsprung’s disease

Abstract

Hirschsprung's disease is characterized by the absence of ganglion cells in the distal bowel and extends proximally for varying distances. In recent years, the purinergic P2Y receptors have begun to receive much attention as they have been recognised as major ATP receptors in many regions of the body, including the intestine. ATP has long been established as an inhibitory neurotransmitter in the enteric nervous system. The aim of our study was to analyse the expression of P2Y1 and P2Y2 receptors in the intestine of patients with Hirschsprung's disease. Frozen sections were cut from rectal tissue segments taken from both the aganglionic and ganglionic regions of patients with Hirschsprung's disease, as well as tissue from normal rectal biopsies, which were used as controls. Sections were incubated overnight with P2Y1 and P2Y2 receptor antibodies and results were analysed by light microscopy. Both P2Y1 and P2Y2 immunoreactivity was absent from the submucosal and myenteric plexuses of aganglionic tissue compared to ganglionic tissue and normal controls, in which large number of immunoreactive neurons were evident, arranged in ganglia in both plexuses and positive nerve fibres, in both the smooth and circular muscles. Our results show a lack of expression of P2Y1 and P2Y2 receptors in the aganglionic gut in Hirschsprung's disease. The absence of these receptors suggests the absence of the inhibitory neurotransmitter ATP, which may help to explain the contracted state of the aganglionic gut in Hirschsprung's disease.

Peripheral Nervous System

“…This finding is consistent with experimental studies that reported that no IJPs could be evoked in smooth muscle by intramural nerve stimulation of the rectosigmoidal part of the large intestine of Hirschsprung's patients, and ATP caused contraction of the muscle (Zagorodnyuk et al 1989). A lack of expression of P2Y 1 and P2Y 2 receptors in the aganglionic intestine in Hirschsprung's disease has been described (O'Donnell and Puri 2008), which suggests that purinergic inhibitory neurotransmission is absent and may explain the contracted state of the aganglionic gut in Hirschsprung's disease.…”

The NANC relaxation of the human ileal longitudinal and circular muscles is inhibited by MRS 2179, a P2 purinoceptor antagonist

“…Lack of P2Y 1 receptors in the intestinal ganglionated plexuses may contribute to the elevated tone of smooth muscle in Hirschprung's disease (O'Donnell and Puri 2008).…”

Purinergic signalling in the gastrointestinal tract and related organs in health and disease

“…In the aganglionic intestine, there was only weak P2X3 receptor immunostaining in the myenteric and submucous plexuses compared to normal intestine [210]. The absence of expression of P2Y 1 and P2Y 2 receptors in the aganglionic intestine in Hirschsprung's disease has been described [518], which suggests that purinergic inhibitory neurotransmission is absent and may account for the contracted state of the aganglionic gut in Hirschsprung's disease.…”