Purinergic component of mechanosensory transduction is increased in a rat model of colitis

Abstract

ATP contributes to mechanosensory transduction in the rat colorectum. P2X3 receptors are present on dorsal root ganglia (DRG) neurons that supply this area of the gut. Previous studies have shown an increased role for ATP in inflamed tissues. We aimed to investigate whether an increased purinergic component exists during mechanosensory transduction in a rat model of colitis. An in vitro rat colorectal preparation was used to investigate whether distension increased ATP release and to evaluate the role of purinergic antagonists in distension-evoked sensory discharges in the pelvic nerve in normal and colitis preparations. DRG neuron purinoceptors were also studied. Distension-evoked responses in the colitis model were attenuated to a significantly greater extent by 2',3'-O-trinitrophenyl-ATP and pyridoxyl 5-phosphate 6-azophenyl-2',4'-disulfonic acid. Inflammation caused augmented distension-evoked sensory nerve excitation after application of ATP and alpha,beta-methylene ATP. Single-fiber analysis confirmed that mean firing per unit was increased. Distension-evoked increases in ATP release from epithelial cells were substantially higher. The number of DRG neurons responding to ATP and the number of those staining for the P2X3 receptor, particularly those containing calcitonin gene-related peptide, were increased. Adenosine, after ectoenzymatic breakdown of ATP, is involved to a lesser degree in the longer-lasting distension-evoked sensory discharge, suggesting reduced ATPase activity. It was therefore concluded that ATP has an enhanced role in mechanosensory transduction in the inflamed rat colorectum. The underlying mechanisms appear to involve increased distension-evoked release of ATP as well as an increase in the number of DRG neurons supplying the colorectum expressing P2X3 receptors, especially those containing calcitonin gene-related peptide.

Inhibitory effect of estrogen receptor beta on P2X3 receptors during inflammation in rats

“…Evidence has shown that estradiol replacement has an antinociceptive effect in OVX rats [23,36,37]. Here, we found that during inflammation, estrogen replacement significantly reversed hyperalgesia in the ovariectomized CFA-treated rats.…”

“…Activation of P2X3R stimulates different cells, such as neurons or immunocytes, to cause abnormal excitability [23,25] or release inflammatory mediators, including TNFα, to induce inflammation [26]. Our results show that the expression of P2X3R in neurons was significantly increased in CFA-treated rat [44] and in TNBS-induced colitis in rats [23,25], indicating a vital role of P2X3R in inflammatory reactions. It has been reported that estrogen replacement decreased P2X3 upregulation in DRG after ovariectomy [30].…”

“…Evidence has shown that P2X3R was involved in the visceral hypersensitivity and intestinal inflammation [23,24], so we further investigated P2X3R expression in rectocolon, DRG, and SCDH before and after TNBS administration. On the 4th day after TNBS injection, the expression of P2X3R in both rectocolon and DRG were significantly increased compared with those of the saline group (n = 8 for each group, p < 0.05).…”

“…In colitis, more internal ATP was produced and expression of P2X3R at the end of colorectal nerves was also increased, thus leading to hypersensitivity of rectocolon [23][24][25]. When using the antagonists of P2X3R, 2′(3′)-O-(2,4,6-trinitrophenyl) ATP (TNP-ATP) or A317491, the expression and function of P2X3R in DRG were inhibited, resulting in the reduction of hypersensitivity in chronic inflammatory pain [26,27].…”

Purines 2008 Meeting 29 June – 2 July 2008, Copenhagen, Denmark

“…Purinergic mechanosensory transduction has also been implicated in reflex control of intestinal secretion, whereby ATP released from mucosal epithelial cells acts on P2Y 1 receptors on enterochromaffin cells to release 5-hydroxytryptamine, which leads to regulation of secretion either directly or via intrinsic reflex activity (Cooke et al, 2003). P2X 3 purinergic signalling enhancement in an animal model of colonic inflammation has been described, due, at least in part, to the appearance of P2X 3 receptor expression in a greater number of calcitonin gene-related peptide-labelled small nociceptive neurons in the DRG (Wynn et al, 2004). P2X 3 receptor expression is increased in the enteric plexuses in human irritable bowel disease suggesting a potential role in dysmotility and pain (Yangiou et al, 2001).…”