The pathogenesis of heartburn and acid regurgitation remain to be fully elucidated, particularly in the numerous NERD patients in whom the 24-h pH-test findings may be within the normal range[39
]. Indeed, an enhanced sensitivity to reflux would appear to be strongly associated with the failure of PPI treatment[40
Although gastric acid plays a pivotal role in the pathogenesis of GERD, other stimuli have been suggested to be involved in the pathogenesis of typical symptoms. In patients with GERD, reflux may result in direct activation of pain receptors, which may be enhanced by greater acid diffusion through the esophageal epithelium caused by impaired mucosal barrier function[19
]. Furthermore, activation of pain receptors may occur following reflux-induced distention of the esophagus. Enhanced esophageal sensitivity to these stimuli may be caused by upregulation of peripheral pain receptors and central sensitization of spinal neurons[19
Little is known about acid-sensitive nerves. Receptors on acid-sensitive nerve endings may play a role in nociception and esophageal sensitivity, as suggested in animal models following chronic acid exposure, and include the anion-sensing ion channel (ASIC), TRPV1 and ionotrophic purinergic (P2X and P2Y) receptors[4
The recently demonstrated presence of acid-sensitive TRPV1 receptors in sensory nerve fibers and in epithelial cells of the esophageal mucosa[41
] provides an interesting mechanism to better understand the onset of neuromodulation and symptoms generation in GERD. TRPV1 activation in primary afferent neurons evokes the sensation of burning pain and may induce neurogenic inflammation following the release of substance P and CGRP[36
On the other hand, growing evidence from animal models during chronic acid exposure supports the involvement of purinergic receptors in nociception and hypersensitivity[38,39
]. The purinergic receptors are involved in several cell functions and may be activated by purine nucleotides as ligands[42
Based on their pharmacological properties and molecular characteristics, two distinct classes of purinergic receptors with preferential responses to adenosine 5’-triphosphate (ATP), as well as other single nucleotides, have been identified: the family of ligand-gated cation channel P2X receptors and the G protein-coupled P2Y receptors.
P2X and P2Y receptors play an important role in signaling visceral pain[19,39,42
]. A working hypothesis of purine-mediated mechano-sensory transduction has been suggested[19,39
]: ATP released from the epithelial cell lining of the gastrointestinal (GI) tract, bladder and ureter might activate P2X receptors present on the sub-epithelial nerve plexus and the signal is transmitted via
the spinal cord to the brain.
To date, a limited number of studies have been performed on changes in purinergic signaling in GI disorders. Extracellular nucleotides and their receptors have been implicated in the pathogenesis of various pathological conditions in the gut; indeed, adenosine increases vagal afferent sensitization in the esophagus and is able to activate a different type of nociceptive nerve terminal in this tissue[43
]. Acid sensitizes P2X receptors to ATP, and acid-induced upregulation and activation of P2X receptors has been confirmed in animal models of esophagitis[44,45
However, the role of purinergic receptors in patients with GERD remains to be fully determined. In a recent investigation, we studied a signaling pathway that might be responsible for esophageal nociception, which involves ATP and purinoceptors. In an experimental model of acid-induced activation of the esophageal mucosal nociceptors, we observed that acid exposure caused activation of TRPV1 receptors on the esophageal epithelial cells, triggering production of ATP, which acts on peripheral nerve terminals inducing the production of neurotransmitters[46
]. Thus, the selective presence of purinergic receptors on esophageal epithelial cells was demonstrated, suggesting a direct effect of the acid on the epithelium and a possible autocrine effect of ATP on these cells[19
]. In fact, P2X4, P2X5 and P2Y14 receptors are expressed in esophageal epithelial cells, and indeed are expressed at higher levels than all the other purinergic receptors[46
]. P2Y receptors appear to be more involved in esophageal motility. Lecea et al[47
] recently reported that purinoceptors are involved in human lower esophageal sphincter (LES) relaxation, mediated by neural nitric oxide and partially by P2Y receptors. Blockade of P2Y receptors reduced the amplitude of contractions without affecting the latency. Farrè et al[48
] had previously demonstrated, in animals, that LES relaxation, induced by stimulation of the inhibitory motor neurons of the mesenteric plexus, was mediated by neural nitric oxide with a minor contribution of purines, acting by way of P2Y and P2X receptors.